Transition-metal-mediated synthesis of novel carbocyclic nucleoside analogues with antitumoral activity

Article abstract of DOI:10.1002/chem.200400079

A diversity-oriented, enantioselective synthesis of new (monoprotected) carbocyclic nucleoside analogues (CNAs) with the nucleobase attached to a 3-hydroxymethyl-4-trialkylsilyloxymethylcyclopent-2-en-l -yl scaffold was developed. As a key intermediate, racemic (5SR,8RS)-8-allyloxy-2-trimethylsilyl- 7-oxa-bicyclo[3.3.0]-oct-1-en-3-one was prepared from 1,1-diallyloxy-3- trimethylsilyl-2-propyne in a cobalt-mediated Pauson-Khand reaction. The enantiomerically pure material was obtained through efficient kinetic resolution (selectivity factor s ≥ 40 at -78°C) by means of an oxazaborolidine- catalyzed borane reduction (CBS reduction) with catecholborane. The absolute configuration of the resolved products was determined by CD spectroscopy, Mosher ester analysis, and chemical correlation. Subsequent steps involve diastereoselective ketone reduction and fully regio- and diastereoselective introduction of the nucleobase through Pd°-catalyzed allylic substitution. The generality of the method was demonstrated by preparation of CNAs in both enantiomeric series with all five natural nucleobases, as well as 5-bromouracil, 5-fluorouracil, and 6-chloropurine. Screening of the various compounds in a cytotoxicity assay with BJAB and ALL tumor cell lines revealed that some of the compounds possess pronounced antitumoral properties (LD₅₀ values down to 9 μM, as determined by lactate dehydrogenase release after 48 h). By measuring DNA fragmentation, it could be shown that the activity results from induction of apoptosis.

Full text of DOI:10.1002/chem.200400079

FULL PAPER
Transition-Metal-Mediated Synthesis of Novel Carbocyclic Nucleoside
Analogues with Antitumoral Activity
Juraj Velcicky,[a] Andreas Lanver,[a] Johann Lex,[a] Aram Prokop,[b] Thomas Wieder,[c] and
Hans-Günther Schmalz*[a]
Abstract: A diversity-oriented, enan-
tioselective synthesis of new (monopro-
tected) carbocyclic nucleoside ana-
logues (CNAs) with the nucleobase at-
tached to a 3-hydroxymethyl-4-trialkyl-
silyloxymethylcyclopent-2-en-1-yl scaf-
fold was developed. As a key interme-
diate, racemic (5SR,8RS)-8-allyloxy-2-
trimethylsilyl-7-oxa-bicyclo[3.3.0]-oct-1-
en-3-one was prepared from 1,1-dial-
dine-catalyzed borane reduction (CBS
reduction) with catecholborane. The
absolute configuration of the resolved
products was determined by CD spec-
troscopy, Mosher ester analysis, and
chemical correlation. Subsequent steps
involve diastereoselective ketone re-
duction and fully regio- and diastereo-
selective introduction of the nucleo-
base through Pd0-catalyzed allylic sub-
stitution. The generality of the method
was demonstrated by preparation of
CNAs in both enantiomeric series with
all five natural nucleobases, as well as
5-bromouracil, 5-fluorouracil, and 6-
chloropurine. Screening of the various
compounds in a cytotoxicity assay with
BJAB and ALL tumor cell lines re-
vealed that some of the compounds
possess pronounced antitumoral prop-
erties (LD50 values down to 9 mm, as
determined by lactate dehydrogenase
release after 48 h). By measuring DNA
fragmentation, it could be shown that
the activity results from induction of
apoptosis.
lyloxy-3-trimethylsilyl-2-propyne in
a
cobalt-mediated Pauson–Khand reac-
tion. The enantiomerically pure materi-
al was obtained through efficient kinet-
ic resolution (selectivity factor sꢀ40 at
ꢁ788C) by means of an oxazaboroli-
Keywords: antitumor
agents
·
kinetic resolution · nucleosides ·
palladium catalysis · Pauson–Khand
reaction
Introduction
While certain nucleoside analogues are incorporated into
nucleic acids as chain terminators, thereby interrupting the
replication of cancer cells or a virus,[3] others are designed to
block certain enzymes necessary for cancer or viral repro-
duction (for example, (S)-adenosyl-l-homocysteine hydro-
lase[4] or reverse transcriptase).[3,5]
The popularity of nucleoside analogues increased after
the Food and Drug Administration (FDA) approval of AZT
(Zidovudin, 1, Scheme 1) against HIV and of acyclovir (Zo-
virax, 2) against the Herpes Simplex virus. In the past two
decades, carbocyclic nucleoside analogues (CNAs) have also
attracted much attention since the natural products aristero-
mycin (3)[6] and neplanocin A (4)[7] were shown to exhibit
interesting biological activities. In the meantime, a large
number of CNAs have been synthesized and tested.[8] Prom-
inent synthetic CNAs are the anti-HIV compounds carbovir
(5)[9] and abacavir (Ziagen) (6).[10]
One advantage of the carbocyclic compounds (CNAs) in
comparison to the furanose-derived nucleoside analogues is
a generally increased resistance against enzymatic degrada-
tion, as well as a decreased toxicity.[8a,11] Even though some
CNAs are already in clinical use, this class of compounds
still possesses a huge and largely unexploited potential for
the development of new pharmaceuticals. The elaboration
Nucleosides and nucleotides are of fundamental importance
for all living systems, for example, as structural modules of
nucleic acids, cofactors, and messenger substances.[1] There-
fore, it is not surprising that nucleoside analogues play an
important role in pharmacology, mainly as antiviral and an-
titumoral drugs.[2]
[a] Dr. J. Velcicky, Dipl.-Chem. A. Lanver, Dr. J. Lex,
Prof. Dr. H.-G. Schmalz
Institut für Organische Chemie
Universität zu Köln, Greinstrasse 4, 50939 Köln (Germany)
Fax : (+49)221-470-3064
E-mail: schmalz@uni-koeln.de
[b] Dr. A. Prokop
Department of Pediatric Oncology/Hematology
University Medical Center CharitØ, Campus Virchow
Humboldt University of Berlin, 13353 Berlin (Germany)
[c] Priv. Doz. Dr. T. Wieder
Department of Physiology I
Eberhard-Karls University Tübingen, 72076 Tübingen (Germany)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. It shows the
structures of 11b, rac-10h, and the acetate derived from rac-18 in
their crystalline states (in color).
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DOI: 10.1002/chem.200400079
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FULL PAPER
Results and Discussion
Our retrosynthetic analysis (Scheme 3) was based on the
consideration that the target structures 9 could be derived
Scheme 3. Retrosynthetic analysis for CNAs of type 9. NB=nucleobase.
from a precursor of type 10, in which the two oxy-function-
alized side chains are jointly protected within an acetal func-
tion. This would also allow for their later differentiation (se-
lective preparation of monoprotected products) because
cleavage of the acetal would lead to a hydroxyaldehyde. We
predicted a bicyclic enone of type 11 to be a suitable precur-
sor of 10; 11 would be formally derived from the symmetric
(achiral) dienyne 12 through an intramolecular Pauson–
Khand reaction (PKR).[15]
While the intramolecular mode of the PKR would guar-
antee the desired regioselectivity, the (relative) configura-
tion at the acetal stereocenter would not be important be-
cause this stereocenter would disappear at a later stage of
the synthesis. A crucial issue, however, was the control of
the absolute configuration of the lasting stereocenter(s). In
order to obtain the target compounds in nonracemic form,
we could either try to perform the (chirogenic) PKR in an
enantioselective fashion[16] or we had to resolve a racemic
intermediate at the stage of rac-11 or beyond.
Scheme 1. Some important synthetic and natural nucleoside analogues.
of efficient methods for the diversity-oriented synthesis of
new types of carbocyclic nucleoside analogues thus repre-
sents an important and challenging research task.
As already indicated in our preliminary communication,[12]
we recently became interested in 2’,3’-unsaturated CNAs,
such as 7 and 8 (Scheme 2), because these compounds might
Scheme 2. Examples of projected target structures.
Synthesis of dienynes as PKR precursors: The synthesis of
the CNAs of type 9 began with the preparation of a suitable
substrate for the planned PKR, that is, a dienyne of type 12
(Scheme 4). By following a known protocol,[17] acrolein (13)
was converted in high yield into a dibrominated diethyl
acetal, from which the protected propargyl aldehyde 14 was
obtained by double elimination with KOH as a base in the
presence of [Oct4N+Brꢁ] (1 mol%) as a phase-transfer cata-
lyst.[18] The conversion of 14 into the desired diallyl acetal
12a was achieved in 40% yield by acid-catalyzed transace-
talization[19] with azeotropic removal of EtOH.
Since the overall yield of the sequence for the synthesis of
12a described above was unsatisfactory, an alternative
method was developed (Scheme 4, right). This new route
began with the conversion of propargyl alcohol (15) into the
TMS-protected derivative 16 by double silylation followed
by selective O-desilylation.[20] After PCC oxidation of 16,[21]
the resulting (sensitive) aldehyde was directly converted
into the stable diallyl acetal 12b[22] by acid-catalyzed acetali-
exhibit interesting biological activities. In addition, such
structures would represent promising building blocks for the
preparation of artificial oligonucleotides[13] and other com-
plex molecules, for instance, hybrids with different pharma-
cophoric units, which would also be of pharmaceutical inter-
est.
In this article we describe an efficient synthesis of enan-
tiomerically pure CNAs of type 9 (see Scheme 3) by follow-
ing a novel strategy that is centrally based on transition-
metal–organic chemistry. Besides exploiting metal-mediated
reactions, the synthesis is characterized by the fact that it is
highly stereoselective and generally suited for the prepara-
tion of a broad variety of structurally diverse compounds (a
scaffold approach).[14] Furthermore, we report the initial re-
sults of the biological testing, which demonstrate that some
of the novel CNAs possess significant potential as antitu-
moral agents by inducing apoptosis of cancer cells.
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Carbocyclic Nucleoside Analogues
5087 – 5110
Scheme 5. Preparation of bicyclic intermediates of type 11 by the
Pauson–Khand
reaction.
Optimized
conditions:
a) [Co2(CO)8]
(1.1 equiv), CH2Cl2, molecular sieves (4 Š, 8 equiv by weight), RT, 2 h;
then TMANO (8.8 equiv), air, 08C!RT, 15 h. For yields, see Table 1.
Scheme 4. Synthesis of the precursors of the Pauson–Khand reaction, 12a
and 12b. a) Br2, 0–58C; then HC(OEt)3, EtOH, RT, 99%; b) KOH
(excess), [Oct4N+Brꢁ] (cat.), CyHex, reflux, 67%; c) allyl-OH (excess),
TsOH (cat.), C6H6 (azeotropic removal of EtOH), 40%; d) nBuLi
(2.3equiv), THF/ n-hexane, ꢁ788C!RT, 4 h; then TMSCl (2.3equiv),
ꢁ788C!RT, 18 h; then aq. HCl (1.3equiv), RT, 1 h, 98%; e) PCC
(1.5 equiv), CH2Cl2, RT, 3h; f) allyl-OH (excess), TsOH (cat.), C 6H6, D,
15 h, 88% over 2 steps; g) TBAF (1 equiv) in THF, H2O/allyl-OH (2:1),
RT, 1 h, 88%. CyHex=cyclohexane, Oct=octyl, PCC=pyridinium chloro-
chromate, TBAF=tetrabutylammonium fluoride, THF=tetrahydrofuran,
TMS=trimethylsilyl, Ts=toluene-4-sulfonyl.
>98:2) than those with 12a, the further optimization was
carried out employing 12b and TMANO. While variation of
the solvent had some effect (Table 1, entries 5 and 6), a
greatly improved yield (72%) was obtained in dichlorome-
thane when the reaction mixture was exposed to the air
once the promoter had been added (entry 8).[25a] A further
improvement was finally achieved by adding molecular
sieves (4 Š).[26] In this way, the conversion of 12b into the
bicyclic product rac-11b could be performed in up to 76%
yield, even on a 60 mmol scale. Under the same conditions,
the desilylated substrate 12a afforded the corresponding
PKR product in only 45% yield and with significantly lower
diastereoselectivity (Table 1, entry 10). From a variety of
other conditions screened for the cobalt-mediated PKR of
substrates 12a/b, only the Sugihara method,[27] which uses
nBuSMe as a promoter, afforded the desired product (rac-
11b from 12b) in a reasonable yield (Table 1, entry 11).
All our attempts to convert enynes 12a and 12b in cata-
lytic Pauson–Khand-type reactions[24] failed, although con-
trol experiments with 1-allyloxy-3-phenyl-2-propyne as a lit-
erature-known model substrate proceeded successfully. For
instance, by using [RhCl(cod)]2 (5 mol%; cod=cycloocta-
1,5-diene) and BINAP (10 mol%; BINAP=2,2’-bis(diphe-
nylphosphanyl)-1,1’-binaphthyl) as a catalyst and cinnamal-
dehyde (2 equiv) as a CO source[16f,g] (no solvent, 1208C,
16 h), the product was obtained in 90% yield and 81% ee in
the model series, while none of the desired product could be
zation. This second route provides a highly efficient and op-
erationally attractive synthesis of the C-silylated acetal 12b
(86% over three steps), from which the desilylated dieneyne
12a is obtained in high yield (88%) by treatment with
TBAF in allylic alcohol/H2O (2:1).[23]
The Pauson–Khand reaction: The PKR is one of the oldest
and synthetically most valuable transition-metal-mediated
reactions, as it allows the construction of substituted cyclo-
pentenones from an alkyne, an alkene, and carbon monox-
ide in a formal [2+2+1] cycloaddition.[15] While the “classi-
cal” PKR involves the thermal reaction of a preformed
alkyne–[Co2(CO)6] complex with an olefin (thus requiring
stoichiometric amounts of the metal), some catalytic meth-
ods for Pauson–Khand-type reactions employing different
metals (such as Ti, Rh, Ir, and Ru) have recently been de-
veloped.[24]
Initial attempts to prepare
the bicyclic intermediates rac-
11a/b from the dienynes 12a/b,
respectively, (Scheme 5) under
Table 1. Optimization of the Pauson–Khand reaction according to Scheme 5.[a]
Entry
R
Solvent
Promoter
T [8C]
Conditions[b]
Yield [%]
dr
1
2
H
H
CH
TMS
TMS
TMS
TMS
TMS
TMS
H
CH2Cl2
CH2Cl2
2Cl2
CH2Cl2
pentane
THF
NMO
TMANO
NMO
20
A
A
A
A
A
A
B
B
C
C
D
18
28
28
31
0
50
27
72
76
45
57
80:20
90:10
93:7
0!20
standard
literature
condi-
3TMS
4
5
6
7
8
9
10
11
20
tions[25] afforded the expected
products in low yields (Table 1,
entries 1–4). We therefore had
to optimize the conditions for
this particular PKR.
TMANO
TMANO
TMANO
TMANO
TMANO
TMANO
TMANO
nBuSMe
0!20
0!20
0!20
0!20
0!20
0!20
0!20
reflux
>98:2
–
>98:2
>98:2
>98:2
>98:2
72:28
>98:2
THF
CH2Cl2
CH2Cl2
CH2Cl2
1,2-DCE
As the first experiments had
shown that TMANO gave
better results than NMO and
that the silylated compound
12b gave rise to somewhat
better yields and higher dia-
stereoselectivities (d.r. up to
TMS
[a] 1,2-DCE=1,2-dichloroethane, NMO=N-methylmorpholine N-oxide, TMANO=trimethylamine N-oxide.
[b] A: [Co2(CO)8] (1.1 equiv), 2 h, RT, then addition of promoter (6 equiv), 15 h at specified temperature; B:
same as A, except that the flask was left open to the air after addition of the promoter; C: same as B except
that molecular sieves (4 Š, 8 equiv by weight) were added to the reaction mixture in the beginning and
8 equivalents of promoter were used; D: same as A except that 3.5 equivalents of promoter were used.
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H.-G. Schmalz et al.
FULL PAPER
detected when 12a or 12b were used. Also, cationic rhodi-
um species generated in situ from [RhCl(cod)]2 and AgOTf
(Tf=triflate=trifluoromethanesulfonyl) in the presence of
various ligands (including propane-1,3-diylbis(diphenylphos-
phane) (dppp) and BINAP)[16d] were not able to catalyze
this particular reaction. Therefore, compounds of type 12
represent particularly difficult substrates, especially for cata-
lytic variants of the PKR. Nevertheless, the stoichiometric
method with [Co2(CO)8] and TMANO in the presence of
4 Š molecular sieves and air (Table 1, entry 9) provides a
convenient and highly diastereoselective access to multigram
amounts of the bicyclic intermediate rac-11b.[28]
Scheme 7. Preparation of enantiomerically pure 11b and ent-11b through
kinetic resolution of the ketone rac-11b by means of a CBS reduction.
a) 17a (20 mol%), CB (0.85 equiv), THF/toluene, ꢁ788C!RT, 6 h, 34%
of 11b (>99% ee), 58% of ent-18 (83% ee, d.r.=83:17); b) MnO2,
CH2Cl2, 08C, 2 h, 89%; then ent-17a (20 mol%), CB (0.85 equiv), THF/
toluene, ꢁ788C!RT, 3h, 72% of ent-11b.
The relative configuration of rac-11a and rac-11b was ini-
tially assigned based on 2D NMR spectroscopy experiments
(NOESY) and later confirmed by X-ray crystal structure
analysis of 11b (Figure 1 and Supporting Information).[29]
in THF (which is easier to handle) to rac-11b in toluene in
the presence of 17a (20 mol%), approximately 60% conver-
sion was observed at ꢁ508C after 16 h, and the slower react-
ing enantiomer, 11b, was isolated in virtually pure form
(99% ee) according to GC analysis on a chiral column.[35]
Lowering the amount of catalyst 17a led to decreased enan-
tioselectivities (after comparable conversions) while larger
amounts gave no improvement. The B-butyl catalyst 17b be-
haved in a similar manner to 17a, while the B-phenyl cata-
lyst 17c showed no significant enantioselectivity at all in this
reaction.
By carefully monitoring the KR of rac-11b at two temper-
atures (ꢁ788C and ꢁ508C), the high efficiency and the tem-
perature dependence of these reactions were shown
(Figure 2). While the KR of rac-11b at ꢁ788C requires only
56% conversion to leave behind the slower reacting enan-
tiomer 11b in greater 99% ee (after 3days), the reaction at
ꢁ508C needs 61% conversion to obtain 11b in such a high
enantiopurity (after 16 h). To express the high efficiency of
these kinetic resolutions in numbers, the so-called selectivity
factors (sꢀkent-11b/k11b, in which k is the rate of reaction)
were determined.[31d,e] The values calculated (sꢀ40 for
ꢁ788C and sꢀ25 for ꢁ508C) are remarkably high; they are
actually comparable to those obtained in typical enzymat-
ic[31e] or particularly efficient chemical[31c,36] kinetic resolu-
tions.
Figure 1. Structure of 11b in the crystalline state.
Kinetic resolution of the PKR product rac-11b: After the
synthesis of CNAs of type 9 had been achieved in the race-
mic series in the course of our preliminary investigation,[12]
a
major task was to develop an enantioselective access to the
target compounds. Since the chirogenic step[30] of the synthe-
sis, that is, the PKR described above, could not be per-
formed in an enantioselective fashion (so far), resolution of
the PKR product rac-11b was the earliest possibility to
enter the nonracemic series. We envisioned that this task
could possibly be achieved through ki-
netic resolution (KR)[31] by means of
an asymmetric reduction. As a prom-
ising method for this purpose, the oxa-
The most convenient protocol for the KR of rac-11b
zaborolidine-catalyzed borane reduc-
(Scheme 7) on a preparative scale (50 mmol) involves
tion (CBS reduction)[32,33] employing
adding a solution of CB in THF at ꢁ788C to a solution of
17a and rac-11b in toluene and then allowing the mixture to
slowly warm up to room temperature (6 h) before the reac-
tion is quenched by addition of MeOH. In this way, ketone
11b (>99% ee) could be obtained in 34% yield along with
58% of the alcohol ent-18 (approximately 83% ee; d.r.=
83:17). As shown in Scheme 7, this material could be effi-
ciently converted into the enantiomerically pure ketone ent-
11b by MnO2 oxidation and a second kinetic-resolution step
employing the enantiomeric CBS catalyst ent-17a.
chiral catalysts of type 17 was investi-
gated (Scheme 6).
In order to prevent any hydrobora-
Scheme 6. Oxazaboro-
lidine catalysts used
for the reduction.
ꢁ
tion of a C C double-bond in the sub-
strate rac-11b by borane, catecholbor-
ane (CB) was used as a less reactive
reducing agent (Scheme 7).[34] In an initial experiment, treat-
ment of rac-11b in toluene with (neat) CB (50 mol%) in
the presence of the B-methyl CBS catalyst 17a (20 mol%)
at ꢁ788C afforded the enantiomerically enriched ketone
11b (90% ee) and the alcohol ent-18 (76% ee) after 45%
conversion. When CB (0.85 equiv) was added as a solution
The stereochemical assignments of the reaction products
were carefully proven: While the relative configuration of
the main alcohol diastereomer (18/ent-18) was secured by
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Carbocyclic Nucleoside Analogues
5087 – 5110
Scheme 8. Two competing transition structures in the kinetic resolution
of rac-11b by CBS reduction with catalyst 17a. Catalyst control is as-
sumed: A) mismatched case (violation of substrate preference);
B) matched case.
face) to give diastereomer 19 (epi-18) is frustrated and this
results in a slower reaction. In contrast, the other substrate
enantiomer (ent-11b) can participate in transition structure
B, in which catalyst and substrate control work synergistical-
ly (“matched” case) to form ent-18 in a fast process. There-
fore, ent-11b is rapidly consumed and 11b is left behind.
Figure 2. Kinetic resolution of ketone rac-11b at ꢁ788C (top) and at
ꢁ508C (bottom).
Planning the further synthesis: Once we had developed an
efficient access to the key intermediate 11b in both racemic
and enantiopure forms, the next goal was to elaborate a se-
quence for the conversion of PKR products 11 into com-
pounds of type 10 according to the general strategic concept
(Scheme 3). We envisioned that an allylic ester of type 21
(obtainable from 11b by reduction, desilylation, and esterifi-
cation) could be used for the diastereoselective introduction
of a nucleobase by means of Pd0-catalyzed allylic substitu-
tion (Scheme 9). Such reactions are known to proceed with
retention of configuration via cationic p-allyl intermediates
of type 22.[38,39] The further synthesis was first developed in
the racemic series[12] and then applied to the preparation of
various enantiomerically pure nucleoside analogues in both
enantiomeric forms. For reasons of clarity, however, we will
describe only the details for compounds with “natural” ste-
reochemistry in the following sections.
X-ray crystal structure analysis of the corresponding (race-
mic) acetate (Figure 3),[37] the absolute configurations of the
reaction products were determined by CD and NMR spec-
troscopic techniques and confirmed by chemical correlation
(as described below in a separate section).
Preparation of the precursor for nucleobase introduction:
The conversion of enone 11b into the allylic esters 21a or
21b (Scheme 9) started with its reduction to the allylic alco-
hol 18. It was found that this transformation was best ach-
ieved by using NaBH4 in the presence of CeCl3 in MeOH[40]
at 08C. Under these conditions, 18 was obtained in virtually
quantitative yield as a single diastereomer. A fully diaste-
reoselective reduction was also achieved with l-Selectride
(THF, ꢁ788C). However, the yield of isolated 18 was only
83% in this case. The presence of the hydroxy group now al-
lowed for a particularly facile, oxygen-assisted[41] removal of
the TMS group under basic conditions. Indeed, when 18 was
treated with KH in THF or, better, with tBuOK in DMSO,
the desilylated product 20 was isolated in 87% yield. Desi-
Figure 3. Structure of the acetate derived from rac-18 in the crystalline
state.
The stereochemical outcome of the CBS kinetic resolu-
tion of rac-11b by using the oxazaborolidine 17a as a cata-
lyst can be nicely rationalized by applying the Corey
model[32b] with the assumption of strong catalyst control[33a]
(Scheme 8). In the case of the substrate enantiomer 11b the
resulting transition structure (A) represents a “mismatched”
case, because the natural preference of the substrate (sub-
strate control, that is, attack of the hydride from the convex
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H.-G. Schmalz et al.
FULL PAPER
astereoselectivity (d.r.>99:1; Table 2). While NaH was used
to deprotonate the pyrimidine nucleobases, Cs2CO3 proved
superior in the case of adenine (!10g) due to the better
solubility of the resulting amide in organic solvents.[43] The
direct introduction of cytosine and guanine failed. However,
the N4-benzoyl derivative of cytosine[44] afforded 10e in up
to 84% yield. For the introduction of guanine, the N2-
acetyl-O-diphenylcarbamoyl derivative was employed ac-
cording to the method of Robins and co-workers[45] to give
10 f as a single regioisomer in 76% yield. In this case,
1,2,2,6,6-pentamethylpiperidine (pempidine) was used as the
base.
An important parameter in these reactions was, of course,
the Pd catalyst. Initially, we used [Pd(PPh3)4] with two addi-
tional equivalents of PPh3 (Method A),[46] a method that
was successful for the introduction uracil, bromouracil, thy-
mine, N-benzoylthymine, and adenine.[12] However, the for-
mation of Ph3P=O (as a result of Ph3P oxidation during
workup) caused severe separation problems and isolated
products 10 were often contaminated with significant
amounts of Ph3P=O.[47] Therefore, a different catalyst system
consisting of [Pd(dba)2] (2 mol%) and (iPrO)3P (14 mol%)
was applied (Method B).[44] While the yields were compara-
ble to those obtained with [Pd(PPh3)4], chromatographic
product purification was generally easier. However, some of
the less polar compounds tended to retain traces of
(iPrO)3P as an impurity.
The introduction of chloropurine onto the allylic acetate
21a under the catalytic conditions decribed above (Methods
A and B) turned out to be difficult (approximately 5%
yield). However, the product 10h was obtained in up to
61% yield when the carbonate 21b was used as the sub-
strate. The catalyst system consisted of [Pd2(dba)3]
(2.5 mol%) and dppp (10.5 mol%) in DMF at RT (Method
C). Here, dppp was a superior ligand to ethane-1,2-diylbis-
(diphenylphosphane) (dppe), 1,1’-bis(diphenylphosphanyl)-
butane (dppb), PPh3, and (iPrO)3P, which afforded 10h in
yields of 8, 0, 51, and 55%, respectively.
Scheme 9. Conversion of 11b into nucleoside precursors of type 10.
a) NaBH4, CeCl3, MeOH, 08C, 30 min, 100%; b) tBuOK, DMSO/H2O
(19:1), RT, 1 h, 87%; c) Ac2O, Et3N, DMAP (cat.), CH2Cl2, RT, 1 h,
99%; d) ClCO2Me, pyridine, CH2Cl2, 08C!RT, 1.5 h, 92%; e) nucleo-
base, Pd0 (cat.), see Table 2 for further details. DMAP=4-dimethylami-
nopyridine, DMSO=dimethylsulfoxide.
lylation with TBAF in THF afforded only impure material
in significantly lower yield (66%). In contrast to the silylat-
ed alcohol 18, the desilylated analogue 20 was found to be
highly sensitive towards hydrolysis of the acetal function.
Therefore, it was usually directly converted into the acetate
21a under standard acetylation conditions[42] (99% yield).
Alternatively, the methyl carbonate 21b was obtained by
treatment of 20 with methyl chloroformate in the presence
of pyridine (92% yield).
Pd-catalyzed nucleobase introduction: Compounds 21a and
21b proved to be perfectly suited substrates for the intro-
duction of various pyrimidine and purine nucleobases by
means of Pd-catalyzed allylic substitution (Scheme 10 and
Table 2).
The constitution of 10e and 10 f (and thus the regioselec-
tivity of N-alkylation at the heterocycles) was confirmed by
NMR spectroscopy exploiting long-range coupling. Nuclear
overhouser effects (NOEs) between the H-3and H-5 pro-
tons confirmed the relative configuration of the products
10a–g. In addition, the structure of rac-10h was unequivo-
cally proven by X-ray crystal structure analysis (Figure 4).[48]
Thus, the Pd-catalyzed allylic aminations had proceeded
with (complete) retention of configuration, as expected.[38,39]
Scheme 10. Final steps of the synthesis of CNAs of type 9. a) Nucleobase
Completing the synthesis of the carbocyclic nucleoside ana-
logues: As shown in Scheme 10, the remaining steps in the
synthesis of CNAs of type 9 were the hydrolysis of the
acetal function in compounds of type 10, the subsequent si-
lylation of the free alcohol group, and the final reduction.
The hydrolysis of the bicyclic acetals 10 was best per-
formed by using catalytic amounts of PPTS in refluxing wet
acetone.[49] While the resulting hydroxyaldehydes[50] could, in
principle, be isolated in pure form by solvent evaporation
and chromatography, the crude products were usually con-
verted directly into the corresponding silylethers by treat-
or derivative, Pd0 (cat.), see Table 2 for further details; b) PPTS, acetone,
ꢁ
reflux, 3h; c) R 3Si Cl (1.5 equiv), pyridine, RT, 16 h; d) NaBH4, MeOH/
CH2Cl2, ꢁ788C, 1 h; then RT, 30 min. For details, see Tables 2 and 3.
PPTS=pyridinium p-toluenesulfonate.
When 21a was treated with preformed salts of nucleobas-
es in the presence of catalytic amounts of a Pd catalyst at
elevated temperatures (50–708C) in a DMSO/THF solvent
mixture, the allylic substitution products of type 10 were
formed in good yields with virtually complete regio- and di-
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Carbocyclic Nucleoside Analogues
5087 – 5110
Table 2. Preparation of various TDS-protected CNAs of type 9 by Pd-catalyzed nucleobase introduction, acetal hydrolysis/silylation, and final reduction
according to Scheme 10.[a]
Entry
1
Method[b]
Product 10
Yield [%]
Product 23
Yield [%]
Product 9
Yield [%]
78
A
56
82
2
3
A
A
ent-10a
rac-10a
65
66
ent-23a
rac-23a
70
80
ent-9a
–
95
–
4
5
6
B
B
A
73
74
82
74
73
83
99
93
99
ent-10b
ent-23b
ent-9b
7
8
9
A
A
C
ent-10c
rac-10c
rac-10c
71
74
72
ent-23c
rac-23c
–
75
83
–
ent-9c
–
–
93
–
–
10
A
63
64
88
11
12
A
A
ent-10d
rac-10d
47
56
ent-23d
rac-23d
60
65
ent-9d
–
99
–
13B
84
67
85[c]
14
15
16
17
A
B
B
B
ent-10e
ent-10 f
65
76
76
52
ent-23e
ent-23 f
75
68
67
40
ent-9e
ent-9 f
95[c]
71[c]
76[c]
93
18
19
A
A
ent-10g
rac-10g
54
73
ent-23g
rac-23g
38
45
ent-9g
–
99
–
20
21
C
63
61
72
75
97
A
rac-10h
rac-23h
rac-9h
99%
[a] Bz=benzoyl, dba=trans,trans-dibenzylideneacetone, DMF=N,N-dimethylformamide, TDS=thexyldimethylsilyl. [b] Method A: nucleobase, base
(NaH for pyrimidine derivatives; Cs2CO3 for adenine), DMSO, 708C (508C for adenine), 30 min, then addition of [Pd(PPh3)4] (5 mol%), PPh3
(11 mol%), and 21a in THF, 708C (508C for adenine), 16 h; Method B: nucleobase, base (NaH for pyrimidines; Cs2CO3 for adenine; pempidine for the
guanine derivative), DMSO, 708C (508C for adenine; RT for the guanine derivative), 5–30 min, then [Pd(dba)2] (2 mol%), P(OiPr)3 (14 mol%), THF,
708C (508C for adenine), 16 h; Method C: [Pd2(dba)3] (2.5 mol%), dppp (10.5 mol%), DMF, 10 min, RT, then 21b, nucleobase, RT, 16 h. [c] Yield of the
deprotected product after treatment of the primary reduction product with NH3 in MeOH at RT for 16 h.
Chem. Eur. J. 2004, 10, 5087 – 5110
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H.-G. Schmalz et al.
FULL PAPER
absence of CeCl3 at ꢁ788C in a solvent mixture of MeOH/
CH2Cl2.[51] Under these conditions the products of type 9
were formed in 78–99% yields (Tables 2 and 3). When the
protected cytosine or guanine derivatives 23e, 23 f, 23k, and
23l were subjected to these conditions, the protecting
groups were already partially removed. By exposing the re-
sulting crude product mixtures to ammonolysis[39b,52] the de-
sired products were obtained in high yields (Table 2 en-
tries 13–16 and Table 3 entries 3,4).
Determination of the absolute configuration: As an impor-
tant part of this work, the absolute configuration of the
products obtained from the CBS kinetic resolution of rac-
11b was carefully determined. As the X-ray crystal structure
analysis of the optically active ketone 11b (Figure 1) did not
provide information about the absolute stereochemistry,
other methods for the configurational assignment had to be
applied.
As a first technique, we used CD spectroscopy, which is
particularly suitable for cyclic ketones.[53] The CD spectra of
ketones 11b and ent-11b (Figure 5) show three Cotton ef-
fects (CEs): a weak CE at 330 nm corresponding to the car-
bonyl n!p* transition, a strong CE at 232 nm characteristic
for the p!p* band, and a CE at 211 nm.
Figure 4. Structure of rac-10h in the crystalline state.
ment with a chlorosilane in pyridine. Thus, compounds 23a–
f and 23h–l (Tables 2 and 3) were obtained in satisfactory
yields (60–82% over two steps). Only for the hydrolysis of
the adenine derivative 10g were two equivalents of PPTS
necessary. In addition, DMAP was employed in this case as
a catalyst in the silylation step to give 23g in acceptable
yields (38–45%).
While the TDS group was chosen in most cases as a pro-
tecting group for the 5’-OH group (Table 2), intermediates
10b, 10c, 10e, and 10 f were also converted into the corre-
sponding TBDPS ethers 23i–l (Table 3).
The final reduction of the a,b-unsaturated aldehydes of
type 23 to the corresponding CNAs of type 9 (Scheme 10)
was initially tried under the Luche conditions (NaBH4/
CeCl3),[40] but the yields were rather low (46–67%).[12] Much
better results, however, were obtained with NaBH4 in the
As the empirical octant rule cannot simply be applied to
the analysis of CD spectra of a,b-unsaturated ketones,[53c]
the so-called enone helicity rule was established.[53b,c] Howev-
er, cyclohexenones and in particular cyclopentenones with a
virtually planar enone chromophore (such as 11b) obey the
inverse enone helicity rule.[53b] According to this rule, the
sign of the octant sector where the substituent at the “satu-
rated part” of the cyclopentenone is located equals that of
the CE for the p!p* transition (230–260 nm). The CE con-
Table 3. Preparation of TBDPS-protected CNAs 9i–l from intermediates of type 10 according to Scheme 10.[a]
Entry
Starting material 10
Product 23
Yield [%]
59
Product 9
Yield [%]
99
1
2
63
99
3
4
57
37
76[b]
99[b]
[a] TBDPS=tert-butyldiphenylsilyl. [b] Yield of the deprotected product after treatment of the primary reduction product with NH3.
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5094

Carbocyclic Nucleoside Analogues
5087 – 5110
of the chiral reagent (S)-
MTPA had to be used. The
four Mosher esters 24a,24b,
25a, and 25b were obtained in
good yields under the standard
N,N’-dicyclohexylcarbidiimide
(DCC) coupling conditions[56]
(Scheme 12).
1
Based on the H NMR spec-
troscopic data of the four
MTPA esters prepared, the
configurational
assignments
were drawn as follows:
1) One can assume that the
esters adopt
conformation, which is
a preferred
Figure 5. CD-spectra of ketones 11b and ent-11b in cyclohexane.
nected to the n!p* transition (at approximately 330 nm)
will then have an opposite sign.[53b] As shown in Scheme 11,
the respective analysis for enone 11b allows a clear assign-
Scheme 11. Application of the inverse helicity rule to ketones 11b and
ent-11b, thereby allowing the prediction of the sign of the Cotton effects.
Scheme 12. Preparation of the Mosher (MTPA) esters from alcohols 18,
ent-18, 20, and ent-20. a) (S)-MTPA (1.1 equiv), DCC (1.1 equiv), DMAP
(12 mol%), CH2Cl2, 08C!RT, 16 h.
ment of the two enantiomorphic CD spectra to the enan-
tiomers. The g-allyloxy substituent should additionally con-
tribute to the (ꢁ) character of the CE at approximately
230 nm.[53c] This analysis is also supported by comparison of
the CD spectrum of 11b with that of a structurally related
compound of known configuration.[54]
As a second independent technique for the determination
of the absolute configuration, the empirical Mosher ester
analysis[55] was applied to the alcohols 18 and 20. This
method is based on the com-
characterized by a horseshoe-type arrangement of the
carbinol hydrogen atom and the carbonyl group as well
as an antiperiplanar position of the CF3 group with re-
spect to the ester CO single bond (Scheme 13).[55]
2) According to the established rules,[55] the signals of pro-
tons on the phenyl side of the plane defined by the ester
moiety undergo an upfield shift, while those of the pro-
tons on the methoxy side are shifted downfield
(Scheme 13).
parison by NMR spectroscopy
of pairs of diastereomeric
esters obtained from a chiral
alcohol by esterification with
methoxytrifluoromethylphenyl-
acetic acid (MTPA) of known
absolute configuration. As
both enantiomers of the alco-
hols to be investigated (18 and
its desilylated analogue 20)
were available, only one form
Scheme 13. Effects of the (S)-MTPA ester group (in its preferred conformation) on the 1H NMR chemical
shift of the signals of the adjacent substituents R and H-4exo. See also Table 4.
Chem. Eur. J. 2004, 10, 5087 – 5110
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H.-G. Schmalz et al.
FULL PAPER
1
3) By comparing the H NMR spectroscopic data, the two
pairs of diastereomers (24a/24b and 25a/25b) could be
clearly assigned. Most characteristic effects were ob-
served for the substituent R at the olefinic position C2
and for the endo-hydrogen atom at C4 (Table 4). In ac-
Table 4. 1H NMR chemical shifts (d in ppm) of selected signals in the
MTPA esters.
Scheme 14. Deprotection of 9 f and 9g. a) TBAF (2 equiv), THF, RT,
16 h.
24a
25a
24b
25b
Dd(24a/24b)
Dd(25a/25b)
H-2
H-4endo
TMS
–
5.71
1.62
–
–
5.78
1.52
–
ꢁ0.07
+0.10
–
The comparison of the specific rotations of 26a ([a]2D0 =
ꢁ11.8; c=0.34 in H2O) and 26b ([a]2D0 =ꢁ30.3; c=0.33 in
H2O) with those reported by Samuelsson and co-workers
([a]2D0 =ꢁ12.8 for 26a and [a]D20 =ꢁ25.8 for 26b)[57] con-
firmed the configurational assignments of all chiral nonrace-
mic compounds described in this work.
1.40
ꢁ0.14
1.27
0.03–
+0.13
ꢁ0.17
cordance with Scheme 13, the signal for substituent R
(TMS or H) showed a relative upfield shift (Dd<0 ppm)
in the spectra of 24a and 25a as compared to that in
their diastereomers, while the signal of H-4endo was shift-
ed downfield (Dd>0 ppm) at the same time. Figure 6 il-
lustrates the significant shift (Dd=ꢁ0.07 ppm) of the H-
2 signal in the spectra of 25a and 25b.
Biological investigations: The cytotoxic activity of some of
the synthesized CNAs of type 9 was evaluated in vitro by
using BJAB cells (Burkitt-like lymphoma cells).[58] The re-
sults summarized in Figure 7 indicate that some of the com-
pounds possess a cytotoxic activity in the lower micromolar
range. While the TDS-protected compounds 9a–h showed
moderate activity (LD50 =40–100 mm) in both enantiomeric
series, the TBDPS-protected compounds 9i–l were generally
more active (LD50 =9–35 mm). Evidently, apart from the ex-
pected influence of the nucleobase on the activity, the silyl
protecting group has a significant impact. Among the tested
compounds the TBDPS-protected bromouracil and cytosine
derivatives, 9j (LD50 =9 mm) and 9k (LD50 =15 mm), were
the most active. As a general trend, the pyrimidine-based
compounds exhibited a stronger activity than their purine-
based relatives. One exception is the chloropurine derivative
rac-9h with an LD50 value of 22 mm.
By using the most active compounds (9i–l), further ex-
periments assessed whether the observed cell death was due
to apoptosis or necrosis. The first evidence for apoptosis[59]
was provided by microscopy, which showed a characteristic
membrane blebbing and cell shrinkage of the tumor cells
(not shown).
Figure 6. Section of the 1H NMR spectra of MTPA esters 25a (top) and
25b (bottom).
As an additional indicator of apoptotic cell death, the
ability of compounds 9i–l to induce DNA fragmentation
(hypoploidity) was investigated.[60] As shown in Table 5, in-
cubation with compounds 9i–l led to substantial hypoploidi-
ty in BJAB cells as well as in primary, leukemic lympho-
blasts of patients suffering from childhood acute lympho-
blastic leukemia (ALL). Consistent with their high cytotoxic
potential, compounds 9j and 9k were also particularly
active in the DNA fragmentation assay. Further evidence
for apoptosis was obtained by probing the activation of cas-
pases 3, 8, and 9, which are principal effectors of apoptotic
signal transduction and execution. Their activation by pro-
teolytic cleavage after treatment of BJAB cells with com-
pounds 9b (50 mm) and 9i–l (30 mm) was investigated by
means of Western blot analysis.[61] As shown in Figure 8,
compounds 9b and 9i–l induced specific processing of pro-
caspase-3(p32), procaspase-8 (p55), and procaspase-9 (p47)
with concomitant appearance of the active subunits of the
caspases (p17, p18, and p37, respectively). Interestingly, 9j
4) As the configuration of the MTPA ester moiety was
known (S), the absolute configuration of the bicyclic al-
cohols (18/ent-18 and 20/ent-20) could be directly de-
duced. It is in agreement with the earlier assignment
based on CD spectroscopy.
After the absolute stereochemistry predicted by the
Corey model (see above) had been confirmed by two empir-
ical methods (CD spectroscopy and Mosher ester analysis)
the correctness of our assignment was additionally support-
ed by chemical correlation. For this purpose, the silylated
compounds 9 f and 9g were converted into the unprotected
CNAs 26a and 26b by fluoride-induced desilylation
(Scheme 14). These compounds had been independently
synthesized before by Samuelsson and co-workers in a “ste-
reorational” manner.[57]
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Carbocyclic Nucleoside Analogues
5087 – 5110
Figure 7. Cytotoxicity data for CNAs of type 9 in BJAB cells after incubation for 48 h. LD50 values are given in mm. Light gray is used for the TDS-pro-
tected compounds and darker gray for the TBDPS-protected compounds.
Table 5. Additional biological data for compounds 9i–l.
Entry Compound Cytotoxicity[a]
Cell death
[%][a]
10 mm 20 mm
Hypoploidity [%]
LD50 [mm]
ALL
BJAB
cells[b]
cells[c]
1
2
3
4
9i
9j
9k
9l
3
5
1
4
28
55
9
61
14
2
69
72
44
44
33
31
54
66
59
15
21
[a] Measured in BJAB cells after incubation for 48 h. [b] DNA fragmen-
tation after incubation for 60 h at a nucleoside concentration of 20 mm.
The hypoploidity of control cells in the presence of the vehicle alone
(0.5% ethanol) was 15%. [c] DNA fragmentation after incubation for
72 h at a nucleoside concentration of 30 mm. The hypoploidity of control
cells in the presence of the vehicle alone (0.5% ethanol) was 4%.
Figure 8. Western blot analysis of CNA-treated BJAB cells after incuba-
tion for 36 h. After incubation with 30 mm 9i–l or with 50 mm 9b, cells
were collected, cellular protein was extracted, and processing of procas-
pase-3(upper panel; procaspase: 32 kDa; cleavage products: 20, 18, and
17 kDa), procaspase-8 (middle panels; procaspase: 55 kDa; cleavage
products: 43and 18 kDa), and procaspase-9 (lower panel; procaspase:
47 kDa; cleavage product: 37 kDa) was detected by Western blot analy-
sis. Arrows indicate the positions of procaspases-3, -8, and -9 and the re-
spective cleavage products.
induced complete processing of procaspase-8 and procas-
pase-9, a result which again demonstrated the high potency
of this compound.
Conclusion
We have developed a convergent and enantioselective syn-
thesis of monoprotected, 2’,3’-unsaturated carbocyclic nu-
cleoside analogues of type 9 with a hydroxymethyl substitu-
ent in the 3’ position (according to normal nucleoside num-
bering). Numerous new CNAs were prepared from proparg-
yl alcohol and were fully characterized.
The synthesis in the racemic series involves only 10 linear
steps with an average overall yield of approximately 25%.
The synthesis centrally exploits transition-metal–organic
chemistry, that is, a Co-mediated Pauson–Khand reaction
(PKR) and a Pd-catalyzed allylic substitution, with the latter
allowing the introduction of various nucleobases with virtu-
ally complete regio- and diastereocontrol.
While the chirogenic step, the Pauson–Khand reaction,
cannot be directly performed in an enantioselective manner
at the moment, an efficient kinetic resolution (sꢀ30) of the
PKR product through CBS reduction opened an operation-
ally convenient access to the enantiomerically pure com-
pounds in both absolute configurations.
The absolute stereochemistry of the chiral products was
carefully determined by three independent methods (CD
spectroscopy, Mosher ester analysis, and chemical correla-
tion) and is in accordance with the predictions drawn from
the Corey model.
Chem. Eur. J. 2004, 10, 5087 – 5110
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H.-G. Schmalz et al.
FULL PAPER
The product thus obtained was pure according to 1H NMR spectroscopy.
For analytical purposes a sample was further purified by vacuum distilla-
tion. B.p. 90–928C/22 mm Hg (literature value:[20a] 768C/20 mm Hg);
1H NMR (250 MHz, CDCl3): d=4.24 (s, 2H; CH2), 1.70 (s, 1H; OH),
0.15 ppm (s, 9H; Si(CH3)3); 13C NMR (63MHz, CDCl 3): d=103.8/90.7
The potential of the new class of compounds as antitu-
moral agents was shown in a first series of biological assays
with a Burkitt-like lymphoma cell line model as well as pri-
mary lymphoblastic tumor cells ex vivo. Cytotoxic activities
at concentrations in the lower micromolar range specifically
result from apoptosis induction and encourage further struc-
tural variation and screening in the future.
ꢁ
(C=C), 51.7 (CH2OH), ꢁ0.2 ppm (CH3Si); IR (ATR): n˜ =3320 (m, O
ꢁ
H), 2956 (m, C H), 2174 (m, C=C), 1248 (s), 1038 (s), 980 (s), 844 (s),
759 (s), 698 cmꢁ1 (s); MS (EI, 70 eV): m/z (%): 113(75) [ Mꢁ15]+, 85
(100), 75 (91), 73(76).
Indeed, the option of flexibly varying the structural mod-
ules (that is, the nucleobase and the substituents at both hy-
droxy groups) in a late stage of the synthesis provides ample
opportunity for a broad structural variation (a diversity-ori-
ented approach).[14] This includes the possibility of using the
monoprotected compounds of type 9 as building blocks for
the synthesis of oligonucleotides or conjugates with other
pharmacophoric units (for example, natural-product hy-
brids).[62] Furthermore, the allylic alcohol unit in compounds
of type 9 provides an anchor for additional structural modi-
fication.
3,3-Diallyloxy-1-propynyltrimethylsilane (12b):[21,22] A solution of alcohol
16 (61.15 g, 336 mmol) in dry CH2Cl2 (100 mL) was added dropwise to a
stirred suspension of pyridinium chlorochromate (111 g, 504 mmol) in
dry CH2Cl2 (450 mL) at 08C. The mixture was allowed to warm to RT
for 2 h and then carefully filtered through a plug of silica. (Note: to pre-
vent the filtration being blocked, the black oily residue should not be
poured onto the silica.) After evaporation of the solvent, the residue was
purified by flash chromatography (EtOAc/CyHex 1:19) to give sensitive
3-trimethylsilyl-2-propyne-1-al as a light-yellow liquid, which was imme-
diately further converted as follows. The crude aldehyde (336 mmol),
allyl alcohol (230 mL, 3.36 mol), and pTsOH (3.2 g, 16.8 mmol) were dis-
solved in benzene (500 mL) and the mixture was heated to reflux for
15 h with azeotropic removal of water (Dean–Stark trap). After cooling
to RT, the mixture was neutralized by addition of NaHCO3 before it was
filtered through a plug of silica and concentrated under reduced pressure.
The residue was purified by flash chromatography (EtOAc/CyHex 1:19)
to afford the acetal 12b as a light-yellow oil (66.34 g, 88% over two
steps). An analytical sample was further purified by vacuum distillation
Experimental Section
through
a Vigreux column (103–1058C, 8 mbar). Rf =0.48 (EtOAc/
General: Anhydrous solvents were obtained by distillation from sodium/
benzophenone (THF), from CaH2 (CH2Cl2), from KOH (pyridine, Et3N),
or by storage over 4 Š MS (DMSO). Reagents (generally 99%) were
used as purchased unless otherwise stated. The concentration of organo-
lithium reagents was determined by titration against menthol in THF
with 1,10-phenanthroline as an indicator.[63] TMANO was dried by azeo-
tropic removal of water with toluene. Water- and/or air-sensitive com-
pounds were handled under an atmosphere of argon by using Schlenk
techniques. Reactions were monitored by analytical TLC with Merck
silica gel 60F 254 aluminum plates. Chromatograms were visualized
either with UV light, by staining with iodine, or with a “cerium reagent”
(prepared by dissolving phosphomolybdic acid (2 g) and Ce(SO4)2 (1 g)
in 100 mL of 10% aqueous H2SO4) and subsequent heating. Flash chro-
matography[64] was performed over silica gel 60 (230–400 mesh) from
Merck. Gas chromatography was performed on an HP-6890 apparatus
with H2 as the carrier gas and flame ionization detector. NMR spectro-
scopy was carried out on Bruker DPX 300, DRX 500, and AC 250 instru-
ments. Chemical shifts (d) are given in ppm relative to the solvent refer-
ence. 13C NMR spectra were measured under proton decoupling and the
number of bound protons (multiplicities) was determined by DEPT
methods. IR spectroscopy was carried out on a Perkin-Elmer FTIR Para-
gon 1000 apparatus by using the ATR technique. Mass spectrometry was
performed on a Finnigan MAT Incos 50 Galaxy system (DIP-MS) or a
Finnigan MAT 900 spectrometer; high-resolution MS was performed on
Finnigan HSQ-30 (HR-EI-MS) or Finnigan MAT 900 (HR-ESI-MS) in-
struments. The method of ionization is given in parentheses. Melting
points were measured on a Büchi B-545 apparatus and are uncorrected.
Specific optical rotations ([a]) were recorded on a Perkin-Elmer 343 ap-
paratus plus polarimeter; concentrations c are given in g per 100 mL and
the cell length was 100 mm. CD spectroscopy was performed on a
Jasco J-810 spectrometer. Elemental analyses were recorded on an Ele-
mentar Vario EL instrument.
1
CyHex 1:4); H NMR (250 MHz, CDCl3): d=5.91 (tdd, J1 =5.4, J2 =17.2,
J3 =10.3Hz, 2H; C H=CH2), 5.30 (s, 1H; H-3), 5.29 (tdd, J1 =1.6, J2 =3.3,
J3 =17.2 Hz, 2H; CH=CH Htrans), 5.18 (tdd, J1 =1.6, J2 =2.9, J3 =10.3Hz,
ꢁ
ꢁ
ꢁ
2H; CH=CH Hcis), 4.20 (tdd, J1 =1.4, J2 =12.6, J3 =5.4 Hz, 2H; CH2
ꢁ
CH=CH2), 4.06 (tdd, J1 =1.4, J2 =12.6, J3 =6.1 Hz, 2H; CH2 CH=CH2),
0.17 ppm (s, 9H; SiCH3); 13C NMR (63MHz, CDCl 3): d=133.9 (CH=
CH2), 117.6 (CH=CH2), 99.5 (C3), 91.1 (C2), 90.3 (C1), 66.2 (CH2CH=
ꢁ
CH2), ꢁ0.4 ppm (SiCH3); IR (ATR): n˜ =2959 (m, C H), 1647 (w, C=C),
ꢁ1
ꢁ
1250 (s, C O), 1098 (s), 1027 (s), 922 (s), 841 (s), 760 cm (s); MS (EI,
70 eV): m/z (%): 167 (27) [MꢁC3H5O]+, 73(100), 57 (57), 55 (74).
1,1-Diallyloxy-2-propyne (12a)
A) By transacetalization of 1,1-diethoxy-2-propyne (14):[19] A solution of
1,1-diethoxy-2-propyne (14)[17, 18] (2.56 g, 20 mmol), allyl alcohol
(13.7 mL, 200 mmol), and pTsOH (190 mg, 1 mmol) in benzene (60 mL)
was heated to reflux. By using a distillation head, the benzene/ethanol
azeotrope (b.p.ꢂ698C) was constantly removed from the system until no
further azeotrope formed. The mixture was cooled to RT and neutralized
by addition of K2CO3. The solvent and excess of allyl alcohol were re-
moved under reduced pressure and the residue was purified by flash
chromatography (CyHex!CyHex/MTBE 9:1) to give the product 12a as
a colorless oil (1.23g, 40%).
B) By desilylation of 12b:[23] A 1m solution of TBAF in THF (10 mL)
was added dropwise to a solution of 12b (2.24 g, 10 mmol) in a mixture
of allyl alcohol (8 mL) and H2O (4 mL) at 08C. After stirring for 1 h at
RT, H2O (30 mL) and MTBE (30 mL) were added and the water phase
was extracted with MTBE (2ꢁ20 mL). The combined organic layers
were washed with water (3ꢁ30 mL) and brine (30 mL) and then dried
(MgSO4). The solvent was removed to give the product 12a as a colorless
oil (1.33 g, 88%). The product was pure according to 1H NMR spec-
troscopy and TLC. Rf =0.35 (EtOAc/CyHex 1:4); 1H NMR (250 MHz,
CDCl3): d=5.92 (tdd, J1 =5.4, J2 =17.2, J3 =10.3Hz, 2H; C H=CH2), 5.33
(d, J=1.6 Hz, 1H; H-1), 5.29 (tdd, J1 =1.6, J2 =17.2, J3 =3.3 Hz, 2H;
3-Trimethylsilyl-2-propyn-1-ol (16):[20] A solution of propargyl alcohol
(15; 24.5 mL, 413mmol) in dry THF (500 mL) was cooled to ꢁ788C
before a 1.6m solution of nBuLi in hexane (600 mL) was added over a
period of 1 h. The yellow-colored suspension was allowed to warm to RT
for 3h and then cooled to ꢁ788C before TMSCl (121 mL, 960 mmol)
was added within a period of 5 min. The cooling bath was removed and
stirring was continued for 10 h before 1.4n HCl (385 mL, 1.3 equiv) was
added within a period of 5 min. The resulting clear mixture was stirred at
RT for 1 h. The water layer was separated and extracted with tert-butyl
methyl ether (MTBE, 3ꢁ200 mL). The combined organic layers were
washed with brine (2ꢁ200 mL), dried (MgSO4), and concentrated under
reduced pressure to give alcohol 16 (73.66 g, 98%) as a colorless liquid.
ꢁ
ꢁ
CH=CH Htrans), 5.19 (tdd, J1 =1.6, J2 =10.3, J3 =2.9 Hz, 2H; CH=CH
Hcis), 4.21 (tdd, J1 =1.4, J2 =12.6, J3 =5.4 Hz, 2H; CH2 CH=CH2), 4.08
ꢁ
ꢁ
(tdd, J1 =1.4, J2 =12.6, J3 =6.1 Hz, 2H; CH2 CH=CH2), 2.55 ppm (d, J=
1.6 Hz, 1H; H-3); 13C NMR (63MHz, CDCl 3): d=133.7 (CH=CH2),
117.6 (CH=CH2), 90.1 (C3) 78.5 (C2); 74.0 (C1), 66.2 ppm (CH2CH=
ꢁ
CH2); IR (ATR): n˜ =2922 (m, C H), 2123(w, C =C), 1667 (w, C=C),
ꢁ1
ꢁ
1246 (m, C O), 1091 (s), 1033 (s), 839 (s), 737 (s), 727 (s), 697 cm (s);
MS (EI, 70 eV): m/z (%): 151 (1) [MꢁH]+, 95 (60), 41 (100).
(5SR,8RS)-8-Allyloxy-2-trimethylsilyl-7-oxa-[3.3.0]-bicyclooct-1-ene-3-
one (rac-11b): A 2 L 2-necked flask was charged with dry, degassed
5098
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5087 – 5110

Carbocyclic Nucleoside Analogues
5087 – 5110
CH2Cl2 (1.5 L), activated 4 Š molecular sieves (108 g), and [Co2(CO)8]
(25 g, 69 mmol) under argon. (Note: the [Co2(CO)8] must be of high
quality, that is, red and nonsticky crystals, to obtain good yields.) The di-
eneyne 12b (13.52 g, 60 mmol) was then added all at once and the mix-
ture was stirred at RT for 2 h under argon. After the mixture was cooled
to ꢁ208C, dry TMANO (39.6 g, 528 mmol) was added in small portions
over a period of 10 min. A stream of air was bubbled through the dark
solution for 10 min before stirring was continued for 15 h at RT (open
flask). The mixture was filtered through a plug of silica (in order to
remove blue- and violet-colored cobalt byproducts) before the solvent
was evaporated and the residue purified by flash chromatography
(EtOAc/CyHex 1:4). The PKR product rac-11b was obtained as a light-
yellow oil (11.56 g, 76%, d.r.>98:2), which solidified on standing in a
fridge at 48C. An analytical sample was further purified by Kugelrohr
distillation (128–1308C oven temperature, 14 mbar). M.p. 31.5–32.58C;
Rf =0.13(EtOAc/CyHex 1:4); 1H NMR (250 MHz, CDCl3): d=5.93(tdd,
J1 =5.4, J2 =17.2, J3 =10.3Hz, 1H; C H=CH2), 5.58 (s, 1H; H-8), 5.31
180 (6) [M]+, 163(8), 151 (11), 147 (15), 139 (28), 123(100), 109 (36), 95
(24); HRMS (EI): calcd for C10H12O3: 180.078 [M]+; found: 180.078.
CBS kinetic resolution of rac-11b: A Schlenk flask was charged with the
azeotropically dried ketone rac-11b (12.60 g, 50 mmol) and an approxi-
mately 0.05m solution of freshly prepared (R)-Me-oxazaborolidine 17a[65]
in toluene (200 mL) was added at RT. The mixture was cooled to ꢁ788C
and after 30 min a solution of catecholborane (42.5 mL, 1m in THF) was
added over a period of 5 min. The mixture was allowed to warm to RT
and stirred for another 6 h. GC analysis showed that the slower reacting
enantiomer (11b) was obtained in >99% ee while the conversion was
59%. (Note: When ketone 11b was not obtained in enantiomerically
pure form, additional catecholborane was added at ꢁ788C.) The reaction
was quenched by addition of a 2m solution of KOH (300 mL). After stir-
ring for 30 min at RT, the mixture was extracted with EtOAc (4ꢁ
150 mL) and the combined organic layers were washed with a 2m solu-
tion of KOH (2ꢁ200 mL) and saturated solutions of NH4Cl (200 mL)
and CuSO4 (2ꢁ200 mL). After the washing process was repeated, the
mixture was finally washed with brine (2ꢁ200 mL) and dried (MgSO4).
After evaporation of the solvent, the residue was purified by flash chro-
matography (EtOAc/CyHex 1:4) to afford ketone 11b (4.24 g, 34%,
>99% ee) and alcohol ent-18 (7.00 g, 58%, 83% ee, 65% de). Ketone
11b: [a]2D0 =ꢁ290.7 (c=1.185 in CHCl3), [a]52406 =ꢁ342.5; CD: V (l)=
+64809 (210.9 nm), ꢁ148828 (232.0 nm), +10071 mdegnmꢁ1 (329.7 nm)
(c=0.148 mgdLꢁ1 in cyclohexane); the ee and de were determined by
chiral GC (Hydrodex b-PM, 1308C, isotherm, 15 psi H2): retention times:
11b: 24.70; ent-11b: 25.44; epi-18: 35.09, 37.56; ent-18: 41.15; 18:
44.35 min.
ꢁ
(tdd, J1 =1.6, J2 =17.2, J3 =1.6 Hz, 1H; CH=CH Htrans), 5.22 (tdd, J1 =
ꢁ
1.2, J2 =10.3, J3 =1.8 Hz, 1H; CH=CH Hcis), 4.38 (dd, J1 =6.6, J2 =
ꢁ
7.2 Hz, 1H; H-6a), 4.29 (tdd, J1 =12.2, J2 =5.6, J3 =1.4 Hz, 1H; CHHa
CH=CH2), 4.10 (tdd, J1 =12.5, J2 =6.4, J3 =1.3Hz, 1H; CH Hb CH=
ꢁ
CH2), 3.46 (m, 1H; H-5), 3.42 (dd, J1 =6.2, J2 =6.7 Hz, 1H; H-6b), 2.66
(dd, J1 =17.6, J2 =6.4 Hz, 1H; H-4a), 2.10 (dd, J1 =17.6, J2 =3.6 Hz, 1H;
H-4b), 0.21 ppm (s, 9H; SiCH3); 13C NMR (63MHz, CDCl 3): d=213.4
(C3), 184.9 (C1), 137.6 (C2), 133.8 (CH=CH2), 118.2 (CH=CH2), 96.7
(C8), 71.0 (C6), 68.8 (CH2CH=CH2), 42.6 (C5), 41.8 (C4), ꢁ1.5 ppm
ꢁ
(SiC); IR (ATR): n˜ =2954 (m, C H), 1703(s, C =O), 1640 (s, C=C), 1247
ꢁ1
Oxidation of alcohol ent-18: A solution of alcohol ent-18 (83% ee, 65%
de, 6.10 g, 24 mmol) in dry CH2Cl2 (20 mL) was added to a stirred sus-
pension of MnO2 (68 g, 90% purity) in dry CH2Cl2 (90 mL) at 08C under
argon. The mixture was allowed to warm to RT and stirred for 2 h. The
suspension was filtered through a plug of celite and the solvent was
evaporated to give the product ent-11b (5.37 g, 89%, 83% ee). The
purity was >98% according to GC analysis and therefore no further pu-
rification was performed.
ꢁ
(s, C O), 1126 (s), 1073(s), 997 (s), 883 (s), 762 cm
(s); MS (EI,
70 eV): m/z (%): 253(1)
[
M+H]+, 237 (2) [MꢁCH3]+, 211 (15)
[MꢁC3H5]+, 195 (20) [MꢁC3H5O]+, 73(100); HRMS (EI): calcd for
C12H17O3Si: 237.095 [MꢁCH3]+; found: 237.095.
Alternative method for the preparation of rac-11b by using nBuSMe as
a promoter:[27] A solution of dieneyne 12b (757 mg, 3mmol) in 1,2-di-
chloroethane (30 mL, freshly filtered through ALOX-B) was added to
[Co2(CO)8] (1.30 g, 3.6 mmol) all at once under argon. After the mixture
was stirred for 1 h at RT, nBuSMe (1.31 mL, 10.5 mmol) was added and
the resulting mixture was refluxed for 18 h. The solvent was evaporated
and the residue was purified by flash chromatography (EtOAc/CyHex
Repeated CBS kinetic resolution–Preparation of ketone ent-11b in enan-
tiomerically pure form: An approximately 0.1m solution of (S)-Me-CBS-
catalyst ent-17a in PhMe (128 mL, 20 mol%) was added to a solution of
the azeotropically dried ketone ent-11b (16.13g, 64 mmol, 83% ee)
under argon and the resulting mixture was cooled to ꢁ788C. After stir-
ring for 30 min, a 1m solution of catecholborane in THF (9.25 mL) was
added within a period of 5 min. The mixture was allowed to warm to RT
and stirred for 3h. When the ketone ent-11b was obtained in the desired
purity (>99% ee), the reaction was quenched by addition of a 2m solu-
tion of KOH (300 mL) and the workup was carried out in the same
manner as that described previously (for 11b). After flash chromatogra-
phy (EtOAc/CyHex 1:4), the ketone ent-11b (11.56 g, 72%, >99% ee)
and the alcohol 18 (3.34 g, 21%) were isolated. ent-11b: [a]2D0 =+290.0
1:9!1:4!1:2) to afford the product rac-11b as
a light-yellow oil
(435 mg, 57%, d.r.=24:1).
(5SR,8RS)-8-Allyloxy-7-oxa-[3.3.0]-bicyclooct-1-ene-3-one (rac-11a): By
following the protocol described above for the preparation of rac-11b,
acetal 12a (760 mg, 5 mmol) was treated with [Co2(CO)8] (with TMANO
as a promoter) to afford an inseparable mixture of rac-11a and rac-epi-
11a (d.r.=2.6:1) as a colorless oil (333 mg, 45%). Rf =0.16 (EtOAc/
CyHex 1:4).
rac-11a: 1H NMR (250 MHz, CDCl3): d=6.09 (d, J=2.4 Hz, H-2), 5.98–
5.85 (m, 1H; CH=CH2), 5.58 (s, 1H; H-8), 5.30 (tdd, J1 =J2 =1.4, J3 =
(c=1.29 in CHCl3); CD:
V
(l)=ꢁ73076 (210.1), +168312 (232.0),
ꢁ11831 mdegnmꢁ1 (330.8) (c=0.308 mgdLꢁ1 in cyclohexane).
ꢁ
17.1 Hz, 1H; CH=CH Hcis), 5.21 (tdd, J1 =J2 =1.4, J3 =10.0 Hz, 1H;
ꢁ
(ꢁ)-(3R,5S,8R)-8-Allyloxy-2-trimethylsilyl-7-oxa-[3.3.0]-bicyclooct-1-ene-
3-ol (18) (Luche reduction):[40b] NaBH4 (3.23 g, 85 mmol) was added por-
tionwise to a solution of 11b (8.57 g, 34 mmol) and CeCl3·7H2O (12.88 g,
34 mmol) in MeOH (340 mL) at ꢁ208C (ice/salt bath) over a period of
30 min. After stirring the mixture at RT for 10 min, the reaction was
quenched by addition of a saturated solution of NaHCO3 (100 mL). The
mixture was extracted with MTBE (4ꢁ100 mL) and the combined organ-
ic layers were washed with saturated NaHCO3 (2ꢁ100 mL) and brine
(100 mL), then dried (MgSO4). The solvents were evaporated and the al-
cohol 18 was obtained as a colorless oil (8.62 g, 99%, d.r.>98:2) that was
pure according to 1H NMR spectroscopy and GC analysis. Rf =0.39
(EtOAc/CyHex 1:1); [a]D20 =ꢁ247.5 (c=1.69 in CHCl3); 1H NMR
(250 MHz, CDCl3): d=5.90 (tdd, J1 =17.2, J2 =10.3, J3 =5.4 Hz, 1H; CH=
CH2), 5.38 (s, 1H; H-8), 5.26 (tdd, J1 =17.2, J2 =1.5, J3 =1.3Hz, 1H;
CH=CH Htrans), 4.39 (dd, J1 =J2 =7.8 Hz, 1H; H-6a), 4.27 (tdd, J1 =12.6,
ꢁ
J2 =5.3, J3 =1.5 Hz, 1H; CHHa CH=CH2), 4.10 (tdd, J1 =12.6, J2 =6.2,
ꢁ
J3 =1.3Hz, 1H; CH Hb CH=CH2), 3.59–3.50 (m, 1H; H-5), 3.44 (dd, J1 =
7.6, J2 =8.8 Hz, 1H; H-6b), 2.69 (dd, J1 =17.9, J2 =6.3Hz, 1H; H-4a),
2.16 ppm (dd, J1 =17.9, J2 =3.5 Hz, 1H; H-4b); 13C NMR (63MHz,
CDCl3): d=209.3 (C3), 178.3 (C1), 133.7 (CH=CH2), 124.8 (C2), 117.9
(CH=CH2), 96.4 (C8), 71.2 (C6), 68.7 (CH2CH=CH2), 41.1 (C5),
40.8 ppm (C4).
rac-epi-11a: 1H NMR (250 MHz, CDCl3): d=6.23(m, 1H; H-2), 5.98–
5.85 (m, 1H; CH=CH2), 5.78 (s, 1H; H-8), 5.30 (tdd, J1 =J2 =1.4, J3 =
ꢁ
17.1 Hz, 1H; CH=CH Hcis), 5.21 (tdd, J1 =J2 =1.4, J3 =10.0 Hz, 1H;
ꢁ
ꢁ
CH=CH Htrans), 4.29 (m, 1H; CHHa CH=CH2), 4.23(dd, J1 =J2 =
ꢁ
7.8 Hz, 1H; H-6a), 4.13(tdd, J1 =1.3, J2 =6.2, J3 =12.6 Hz, 1H; CHHb
CH=CH2), 3.53 (dd, J1 =7.8, J2 =10.8 Hz, 1H; H-6b), 3.34–3.25 (m, 1H;
H-5), 2.60 (dd, J1 =17.9, J2 =6.2 Hz, 1H; H-4a), 2.21 ppm (dd, J1 =17.9,
J2 =3.5 Hz, 1H; H-4b); 13C NMR (63MHz, CDCl 3): d=208.7 (C3), 182.5
(C1), 133.7 (CH=CH2), 127.6 (C2), 117.9 (CH=CH2), 98.2 (C8), 70.7
(C6), 69.7 (CH2CH=CH2), 45.2 (C5), 39.8 ppm (C4).
ꢁ
CH=CH Htrans), 5.17/5.16 (m/tdd, J1 =10.3, J2 =1.8, J3 =1.1 Hz, 2H; H-3/
ꢁ
CH=CH Hcis), 4.20 (dd, J1 =J2 =8.2 Hz, 1H; H-6a), 4.19 (tdd, J1 =12.4,
ꢁ
J2 =5.3, J3 =1.4 Hz, 1H; CHHa CH=CH2), 4.00 (tdd, J1 =12.4, J2 =6.4,
ꢁ
J3 =1.3Hz, 1H; CH Hb CH=CH2), 3.42 (dd, J1 =J2 =7.9 Hz, 1H; H-6b);
3.20 (m, 1H; H-5), 2.69 (ddd, J1 =12.1, J2 =6.5, J3 =6.0 Hz, 1H; H-4a),
1.64 (brs, 1H; OH), 1.22 (ddd, J1 =12.0, J2 =J3 =8.6 Hz, 1H; H-4b),
0.21 ppm (s, 9H; SiCH3); 13C NMR (63MHz, CDCl 3): d=156.8 (C1),
ꢁ
Analytical data for the mixture: IR (ATR): n˜ =2917 (w, C H), 1713(s,
C=O), 1660 (s, C=C), 1069 (s), 996 cmꢁ1 (s); MS (EI, 70 eV): m/z (%):
Chem. Eur. J. 2004, 10, 5087 – 5110
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5099

H.-G. Schmalz et al.
FULL PAPER
140.3(C2), 143.3(
CH=CH2), 117.7 (CH=CH2), 97.3(C8), 87.61 (C)3,
12.7, J2 =J3 =6.8 Hz, 1H; H-4a), 2.03(s, 1H; C H3COO), 1.50 ppm (ddd,
J1 =12.7, J2 =J3 =7.7 Hz, 1H; H-4b); 13C NMR (63MHz, CDCl 3): d=
170.0 (C=O), 150.2 (C1), 134.2 (CH=CH2), 122.6 (C2), 117.4 (CH=CH2),
96.8 (C8), 84.1 (C3), 72.6 (C6), 68.0 (CH2CH=CH2), 45.0 (C5), 39.0 (C4),
72.1 (C6), 68.3( CH2CH=CH2), 46.4 (C5), 43.9 (C4), ꢁ0.6 ppm (SiC); IR
ꢁ
ꢁ
(ATR): n˜ =3437 (m, O H), 2952 (s, C H), 1657 (m, C=C), 1324 (s), 1245
ꢁ1
ꢁ
(s, C O), 1107 (s), 1064 (s), 989 (s), 834 (s), 753 cm (s); MS (EI,
70 eV): m/z (%): 253(1) [ MꢁH]+, 197 (22) [MꢁC3H5O]+, 73(100); ele-
mental analysis: calcd (%) for C13H22O3Si: C 61.38, H 8.72; found: C
61.37, H 8.57.
ꢁ
21.1 ppm (CH3COO); IR (ATR): n˜ =2973(m, C H), 1732 (s, C=O),
ꢁ1
ꢁ
1362 (s), 1232 (s, C O), 1152 (s), 1065 (s), 1023(s), 991 (s), 891 cm (s);
MS (EI, 70 eV): m/z (%): 225 (2) [M+H]+, 167 (42) [MꢁC3H5O]+, 94
(100), 66 (74); elemental analysis: calcd (%) for C12H16O4: C 64.27, H
7.19; found: C 64.12, H 7.13.
Alternative method for the reduction of ketone 11b (l-Selectride reduc-
tion): A 1m solution of l-Selectride in THF (750 mL) was added dropwise
at ꢁ788C under argon to a solution of ketone 11b (126 mg, 0.5 mmol) in
dry THF (3mL) and the mixture was stirred for 6 h at ꢁ788C followed
by 15 h at RT. The reaction was quenched by addition of MeOH (2 mL),
2m NaOH (6 mL), 30% H2O2 (aq, 12 mL), and finally MTBE (20 mL).
The resulting mixture was stirred at RT for 1.5 h. The aqueous phase was
extracted with MTBE (2ꢁ30 mL) and the combined organic phases were
washed with saturated NaHCO3 (20 mL) and brine (20 mL). After drying
(MgSO4) and removal of the solvent the residue was purified by flash
chromatography (EtOAc/CyHex 1:2) to give the alcohol 18 as a colorless
oil (105 mg, 83%, d.r. >98:2).
(+)-(3S,5R,8S)-Acetic acid 8-allyloxy-7-oxa-[3.3.0]-bicyclooct-1-ene-3-yl
ester (ent-21a): By following the method described for ester 21a, alcohol
ent-20 (2.37 g, 13 mmol) was converted into ester ent-21a, which was ob-
tained as a colorless oil (2.77 g, 95%). [a]2D0 =+179.1 (c=0.45 in CHCl3),
[a]25046 =+205.6.
(ꢁ)-(3R,5S,8R)-Carbonic acid 8-allyloxy-7-oxa-[3.3.0]-bicyclooct-1-ene-3-
yl ester methyl ester (21b): Pyridine (5 mL) and methyl chloroformate
(1.27 mL, 16.5 mmol) were added to a solution of alcohol 20 (1.00 g,
5.48 mmol) in CH2Cl2 (75 mL) at 08C and the mixture was stirred for 1 h
under argon. The reaction was quenched with water (50 mL) and stirred
for an additional 30 min. The phases were separated and the aqueous
phase was extracted with CH2Cl2 (3ꢁ50 mL). The combined organic
phases were washed with brine (50 mL) and dried (MgSO4), then the sol-
vent was removed under reduced pressure. After purification by flash
chromatography (CyHex/EtOAc 4:1), compound 21b was obtained in
(+)-(3S,5R,8S)-8-Allyloxy-2-trimethylsilyl-7-oxa-[3.3.0]-bicyclooct-1-ene-
3-ol (ent-18): By following the reduction method described above (Luche
conditions), ketone ent-11b (10.08 g, 40 mmol) was converted into alco-
hol ent-18 (10.2 g, 99%). [a]2D0 =+250.2 (c=0.59 in CHCl3).
(ꢁ)-(3R,5S,8R)-8-Allyloxy-7-oxa-[3.3.0]-bicyclooct-1-ene-3-ol
(20):
92% yield (1.21 g, 5.05 mmol). Rf =0.40 (EtOAc/CyHex 1:4); [a]D20
=
tBuOK (4.6 g, 40.7 mmol) was added to solution of 18 (8.62 g,
a
ꢁ141.6 (c=0.820 in CHCl3), [a]25406 =ꢁ168.8; H NMR (250 MHz, CDCl3):
1
33.9 mmol) in DMSO/H2O (19:1, 100 mL) at RT and the color of the
mixture turned immediately to brown. After stirring for 30 min at RT the
mixture was diluted by addition of water (200 mL) and extracted with
EtOAc (4ꢁ100 mL). The combined organic phases were washed with
water (3ꢁ100 mL) and brine (100 mL), then dried (MgSO4). The solvent
was removed under reduced pressure. The product 20, obtained as a col-
orless oil (5.03g, 82%), was pure according to 1H NMR spectroscopy
and TLC and therefore no further purification was necessary. Rf =0.20
(EtOAc/CyHex 1:1); [a]D20 =ꢁ236.4 (c=0.77 in CHCl3), [a]25406 =ꢁ282.1;
1H NMR (250 MHz, CDCl3): d=5.85 (tdd, J1 =17.2, J2 =10.3, J3 =5.4 Hz,
1H; CH=CH2), 5.70 (m, 1H; H-2), 5.36 (s, 1H; H-8), 5.22 (tdd, J1 =17.2,
J2 =1.6, J3 =1.2 Hz, 1H; CH=CH Htrans), 5.13/5.12 (m/tdd, J1 =10.3, J2 =
1.6, J3 =1.2 Hz, 2H; H-3/CH=CH Hcis), 4.18 (dd, J1 =J2 =8.2 Hz, 1H; H-
6a), 4.12 (tdd, J1 =12.6, J2 =5.3, J3 =1.6 Hz, 1H; CHHa CH=CH2), 3.96
(tdd, J1 =12.6, J2 =6.1, J3 =1.6 Hz, 1H; CHHb CH=CH2), 3.38 (dd, J1 =
J2 =7.1 Hz, 1H; H-6b), 3.20 (m, 1H; H-5), 2.66 (ddd, J1 =12.4, J2 =6.3,
J3 =6.1 Hz, 1H; H-4a), 2.11 (brs, 1H; OH), 1.29 ppm (ddd, J1 =12.3, J2 =
J3 =8.0 Hz, 1H; H-4b); 13C NMR (63MHz, CDCl 3): d=147.9 (C1), 134.0
(CH=CH2), 126.8 (C2), 117.3(CH =CH2), 96.8 (C8), 82.2 (C3), 72.7 (C6),
67.8 (CH2CH=CH2), 44.9 (C5), 42.9 ppm (C4); IR (ATR): n˜ =3396 (w,
d=5.95–5.84 (m, 2H; H-3, CH=CH2), 5.76 (m, 1H; H-2), 5.40 (s, 1H; H-
ꢁ
8), 5.25 (ddt, J1 =17.2, J2 =3.2, J3 =1.2 Hz, 1H; CH=CH Htrans), 5.15
ꢁ
(ddt, J1 =10.4, J2 =3.0, J3 =1.5 Hz, 1H; CH=CH Hcis), 4.23(dd, J1 =J2 =
ꢁ
8.1 Hz, 1H; H-6a), 4.16 (ddt, J1 =12.7, J2 =5.4, J3 =1.4 Hz, 1H; CHHa
CH=CH2), 3.99 (ddt, J1 =12.7, J2 =6.0, J3 =1.3Hz, 1H; CH Hb CH=
ꢁ
CH2), 3.75 (s, 1H; CH3OCO2), 3.43 (dd, J1 =J2 =7.9 Hz, 1H; H-6b), 3.34–
3.28 (m, 1H; H-5), 2.79 (ddd, J1 =12.7, J2 =J3 =6.7 Hz, 1H; H-4a),
1.57 ppm (ddd, J1 =12.7, J2 =J3 =7.6 Hz, 1H; H-4b); 13C NMR (63MHz,
CDCl3): d=155.0 (C=O), 150.6 (C1), 134.1 (CH=CH2), 122.1 (C2), 117.4
(CH=CH2), 96.7 (C8), 87.6 (C3), 72.4 (C6), 68.0 (CH2CH=CH2), 54.7
ꢁ
ꢁ
(CH3OCO2), 45.0 (C5), 38.6 ppm (C4); IR (ATR): n˜ =2952 (m, C H),
ꢁ
ꢁ
1740 (s, C=O), 1687 (m), 1441 (s), 1256 (s, C O), 1153(m), 1064 (m), 975
(s), 791 cmꢁ1 (m); MS (EI, 70 eV): m/z (%): 240 (3) [M]+, 239 (13), 183
(57), 134 (36), 119 (23), 107 (28), 95 (23), 79 (100), 67 (39), 59 (58);
HRMS (EI): calcd for C12H16O5: 240.100 [M]+; found: 240.100.
ꢁ
ꢁ
Pd-catalyzed introduction of nucleobases
Protocol A: A suspension of a pyrimidine nucleobase (3.3 mmol) and
NaH (120 mg, 3mmol, 60% dispersion in mineral oil) in dry, degassed
DMSO (20 mL) was heated to 708C for 30 min under argon to give a
clear solution. After cooling to RT, [Pd(PPh3)4] (116 mg, 100 mmol,
5 mol%), PPh3 (58 mg, 220 mmol, 11 mol%) and 21a (448 mg, 2 mmol,
unless stated otherwise) in dry, degassed THF (4 mL) were added under
argon and the resulting mixture was stirred at 708C (508C for adenine)
for 16 h. After cooling to RT, the black mixture was filtered and washed
with CH2Cl2. The filtrate was washed with brine (4ꢁ25 mL) and dried
(MgSO4), then the solvent was evaporated. The residue was purified by
flash chromatography (EtOAc/CyHex 1:4!4:1). The purity of products
ꢁ
ꢁ
ꢁ
O H), 2920 (s, C H), 1646 (w, C=C), 1295 (m, C O), 1033 (s), 985 (s),
823cm ꢁ1 (s); MS (EI, 70 eV): m/z (%): 183(4) [ M+H]+, 125 (13)
[MꢁC3H5O]+, 95 (82), 83(64), 69 (60), 66 (98), 55 (100).
(+)-(3S,5R,8S)-8-Allyloxy-7-oxa-[3.3.0]-bicyclooct-1-ene-3-ol (ent-20): By
following the desilylation method described for alcohol 20, alcohol ent-18
(4.32 g, 17 mmol) was converted into alcohol ent-20 (2.49 g, 81%). [a]D20
+231.5 (c=0.69 in CHCl3), [a]25406 =+276.1.
=
(ꢁ)-(3R,5S,8R)-Acetic acid 8-allyloxy-7-oxa-[3.3.0]-bicyclooct-1-ene-3-yl
ester (21a): Ac2O (4.2 mL, 44 mmol) was added at RT to a stirred solu-
tion of 20 (3.64 g, 20 mmol), Et3N (3.6 mL, 24 mmol), and DMAP
(300 mg, 2.4 mmol) in CH2Cl2 (80 mL). The resulting mixture was stirred
for 1 h at RT and was then quenched by addition of saturated NaHCO3
(50 mL). The water phase was extracted with CH2Cl2 (3ꢁ50 mL) and the
combined organic layers were washed with saturated NaHCO3 (2ꢁ
50 mL) and brine (50 mL), dried (MgSO4), and concentrated. The residue
was purified by flash chromatography (EtOAc/CyHex 1:4) to give the
product 21a as a colorless oil (4.42 g, 99%). Rf =0.53(EtOAc/CyHex
1:1); [a]2D0 =ꢁ183.6 (c=1.375 in CHCl3), [a]25406 =ꢁ218.6; 1H NMR
(250 MHz, CDCl3): d=5.95 (m, 1H; H-3), 5.87 (ddt, J1 =17.2, J2 =10.3,
J3 =5.4 Hz, 1H; CH=CH2), 5.73(m, 1H; H-2), 5.41 (s, 1H; H-8), 5.26
1
10 was measured by H NMR spectroscopy.
Modifications: For cytosine: N4-benzoylcytosine (2.2 equiv) and NaH
(2 equiv) were used. For adenine: adenine (1.5 equiv) and Cs2CO3
(1.5 equiv) were utilized with heating to 508C for 30 min. For guanine:
N2-acetyl-O-diphenylcarbamoylguanine[45] (1.2 equiv) and pempidine
(2.3equiv) were dissolved in dry, degassed DMSO and stirred at RT for
5 min before use.
Protocol B: P(iPrO)3 (68 mL, 95%, 280 mmol, 14 mol%) was added to a
solution of [Pd(dba)2] (23mg, 40 mmol, 2 mol%) in dry, degassed THF
(4 mL) at RT under argon. (The color of mixture changed from red to
green.) The prepared solution of the nucleobase salt (see protocol A) in
dry, degassed DMSO (20 mL) and a solution of acetate 21a (448 mg,
2 mmol, unless stated otherwise) in dry, degassed THF (4 mL) were
added to the catalyst mixture at RT under argon. The resulting mixture
was heated to 708C (508C for adenine) for 16 h. After cooling to RT, the
same workup as that described in protocol A was carried out.
ꢁ
(ddt, J1 =17.2, J2 =1.6, J3 =1.2 Hz, 1H; CH=CH Htrans), 5.17 (ddt, J1 =
10.3, J2 =1.6, J3 =1.3Hz, 1H; CH =CH Hcis), 4.25 (dd, J1 =J2 =8.0 Hz,
1H; H-6a), 4.18 (ddt, J1 =12.4, J1 =5.4, J1 =1.6 Hz, 1H; CHHa CH=
CH2), 3.96 (ddt, J1 =12.4, J2 =6.1, J3 =1.4 Hz, 1H; CHHb CH=CH2),
ꢁ
ꢁ
ꢁ
3.44 (dd, J1 =J2 =7.91 Hz, 1H; H-6b), 3.32 (m, 1H; H-5), 2.77 (ddd, J1 =
5100
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5087 – 5110

Carbocyclic Nucleoside Analogues
5087 – 5110
ꢁ
ꢁ
Protocol C: dppp (87 mg, 0.210 mmol, 10.5 mol%) was added to a solu-
tion of [Pd2(dba)3] (46 mg, 0.05 mmol, 2.5 mol%) in dry, degassed DMF
(10 mL) at RT under argon. The solution was stirred for 5 min. Carbon-
ate 21b (481 mg, 2 mmol, unless otherwise stated) in DMF (2 mL) and
the nucleobase (1.5 equiv) in DMF (2 mL) were added to the mixture.
After stirring at RT for 16 h, the reaction was quenched by addition of
water (40 mL). The layers were separated and the aqueous phase was ex-
tracted with EtOAc (5ꢁ30 mL). The combined organic layers were
washed with water (3ꢁ30 mL) and brine (30 mL), then dried. Finally, the
solvent was removed under reduced pressure. The residue was purified
by flash chromatography.
(C5’), 40.3ppm (C4 ’); IR (ATR): n˜ =3155 (w, N H), 3016 (m, N H),
ꢁ
2890 (w, C H), 1730 (s), 1704 (s, C=O), 1686 (s, C=O), 1653(s, C =C),
ꢁ1
ꢁ
1243(s, C O), 987 cm (s); MS (EI, 70 eV): m/z (%): 709 (82), 677
(100), 655 (13) [2M+Na]+, 317 (58) [M+H]+, 237 (80); elemental analy-
sis: calcd (%) for C13H22O3Si: C 57.14, H 5.14, N 9.52; found: C 57.36, H
5.26, N 9.50.
(+)-(3’S,5’R,8’S)-1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-5-
fluoro-1H-pyrimidine-2,4-dione (ent-10b): When the general protocol B
for the Pd-catalyzed introduction of nucleobases was followed, 5-fluo-
rouracil and ent-21a afforded ent-10b (468 mg, 74%, 93% purity) as a
white solid. The product ent-10b was obtained in 99% purity after crys-
tallization from EtOAc/Hex. [a]2D0 =+259.4 (c=0.48 in CHCl3), [a]25046
+314.4.
=
Synthesis of compounds of type 10 (Scheme 15)
(ꢁ)-(3’R,5’S,8’R)-1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-1H-
pyrimidine-2,4-dione (10a): When the general protocol A for the Pd-cat-
alyzed introduction of nucleobases was followed, uracil and 21a afforded
(ꢁ)-(3’R,5’S,8’R)-1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-5-
bromo-1H-pyrimidine-2,4-dione (10c): When the general protocol A for
the Pd-catalyzed introduction of nucleobases was followed, 5-bromoura-
cil and 21a afforded 10c (590 mg, 83%, 99% purity) as a white solid.
M.p. 144–1468C, Rf =0.43(EtOAc/CyHex 4:1); [ a]2D0 =ꢁ160.6 (c=0.36 in
CHCl3), [a]25406 =ꢁ194.0; 1H NMR (250 MHz, CDCl3): d=8.81 (brs, 1H;
NH), 7.47 (s, 1H; H-6), 6.03(m, 1H; H-3 ’), 5.89 (tdd, J1 =5.4, J2 =17.1,
J3 =10.2 Hz, 1H; CH=CH2), 5.60 (m, 1H; H-2’), 5.51 (s, 1H; H-8’), 5.28
ꢁ
(tdd, J1 =1.2, J2 =17.1, J3 =1.5 Hz, 1H; CH=CH Htrans), 5.18 (tdd, J1 =
ꢁ
1.2, J2 =10.2, J3 =1.5 Hz, 1H; CH=CH Hcis), 4.29 (dd, J1 =J2 =7.8 Hz,
ꢁ
1H; H-6’a), 4.21 (tdd, J1 =1.5, J2 =12.7, J3 =5.4 Hz, 1H; CHHa CH=
CH2), 4.18 (tdd, J1 =1.3, J2 =12.7, J3 =5.4 Hz, 1H; CHHb CH=CH2),
ꢁ
3.54 (dd, J1 =7.8, J2 =7.6 Hz, 1H; H-6’b), 3.45 (m, 1H; H-5’), 2.90 (ddd,
J1 =12.4, J2 =J3 =6.8 Hz, 1H; H-4’a), 1.42 ppm (ddd, J1 =12.4, J2 =8.3,
J3 =8.8 Hz, 1H; H-4’b); 13C NMR (63MHz, CDCl 3): d=159.0 (C4), 152.6
(C1’), 150.0 (C2), 140.0 (C6), 133.7 (CH=CH2), 120.2 (C2’), 117.3(CH =
CH2), 97.1 (C5), 96.1 (C8’), 71.6 (C6’), 67.7 (CH2CH=CH2), 65.8 (C3’),
Scheme 15. Numbering used for compounds of type 10, NB=various nu-
cleobases.
10a (330 mg, 56%, 94% purity) as a white solid. M.p. 146–1508C; Rf =
0.08 (EtOAc/CyHex 4:1); [a]2D0 =ꢁ247.0 (c=0.495 in CHCl3), [a]25046
=
ꢁ
45.3(C5 ’), 40.4 ppm (C4’); IR (ATR): n˜ =3167/3046 (w, N H), 2975 (w,
ꢁ297.8; 1H NMR (250 MHz, CDCl3): d=10.09 (brs, 1H; NH), 7.17 (d,
J=8.0 Hz, 1H; H-6), 6.04 (dd, J1 =7.2, J2 =8.7 Hz, 1H; H-3’), 5.86 (tdd,
J1 =5.4, J2 =17.2, J3 =10.4 Hz, 1H; CH=CH2), 5.70 (d, J=8.0 Hz, 1H; H-
5), 5.57 (m, 1H; H-2’), 5.43(s, 1H; H-8 ’), 5.23(tdd, J1 =1.2, J2 =17.2, J3 =
ꢁ1
ꢁ
ꢁ
C H), 1691 (s, C=O), 1615 (m, C=C), 1242 cm (m, C O); MS (EI,
70 eV): m/z (%): 356 (4) [81BrM]+, 354 (4) [79BrM]+, 135 (55), 119 (51),
79 (100); HRMS (EI): calcd for C14H15BrN2O5: 354.022 [79BrM]+; found:
354.021.
ꢁ
1.6 Hz, 1H; CH=CH Htrans), 5.13(tdd, J1 =1.1, J2 =10.3, J3 =1.6 Hz, 1H;
(+)-(3’S,5’R,8’S)-1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-5-
bromo-1H-pyrimidine-2,4-dione (ent-10c): When the general protocol A
for the Pd-catalyzed introduction of nucleobases was followed, 5-bro-
mouracil and ent-21a afforded ent-10c (501 mg, 71%, 99% purity) as a
white solid. [a]D20 =+158.8 (c=0.56 in CHCl3), [a]25406 =+192.5.
ꢁ
CH=CH Hcis), 4.24 (dd, J1 =J2 =7.4 Hz, 1H; H-6’a), 4.05 (tdd, J1 =1.6,
ꢁ
J2 =12.7, J3 =5.4 Hz, 1H; CHHa CH=CH2), 4.04 (tdd, J1 =1.3, J2 =12.6,
J3 =6.1 Hz, 1H; CHHb CH=CH2), 3.47 (dd, J1 =J2 =7.6 Hz, 1H; H-6’b),
ꢁ
3.44 (m, 1H; H-5’), 2.84 (ddd, J1 =12.5, J2 =7.0, J3 =6.8 Hz, 1H; H-4’a),
1.37 ppm (ddd, J1 =12.5, J2 =8.3, J3 =7.6 Hz, 1H; H-4’b); 13C NMR
(63MHz, CDCl 3): d=163.5 (C4), 152.4 (C1’), 150.8 (C2), 140.4 (C6),
133.8 (CH=CH2), 120.6 (C2’), 117.5 (CH=CH2), 103.0 (C5), 96.2 (C8’),
71.8 (C6’), 67.9 (CH2CH=CH2), 65.5 (C3’), 45.4 (C5’), 40.4 ppm (C4’); IR
(ꢁ)-(3’R,5’S,8’R)-1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-5-
methyl-1H-pyrimidine-2,4-dione (10d): When the general protocol A for
the Pd-catalyzed introduction of nucleobases was followed, thymine and
21a afforded 10d (140 mg in 99% purity and 250 mg in 89% purity, 63%
total yield) as a white solid. M.p. 155–1578C; Rf =0.15 (EtOAc/CyHex
4:1); [a]2D0 =ꢁ234.2 (c=0.47 in CHCl3), [a]25406 =ꢁ282.8; 1H NMR
(250 MHz, CDCl3): d=8.63(brs, 1H; N H), 6.96 (dq, J1 =1.3, J2 =1.0 Hz,
1H; H-6), 6.04 (dddd, J1 =2.2, J2 =1.3, J3 =6.8, J4 =8.5 Hz, 1H; H-3’),
5.91 (tdd, J1 =5.4, J2 =17.2, J3 =10.3Hz, 1H; C H=CH2), 5.60 (m, 1H; H-
2’), 5.50 (s, 1H; H-8’), 5.29 (tdd, J1 =1.2, J2 =17.2, J3 =1.6 Hz, 1H; CH=
ꢁ
ꢁ
(ATR): n˜ =3180/3051 (w, N H), 2970 (m, C H), 1681 (s, C=O), 1626 (w,
C=C), 1242 cmꢁ1 (m, C O); MS (EI, 70 eV): m/z (%): 277 (8) [M+H] ,
+
ꢁ
276 (5) [M]+, 219 (78) [MꢁC3H5O]+, 205 (100), 134 (52), 79 (57).
(+)-(3’S,5’R,8’S)-1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-1H-
pyrimidine-2,4-dione (ent-10a): When the general protocol A for the Pd-
catalyzed introduction of nucleobases was followed, uracil and ent-21a
afforded ent-10a (379 mg, 65%, 94% purity) as a white solid. [a]D20
+230.7 (c=0.59 in CHCl3), [a]25406 =+278.2.
=
ꢁ
ꢁ
CH Htrans), 5.20 (tdd, J1 =1.3, J2 =10.3, J3 =1.7 Hz, 1H; CH=CH Hcis),
4.30 (dd, J1 =J2 =8.1 Hz, 1H; H-6’a), 4.20 (tdd, J1 =1.6, J2 =12.6, J3 =
5.4 Hz, 1H; CHHa CH=CH2), 4.04 (tdd, J1 =1.3, J2 =12.6, J3 =6.1 Hz,
(ꢁ)-(3’R,5’S,8’R)-1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-5-
ꢁ
fluoro-1H-pyrimidine-2,4-dione (10b): When the general protocol B for
the Pd-catalyzed introduction of nucleobases was followed, 5-fluorouracil
and 21a afforded 10b (460 mg, 73%, 93% purity) as a white solid. The
product 10b was obtained in 99% purity after crystallization from
ꢁ
1H; CHHb CH=CH2), 3.53 (dd, J1 =J2 =7.8 Hz, 1H; H-6’b), 3.45 (m,
1H; H-5’), 2.86 (ddd, J1 =12.4, J2 =7.0, J3 =6.8 Hz, 1H; H-4’a), 1.91 (d,
J=1.0 Hz, 1H; CH3), 1.42 ppm (ddd, J1 =12.4, J2 =J3 =7.7 Hz, 1H; H-
4’b); 13C NMR (63MHz, CDCl 3): d=163.4 (C4), 152.3 (C1’), 150.5 (C2),
136.1 (C6), 134.0 (CH=CH2), 120.9 (C2’), 117.7 (CH=CH2), 111.7 (C5),
96.4 (C8’), 72.0 (C6’), 68.1 (CH2CH=CH2), 65.4 (C3’), 45.5 (C5’), 40.5
EtOAc/Hex. M.p. 155–1578C; Rf =0.35 (EtOAc/CyHex 4:1); [a]D20
=
ꢁ254.5 (c=0.41 in CHCl3), [a]25406 =ꢁ306.9; 1H NMR (250 MHz, CDCl3):
d=8.47 (brs, 1H; NH), 7.24 (d, J=4.8 Hz, 1H; H-6), 6.04 (dd, J1 =J2 =
7.5 Hz, 1H; H-3’), 5.91 (tdd, J1 =5.6, J2 =17.2, J3 =10.3Hz, 1H; C H=
CH2), 5.59 (s, 1H; H-2’), 5.49 (s, 1H; H-8’), 5.28 (dd, J1 =17.2, J2 =
ꢁ
ꢁ
(C4’), 12.5 ppm (CH3); IR (ATR): n˜ =3171/3052 (w, N H), 2923(w, C
H), 1682 (s, C=O), 1246 cmꢁ1 (m, C O); MS (EI, 70 eV): m/z (%): 207
(20), 98 (21), 97 (42), 91 (23), 83 (35), 71 (23), 70 (28), 69 (48), 57 (62),
55 (100).
ꢁ
ꢁ
1.6 Hz, 1H; CH=CH Htrans), 5.20 (dd, J1 =10.3, J2 =1.2 Hz, 1H; CH=
ꢁ
CH Hcis), 4.30 (dd, J1 =J2 =7.7 Hz, 1H; H-6’a), 4.22 (dd, J1 =12.6, J2 =
(+)-(3’S,5’R,8’S)-1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-5-
methyl-1H-pyrimidine-2,4-dione (ent-10d): When the general protocol A
for the Pd-catalyzed introduction of nucleobases was followed, thymine
and ent-21a afforded ent-10d (295 mg, 47%, 92% purity) as a white
solid. [a]2D0 =+197.4 (c=0.49 in CHCl3), [a]25406 =+237.9.
ꢁ
5.3Hz, 1H; CH Ha CH=CH2), 4.04 (dd, J1 =12.6, J2 =6.1 Hz, 1H;
ꢁ
CHHb CH=CH2), 3.52 (dd, J1 =J2 =7.6 Hz, 1H; H-6’b), 3.50 (m, 1H; H-
5’), 2.90 (ddd, J1 =12.7, J2 =J3 =6.6 Hz, 1H; H-4’a), 1.41 ppm (ddd, J1 =
12.7, J2 =J3 =8.5 Hz, 1H; H-4’b); 13C NMR (63MHz, CDCl 3): d=156.4
(d, J(C,F)=27 Hz, C4), 153.5 (C1’), 149.0 (C2), 140.9 (d, J(C,F)=238 Hz,
C5), 133.9 (CH=CH2), 124.5 (d, J(C,F)=33 Hz, C6), 119.8 (C2’), 117.7
(CH=CH2), 96.3(C8 ’), 71.9 (C6’), 68.1 (CH2CH=CH2), 66.1 (C3’), 45.6
(ꢁ)-(3’R,5’S,8’R)-N-[1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-
2-oxo-1,2-dihydro-pyrimidin-4-yl]-benzamide (10e): When the general
Chem. Eur. J. 2004, 10, 5087 – 5110
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5101

H.-G. Schmalz et al.
FULL PAPER
ꢁ
protocol A for the Pd-catalyzed introduction of nucleobases was fol-
lowed, N4-benzoylcytosine and 21a (114 mg, 0.5 mmol) afforded 10e
(98 mg, 52%, 99% purity) as a white solid. M.p. 162–1648C; Rf =0.22
(EtOAc/CyHex 4:1); [a]D20 =ꢁ205 (c=0.065 in CHCl3), [a]25406 =ꢁ256;
1H NMR (250 MHz, CDCl3): d=7.64–7.31 (m, 7H; H-Ph, H-5, H-6), 6.12
(m, 1H; H-3’), 5.89 (dddd, J1 =5.4, J2 =6.1, J3 =17.1, J4 =10.2 Hz, 1H;
CH=CH2), 5.62 (m, 1H; H-2’), 5.43(s, 1H; H-8 ’), 5.20 (tdd, J1 =1.1, J2 =
J3 =6.1 Hz, 1H; CHHb CH=CH2), 3.56 (dd, J1 =7.1, J2 =7.5 Hz, 1H; H-
6’b), 3.51 (m, 1H; H-5’), 2.99 (ddd, J1 =12.4, J2 =7.1, J3 =6.6 Hz, 1H; H-
4’a), 1.75 ppm (ddd, J1 =12.4, J2 =8.6, J3 =9.1 Hz, 1H; H-4’b); 13C NMR
(63MHz, CDCl 3): d=155.8 (C6), 152.9 (C2), 151.9 (C1’), 149.5 (C4),
138.2 (C8), 133.9 (CH=CH2), 121.3(C2 ’), 119.6 (C5), 117.6 (CH=CH2),
96.5 (C8’), 72.0 (C6’), 68.1 (CH2CH=CH2), 64.1 (C3’), 45.9 (C5’),
ꢁ
ꢁ
41.9 ppm (C4’); IR (ATR): n˜ =3315/3162 (m, N H), 2970 (w, C H), 1644
(s, C=C), 1596 (s), 1247 cmꢁ1 (m, C O); MS (EI, 70 eV): m/z (%): 299
ꢁ
17.1, J3 =1.6 Hz, 1H; CH=CH Htrans), 5.10 (tdd, J1 =1.2, J2 =10.2, J3 =
ꢁ
(3) [M]+, 258 (61) [MꢁC3H5]+, 242 (57) [MꢁC3H5O]+, 164 (63), 136
(100), 135 (63), 79 (39); HRMS (EI): calcd for C15H17N5O2: 299.138
[M]+; found: 299.139.
ꢁ
1.6 Hz, 1H; CH=CH Hcis), 4.21 (dd, J1 =7.1, J2 =5.7 Hz, 1H; H-6’a), 4.12
ꢁ
(tdd, J1 =1.5, J2 =12.7, J3 =5.4 Hz, 1H; CHHa CH=CH2), 4.18 (tdd, J1 =
ꢁ
1.4, J2 =12.7, J3 =6.0 Hz, 1H; CHHb CH=CH2), 3.45 (dd, J1 =7.1, J2 =
7.5 Hz, 1H; H-6’b), 3.40 (m, 1H; H-5’), 2.93(ddd, J1 =12.5, J2 =J3 =
6.5 Hz, 1H; H-4’a), 1.35 ppm (ddd, J1 =12.5, J2 =J3 =8.8 Hz, 1H; H-4’b);
13C NMR (63MHz, CDCl 3): d=161.8 (PhC=O), 153.0 (C1’), 145.1 (C2),
136.1 (C6), 134.0 (CH=CH2), 133.2/130.0/129.0/127.6 (all Ph), 120.7 (C2’),
117.7 (CH=CH2), 111.7 (C5), 96.4 (C8’), 72.0 (C6’), 68.1 (CH2CH=CH2),
67.3(C3 ’), 45.9 (C5’), 41.5 ppm (C4’); IR (ATR): n˜ =3215/3144/3061 (w,
(+)-(3’S,5’R,8’S)-9-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-9H-
purin-6-ylamine (ent-10g): When the general protocol A for the Pd-cata-
lyzed introduction of nucleobases was followed, adenine and ent-21a af-
forded ent-10g (324 mg, 54%, 99% purity) as a yellow waxy solid (73%
yield was achieved for a racemic version on a 5 mmol scale[12]). [a]D20
+164.0 (c=0.45 in MeOH), [a]25406 =+195.0.
=
ꢁ
ꢁ
N H), 2942 (w, C H), 1690 (s, C=O), 1658 (s, C=N), 1620 (s, C=C), 1556
(ꢁ)-(3’R,5’S,8’R)-9-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-9H-
6-chloropurine (10h): When the general protocol C for the Pd-catalyzed
introduction of nucleobases was followed, 6-chloropurine and 21b
(1.06 g, 4.4 mmol) afforded 10h (880 mg, 63%, >99% purity) as a white,
crystalline solid. M.p. 147–1498C; Rf =0.50 (EtOAc); [a]2D0 =ꢁ92.2 (c=
0.60 in MeOH), [a]25406 =ꢁ99.5; 1H NMR (250 MHz, CDCl3): d=8.73(s,
1H; H-2), 8.17 (s, 1H; H-8), 6.15–6.09 (m, 1H; H-3’), 5.92 (dddd, J1 =5.4,
J2 =6.0, J3 =17.3, J4 =10.3Hz, 1H; C H=CH2), 5.85 (m, 1H; H-2’), 5.54 (s,
(s), 1483 (s), 1382 (s), 1301 (s), 1244 cmꢁ1 (s, C O); MS (EI, 70 eV): m/z
ꢁ
(%): 379 (10) [M]+, 322 (32) [MꢁC3H5O]+, 216 (27), 105 (100), 79 (21),
77 (43); HRMS (ESI): calcd for C21H22N3O4: 380.161 [M+H]+; found:
380.161.
(+)-(3’S,5’R,8’S)-N-[1-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-
2-oxo-1,2-dihydro-pyrimidin-4-yl]-benzamide (ent-10e): When the gener-
al protocol A for the Pd-catalyzed introduction of nucleobases was fol-
lowed, N4-benzoylcytosine and ent-21a afforded ent-10e (490 mg, 65%,
ꢁ
1H; H-8’), 5.29 (tdd, J1 =1.5, J2 =17.3, J3 =1.6 Hz, 1H; CH=CH Htrans),
99% purity) as a white solid. [a]2D0 =+229.1 (c=0.43in CHCl 3), [a]25046
+280.5.
=
ꢁ
5.20 (tdd, J1 =1.2, J2 =10.3, J3 =1.6 Hz, 1H; CH=CH Hcis), 4.33 (dd, J1 =
J2 =6.8 Hz, 1H; H-6’a), 4.23(tdd, J1 =1.5, J2 =12.7, J3 =5.4 Hz, 1H;
(ꢁ)-(3’R,5’S,8’R)-Diphenylcarbamic acid 2-acetylamino-9-(8’-allyloxy-7’-
oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-9H-purin-6-yl ester (10 f): When the
general protocol B for the Pd-catalyzed introduction of nucleobases was
followed, the N2-acetyl-O-diphenylcarbamoylguanine derivative and 21a
(896 mg, 4 mmol) afforded 10 f (1.67 g, 76%, 99% purity) as a pale-
yellow solid. M.p. 90–948C; Rf =0.68 (EtOAc/MeOH 4:1); [a]2D0 =ꢁ75.1
(c=0.58 in CHCl3), [a]52406 =ꢁ90.1; 1H NMR (250 MHz, CDCl3): d=8.02
(s, 1H; NH), 7.94 (s, 1H; H-8), 7.40–7.22 (m, 10H; 2ꢁPh), 5.99–5.86 (m,
2H; H-3’, CH=CH2), 5.81 (s, 1H; H-2’), 5.51 (s, 1H; H-8’), 5.30 (tdd, J1 =
ꢁ
ꢁ
CHHa CH=CH2), 4.06 (tdd, J1 =1.3, J2 =12.7, J3 =6.0 Hz, 1H; CHHb
CH=CH2), 3.62 (dd, J1 =J2 =7.6 Hz, 1H; H-6’b), 3.60 (m, 1H; H-5’), 3.04
(ddd, J1 =12.5, J2 =J3 =6.5 Hz, 1H; H-4’a), 1.91–1.80 ppm (m, 1H; H-
4’b); 13C NMR (63MHz, CDCl 3): d=151.9 (C2), 151.3/151.1/150.5 (C4/
C6/C1’), 143.2 (C8), 133.9 (CH=CH2), 128.8 (C5), 120.3(C2 ’), 117.7
(CH=CH2), 96.4 (C8’), 71.9 (C6’), 68.2 (CH2CH=CH2), 65.0 (C3’), 46.0
ꢁ
(C5’), 41.5 ppm (C4’); IR (ATR): n˜ =3361 (m), 2870 (m, C H), 1684 (m,
C=C), 1588 (s), 1556 (s), 1332 (s), 1202 (s), 1039 (s), 951(s), 635 cmꢁ1
(m); MS (EI, 70 eV): m/z (%): 318 (15) [M]+, 317 (19), 261 (50)
[MꢁC3H5O]+, 219 (23), 164 (94), 155 (51), 135 (38), 79 (100), 65 (41);
HRMS (EI): calcd for C15H15ClN4O2: 318.088 [M]+; found: 318.088.
ꢁ
1.7, J2 =17.1, J3 =3.2 Hz, 1H; CH=CH Htrans), 5.20 (tdd, J1 =1.3, J2 =
ꢁ
10.3, J3 =2.5 Hz, 1H; CH=CH Hcis), 4.32 (dd, J1 =J2 =6.4 Hz, 1H; H-
ꢁ
6’a), 4.22 (tdd, J1 =1.3, J2 =12.5, J3 =5.3Hz, 1H; CH Ha CH=CH2), 4.06
(tdd, J1 =1.3, J2 =12.7, J3 =6.3Hz, 1H; CH Hb CH=CH2), 3.58 (dd, J1 =
J2 =7.7 Hz, 1H; H-6’b), 3.55 (m, 1H; H-5’), 2.96 (ddd, J1 =13.0, J2 =J3 =
6.4 Hz, 1H; H-4’a), 2.51 (s, 3H; CH3), 1.87 ppm (ddd, J1 =13.2, J2 =J3 =
8.6 Hz, 1H; H-4’b); 13C NMR (63MHz, CDCl 3): d=170.8 (CH3C=O),
General one-pot procedure for hydrolysis and silylation: A solution of
10a–f or 10h–l (1 mmol, unless otherwise stated) and PPTS (76 mg,
300 mmol) in wet acetone (10 mL) was stirred under reflux for 3h. The
solvent was evaporated and the flask was flushed with argon (3times).
Dry pyridine (3mL) was added and, after stirring at RT for 5 min,
ThxMe2SiCl (310 mL, 1.5 mmol; used for 10a–f and 10h) or tBuPh2SiCl
(79 mL, 300 mmol; used for 200 mmol of 10i–l) was added. After stirring
at RT for 16 h, the reaction was quenched by addition of saturated
NaHCO3 (20 mL). After stirring the resulting mixture at RT for 30 min,
the water phase was extracted with EtOAc (4ꢁ20 mL) and the combined
organic layers were washed with 10% HCl (3ꢁ20 mL), saturated
NaHCO3 (20 mL), and brine (40 mL), dried (MgSO4), and concentrated.
The residue was then purified by flash chromatography to yield to 23a–f
and 23h–l.
ꢁ
ꢁ
156.3/152.0/150.4 (C2/C6/O C=O), 154.6 (C4), 152.1 (C1’), 142.1 (C8),
141.7/129.2/127.0 (br, all Ph), 134.0 (CH=CH2), 121.0 (C5), 120.8 (C2’),
117.7 (CH=CH2), 96.5 (C8’), 72.0 (C6’), 68.2 (CH2CH=CH2), 65.0 (C3’),
ꢁ
45.9 (C5’), 41.3(C4 ’), 25.2 ppm (CH3); IR (ATR): n˜ =3262/3095 (w, N
ꢁ
H), 2977 (w, C H), 1739 (s, C=O), 1687 (m, C=O), 1619 (s, C=C), 1491
ꢁ1
(s), 1293(s), 1186 cm
(s); MS (ESI, 70 eV): m/z (%): 575 (100)
[M+Na]+, 553(6) [ M+H]+; HRMS (ESI): calcd for C30H28N6NaO5:
575.202 [M+Na]+; found: 575.201.
(+)-(3’S,5’R,8’S)-Diphenylcarbamic acid 2-acetylamino-9-(8’-allyloxy-7’-
oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-9H-purin-6-yl ester (ent-10 f): When
the general protocol B for the Pd-catalyzed introduction of nucleobases
was followed, the N2-acetyl-O-diphenylcarbamoylguanine derivative and
ent-21a (896 mg, 4 mmol) afforded ent-10 f (1.31 g in 99% purity and
Modifications: For adenine derivative 23g: 10g (0.8 mmol) and PPTS
(2 equiv) were used for the hydrolysis; ThxMe2SiCl (3.3 equiv) and
DMAP (33 mg, 260 mmol, 33 mol%) in a solvent mixture consisting of
Et3N (0.4 mL) and CH2Cl2 (4 mL) were used for the silylation step.
388 mg in 84% purity, 76% total yield) as a pale-yellow solid. [a]D20
=
+82.8 (c=0.43in CHCl ), [a]25406 =+99.5.
3
Synthesis of compounds of type 23 (Scheme 16)
(ꢁ)-(3’R,5’S,8’R)-9-(8’-Allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)-9H-
purin-6-ylamine (10g): When the general protocol B for the Pd-catalyzed
introduction of nucleobases was followed, adenine and 21a afforded 10g
(313 mg, 52%, 99% purity) as a pale-yellow solid. M.p. 170–1728C; Rf =
20
546
0.32 (EtOAc/MeOH 4:1); [a]2D0 =ꢁ164.9 (c=0.45 in CHCl3), [a]
=
ꢁ196.6; 1H NMR (250 MHz, CDCl3): d=8.29 (s, 1H; H-2), 7.47 (s, 1H;
H-8), 6.42 (brs, 2H; NH2), 6.04 (tdd, J1 =2.0, J2 =7.3, J3 =8.6 Hz, 1H; H-
3’), 5.90 (dddd, J1 =5.4, J2 =6.1, J3 =17.1, J4 =10.2 Hz, 1H; CH=CH2),
5.83(m, 1H; H-2 ’), 5.51 (s, 1H; H-8’), 5.26 (tdd, J1 =1.4, J2 =17.1, J3 =
ꢁ
1.8 Hz, 1H; CH=CH Htrans), 5.17 (tdd, J1 =1.2, J2 =10.2, J3 =1.8 Hz, 1H;
ꢁ
CH=CH Hcis), 4.29 (dd, J1 =J2 =7.1 Hz, 1H; H-6’a), 4.19 (tdd, J1 =1.5,
Scheme 16. Numbering used for compounds of type 23, NB=various nu-
cleobases.
ꢁ
J2 =12.6, J3 =5.4 Hz, 1H; CHHa CH=CH2), 4.03(tdd, J1 =1.2, J2 =12.6,
5102
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5087 – 5110

Carbocyclic Nucleoside Analogues
5087 – 5110
ꢁ
ꢁ
(+)-(3R,5S)-3-(2’,4’-Dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-[dimethyl-
(1,1,2-trimethylpropyl)-silanyloxymethyl]-cyclopent-1-enecarbaldehyde
(23a): When the general hydrolysis/silylation procedure was followed,
10a (294 mg, 1 mmol, 94% purity) afforded the aldehyde 23a (309 mg,
82%) as a white solid. M.p. 115–1168C; Rf =0.24 (EtOAc/CyHex 4:1);
[a]2D0 =+59.3( c=0.62 in CHCl3), [a]52406 =+72.2; 1H NMR (250 MHz,
CDCl3): d=9.85 (s, 1H; HC=O), 8.78 (brs, 1H; NH), 7.47 (d, J1 =8.0 Hz,
1H; H-6’), 5.56 (dd, J1 =J2 =2.2 Hz, 1H; H-2), 5.90 (dddd, J1 =9.5, J2 =
7.1, J3 =J4 =2.2 Hz, 1H; H-3), 5.71 (dd, J1 =8.0, J2 =2.4 Hz, 1H; H-5’),
4.27 (dd, J1 =10.0, J2 =3.0 Hz, 1H; SiOCHa), 3.58 (dd, J1 =10.0, J2 =
2.5 Hz, 1H; SiOCHb), 3.18 (m, 1H; H-5), 2.79 (ddd, J1 =14.2, J2 =J3 =
9.5 Hz, 1H; H-4a), 1.82 (ddd, J1 =14.2, J2 =J3 =7.5 Hz, 1H; H-4b), 1.56
(septet, J=6.8 Hz, 1H; Me2CH), 0.81 (d, J=6.8 Hz, 6H; (CH3)2CH),
0.788/0.786 (2s, 6H; C(CH3)2), 0.042/0.036 ppm (2s, 6H; SiCH3);
13C NMR (63MHz, CDCl 3): d=188.9 (CH=O), 163.2 (C4’), 150.8 (C2’),
150.3(C1), 147.8 (C2), 141.4 (C6 ’), 103.2 (C5’), 62.2 (CH2OSi), 58.9 (C3),
44.3(C5), 34.0 (Me 2CH), 33.3 (C4), 25.4 (Me2CSi), 20.3/20.2 ((CH3)2CH),
18.5/18.4 ((CH3)2CSi), ꢁ3.5/ꢁ3.6 ppm ((CH3)2Si); IR (ATR): n˜ =3038 (w,
ꢁ3.7 ppm (CH3Si); IR (ATR): n˜ =3177/3046 (w, N H), 2954 (m, C H),
1704 (s, C=O), 1684 (s, C=O), 1617 (m, C=C), 1249 cmꢁ1 (m, C O); MS
ꢁ
(EI, 70 eV): m/z (%): 373 (95), 372 (28), 371 (100) [MꢁC6H13]+, 355 (34),
353 (32), 281 (92), 279 (89), 182 (58), 181 (90), 75 (31); HRMS (EI):
calcd for C13H16BrN2O4Si: 371.006 [MꢁC6H13]+; found: 371.005.
(ꢁ)-(3S,5R)-3-(5’-Bromo-2’,4’-dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-
[dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-cyclopent-1-enecarb-
aldehyde (ent-23c): When the general hydrolysis/silylation procedure was
followed, ent-23c (355 mg, 1 mmol) afforded the aldehyde ent-23c
(342 mg, 75%) as a white solid. [a]2D0 =ꢁ67.6 (c=0.53in CHCl 3), [a]25046
=
ꢁ82.7.
(+)-(3R,5S)-3-(5’-Methyl-2’,4’-dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-
[dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-cyclopent-1-enecarb-
aldehyde (23d): When the general hydrolysis/silylation procedure was
followed, 10d (290 mg, 1 mmol) afforded the aldehyde 23d (252 mg,
64%) as a white solid. M.p. 58–618C; Rf =0.26 (EtOAc/CyHex 4:1);
[a]2D0 =+28.8 (c=0.53in CHCl 3), [a]52406 =+35.4; 1H NMR (250 MHz,
CDCl3): d=10.06 (brs, 1H; NH), 9.81 (s, 1H; HC=O), 6.99 (q, J=
1.2 Hz, 1H; H-6’), 6.58 (m, 1H; H-2), 5.83(dddd, J1 =J2 =8.6, J3 =J4 =
2.4 Hz, 1H; H-3), 4.18 (dd, J1 =10.0, J2 =3.4 Hz, 1H; SiOCHa), 3.53 (dd,
J1 =10.0, J2 =2.4 Hz, 1H; SiOCHb), 3.10 (m, 1H; H-5), 2.65 (ddd, J1 =
13.4, J2 =J3 =8.8 Hz, 1H; H-4a), 1.85 (d, J=1.2 Hz, 3H; CH3), 1.80 (ddd,
J1 =13.4, J2 =J3 =8.4 Hz, 1H; H-4b), 1.51 (septet, J=7.1 Hz, 1H;
Me2CH), 0.83(d, J=7.1 Hz, 6H; (CH3)2CH), 0.793/0.790 (2s, 6H;
C(CH3)2), 0.058/0.057 ppm (2s, 6H; SiCH3); 13C NMR (63MHz, CDCl 3):
d=188.9 (CH=O), 164.1 (C4’), 151.1 (C2’), 149.8 (C1), 148.4 (C2), 136.2
(C6’), 111.8 (C5’), 61.4 (CH2OSi), 59.0 (C3), 44.2 (C5), 34.0 (Me2CH),
33.4 (C4), 25.1 (Me2CSi), 20.2/20.2 ((CH3)2CH), 18.4/18.4 ((CH3)2CSi),
ꢁ
ꢁ
N H), 2955 (m, C H), 1697 (s, C=O), 1680 (s, C=O), 1649 (s, C=C),
+
1248 cmꢁ1 (m, C O); MS (EI, 70 eV): m/z (%): 293(100) [ MꢁC6H13] ,
ꢁ
201 (55), 181 (62); HRMS (EI): calcd for C13H17N2O4Si: 293.096
[MꢁC6H13]+; found: 293.096.
(ꢁ)-(3S,5R)-3-(2’,4’-Dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-[dimethyl-
(1,1,2-trimethylpropyl)-silanyloxymethyl]-cyclopent-1-enecarbaldehyde
(ent-23a): When the general hydrolysis/silylation procedure was fol-
lowed, ent-10a (294 mg, 1 mmol, 94% purity) afforded the aldehyde ent-
23a (264 mg, 70%) as a white solid. [a]2D0 =ꢁ55.5 (c=0.45 in CHCl3),
[a]25046 =ꢁ67.7.
(+)-(3R,5S)-3-(5’-Fluoro-2’,4’-dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-
[dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-cyclopent-1-enecarb-
aldehyde (23b): When the general hydrolysis/silylation procedure was
followed, 10b (176 mg, 0.6 mmol) afforded the aldehyde 23b (173mg,
74%) as a white solid. M.p. 148–1498C; Rf =0.50 (EtOAc/CyHex 4:1);
[a]2D0 =+53.6 (c=0.50 in CHCl3), [a]52406 =+65.2; 1H NMR (250 MHz,
CDCl3): d=9.86 (s, 1H; HC=O), 9.06 (brs, 1H; NH), 7.55 (d, J=5.6 Hz,
1H; H-6’), 6.56 (dd, J1 =J2 =2.1 Hz, 1H; H-2), 5.90 (m, 1H; H-3), 4.29
(dd, J1 =10.1, J2 =2.9 Hz, 1H; SiOCHa), 3.58 (dd, J1 =10.1, J2 =2.2 Hz,
1H; SiOCHb), 3.18 (m, 1H; H-5), 2.79 (ddd, J1 =14.2, J2 =J3 =9.4 Hz,
1H; H-4a), 1.82 (ddd, J1 =14.3, J2 =J3 =6.7 Hz, 1H; H-4b), 1.57 (septet,
J=6.8 Hz, 1H; Me2CH), 0.82 (d, J=7.4 Hz, 6H; (CH3)2CH), 0.798/0.794
(2s, 6H; C(CH3)2), 0.06 ppm (s, 6H; SiCH3); 13C NMR (63MHz, CDCl 3):
d=188.7 (CH=O), 156.6 (d, J(C,F)=27 Hz, C4’), 150.6 (C2’), 149.3(C1),
147.0 (C2), 145.0 (d, J(C,F)=269 Hz, C5’), 125.2 (d, J(C,F)=32 Hz, C6’),
62.3( CH2OSi), 59.4 (C3), 44.3 (C5), 34.0 (Me2CH), 32.9 (C4), 25.5
(Me2CSi), 20.4/20.2 ((CH3)2CH), 18.44/18.37 ((CH3)2CSi), ꢁ3.4/ꢁ3.6 ppm
ꢁ
12.3(CH 3), ꢁ3.5/ꢁ3.7 ppm (SiCH3); IR (ATR): n˜ =3177/3050 (w, N H),
ꢁ1
ꢁ
ꢁ
2954/2864 (m, C H), 1683(s, C =O), 1249 cm (m, C O); MS (EI,
70 eV): m/z (%): 393 (4) [M+H]+, 307 (100) [MꢁC6H13]+, 215 (52), 181
(73); HRMS (ESI): calcd for C20H33N2O4Si: 393.221 [M+H]+; found:
393.221.
(ꢁ)-(3S,5R)-3-(5’-Methyl-2’,4’-dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-
[dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-cyclopent-1-enecar-
baldehyde (ent-23d): When the general hydrolysis/silylation procedure
was followed, ent-10d (290 mg, 1 mmol) afforded the aldehyde ent-23d
(235 mg, 60%) as a white solid. [a]2D0 =ꢁ23.6 (c=0.54 in CHCl3), [a]25046
=
ꢁ29.4.
(+)-(3R,5S)-N-(1-{4-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3-formyl-cyclopent-2-enyl}-2’-oxo-1’,2’-dihydro-pyrimidin-4’-yl)-benza-
mide (23e): When the general hydrolysis/silylation procedure was fol-
lowed, 10e (403mg, 1 mmol, 94% purity) afforded the aldehyde 23e
(324 mg, 67%) as a yellow solid. M.p. 78–818C; Rf =0.28 (EtOAc/CyHex
4:1); [a]2D0 =+59.5 (c=0.59 in CHCl3), [a]25406 =+70.5; 1H NMR
(250 MHz, CDCl3): d=9.88 (s, 1H; HC=O), 8.23(brs, 1H; N H), 7.89 (d,
J=6.3Hz, 3H; H-6 ’, 2H-Ph), 7.63–7.46 (m, 4H; H-5’, 3H-Ph), 6.63 (t,
J=2.1 Hz, 1H; H-2), 6.10 (m, 1H; H-3), 4.26 (dd, J1 =10.0, J2 =3.2 Hz,
1H; SiOCHa), 3.59 (dd, J1 =10.0, J2 =2.3Hz, 1H; SiOC Hb), 3.22 (m,
1H; H-5), 2.90 (ddd, J1 =14.0, J2 =J3 =9.3Hz, 1H; H-4a), 1.84 (ddd, J1 =
14.0, J2 =J3 =6.7 Hz, 1H; H-4b), 1.57 (septet, J=6.8 Hz, 1H; Me2CH),
0.82 (d, J=6.9 Hz, 6H; (CH3)2CH), 0.80 (s, 6H; C(CH3)2), 0.05 ppm (s,
6H; SiCH3); 13C NMR (63MHz, CDCl 3): d=188.9 (CH=O), 161.9 (C=O
(Bz)), 150.4 (C2’), 147.9 (C6’) 146.1 (C2), 133.3/129.0/127.6 (all Ph), 62.3
(CH2OSi), 60.6 (C3), 44.5 (C5), 34.3 (C4), 33.0 (Me2CH), 25.4 (Me2CSi),
ꢁ
ꢁ
ꢁ
(CH3Si); IR (ATR): n˜ =3160 (w, N H), 3049 (m, N H), 2955 (m, C H),
ꢁ
1720 (s, C=O), 1711 (s, C=O), 1685 (s, C=O), 1657 (s, C=C), 1248 (s, C
O), 1110 (s), 830 (s), 780 cmꢁ1 (s); MS (EI, 70 eV): m/z (%): 397 (49)
[M+H]+, 251 (25), 237 (14).
(ꢁ)-(3S,5R)-3-(5’-Fluoro-2’,4’-dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-
[dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-cyclopent-1-enecarb-
aldehyde (ent-23b): When the general hydrolysis/silylation procedure
was followed, ent-10b (176 mg, 0.6 mmol) afforded the aldehyde ent-23b
(171 mg, 73%) as a white solid. [a]2D0 =ꢁ53.3 (c=0.52 in CHCl3), [a]25046
=
ꢁ65.2.
(+)-(3R,5S)-3-(5’-Bromo-2’,4’-dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-
20.4/20.2
((CH3)2CH),
18.5/18.4
((CH3)2CSi),
ꢁ3.47/ꢁ3.49 ppm
[dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-cyclopent-1-enecarb-
aldehyde (23c): When the general hydrolysis/silylation procedure was fol-
lowed, 10c (355 mg, 1 mmol) afforded the aldehyde 23c (350 mg, 77%)
ꢁ
ꢁ
(Si(CH3)2); IR (ATR): n˜ =3230/3142/3061 (w, N H), 2954/2864 (m, C
H), 1684 (s, C=O), 1661 (s, C=N), 1622 (s, C=C), 1484 (s), 1249 cmꢁ1 (s,
+
ꢁ
C O); MS (ESI, 70 eV): m/z (%): 1177 (11) [2M+Na] , 632 (49), 610
as a white solid. M.p. 80–838C; Rf =0.55 (EtOAc/CyHex 4:1); [a]D20
=
(100) [M+Na]+, 578 (27) [M+H]+, 216 (57).
+62.6 (c=0.58 in CHCl3), [a]25406 =+76.3; 1H NMR (250 MHz, CDCl3):
d=9.87 (s, 1H; HC=O), 8.52 (brs, 1H; NH), 7.54 (s, 1H; H-6’), 6.57 (m,
1H; H-2), 5.85 (dddd, J1 =J2 =2.3, J3 =8.7, J4 =7.6 Hz, 1H; H-3), 4.25
(dd, J1 =10.0, J2 =3.2 Hz, 1H; SiOCHa), 3.52 (dd, J1 =10.0, J2 =2.3Hz,
1H; SiOCHb), 3.17 (m, 1H; H-5), 2.75 (ddd, J1 =13.7, J2 =J3 =8.8 Hz,
1H; H-4a), 1.85 (ddd, J1 =13.7, J2 =J3 =7.7 Hz, 1H; H-4b), 1.55 (septet,
J=6.8 Hz, 1H; Me2CH), 0.83(d, J=6.8 Hz, 6H; (CH3)2CH), 0.810/0.805
(2s, 6H; C(CH3)2), 0.06 ppm (s, 6H; SiCH3); 13C NMR (63MHz, CDCl 3):
d=188.9 (CH=O), 159.2 (C4’), 150.5 (C2’), 150.4 (C1), 147.3(C2), 140.2
(C6’), 97.7 (C5’), 61.5 (CH2OSi), 59.9 (C3), 44.3 (C5), 34.0 (Me2CH), 33.5
(C4), 25.3(Me 2CSi), 20.4/20.3(( CH3)2CH), 18.5/18.4 ((CH3)2CSi), ꢁ3.5/
(ꢁ)-(3S,5R)-N-(1-{4-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3-formyl-cyclopent-2-enyl}-2’-oxo-1’,2’-dihydro-pyrimidin-4’-yl)-benza-
mide (ent-23e): When the general hydrolysis/silylation procedure was fol-
lowed, ent-10e (379 mg, 1 mmol) afforded the aldehyde ent-23e (316 mg,
66%) as a yellow solid. [a]2D0 =ꢁ47.1 (c=0.32 in CHCl3), [a]25406 =ꢁ56.3.
(+)-(3R,5S)-Diphenylcarbamic acid 2’-acetylamino-9’-{4-[dimethyl-(1,1,2-
trimethylpropyl)-silanyloxymethyl]-3-formyl-cyclopent-2-enyl}-9H-purin-
6’-yl ester (23 f): When the general hydrolysis/silylation procedure was
followed, 10 f (1.104 g, 2 mmol) afforded the aldehyde 23 f (895 mg,
68%) as a light-yellow solid. M.p. 79–848C; Rf =0.33 (EtOAc/CyHex
Chem. Eur. J. 2004, 10, 5087 – 5110
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5103

H.-G. Schmalz et al.
FULL PAPER
4:1); [a]2D0 =+5.7 (c=0.37 in CHCl3), [a]52406 =+5.7; 1H NMR (250 MHz,
CDCl3): d=9.88 (s, 1H; HC=O), 8.06 (s, 1H; H-8’), 7.99 (s, 1H; NH),
7.40–6.72 (m, 10H; 2ꢁPh), 6.72 (s, 1H; H-2), 5.82 (m, 1H; H-3), 4.17
(dd, J1 =8.5, J2 =3.5 Hz, 1H; SiOCHa), 3.69 (dd, J1 =8.3, J2 =2.3Hz, 1H;
SiOCHb), 3.27 (m, 1H; H-5), 2.89 (ddd, J1 =11.5, J2 =J3=7.5 Hz, 1H;
H-4a), 2.52 (s, 3H; CH3CO), 2.12 (ddd, J1 =11.5, J2 =J3 =6.0 Hz, 1H; H-
4b), 1.56 (septet, J=6.8 Hz, 1H; Me2CH), 0.81 (d, J=6.9 Hz, 6H;
(CH3)2CH), 0.79 (s, 6H; C(CH3)2), 0.05 ppm (s, 6H; SiCH3); 13C NMR
(63MHz, CDCl 3): d=189.1 (CH=O), 170.6 (CH3C=O), 154.7 (C4’),
156.3/152.1/150.4 (C4’, C6’, Ph2NC=O), 149.7 (C1), 146.8 (C2), 142.1
(C8’), 141.7/129.1/127.0 (br, all Ph), 120.6 (C5’), 62.2 (CH2OSi), 57.9 (C3),
44.7 (C5), 35.0 (C4), 34.0 (Me2CH), 25.3(Me 2CSi), 25.0 (CH3C=O),
20.35/20.29 ((CH3)2CH), 18.45/18.43(( CH3)2CSi), ꢁ3.55 ppm (Si(CH3)2);
C20H29ClN4O2Si: C 57.06, H 6.94, N 13.31; found: C 57.01, H 6.95, N
13.25.
(+)-(3R,5S)-3-(5’-Fluoro-2’,4’-dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-
(tert-butyldiphenylsilanyloxymethyl)-cyclopent-1-enecarbaldehyde (23i):
When the general protocol for the hydrolysis/silylation procedure was
followed, 10b (29 mg, 0.1 mmol) afforded the aldehyde 23i (29 mg, 59%)
as a white solid. Rf =0.49 (EtOAc/CyHex 4:1); [a]2D0 =+63.0 (c=0.56 in
CHCl3), [a]25406 =+76.5; 1H NMR (250 MHz, CDCl3): d=9.88 (s, 1H;
HC=O), 9.67 (brs, 1H; NH), 7.56 (d, J=5.9 Hz, 4H; Ph), 7.45–7.31 (m,
6H; Ph), 7.29 (d, J=5.5 Hz, 1H; H-6’), 6.61 (dd, J1 =J2 =2.1 Hz, 1H; H-
2), 5.86 (dd, J1 =J2 =7.7 Hz, 1H; H-3), 4.23 (dd, J1 =10.3, J2 =4.1 Hz, 1H;
SiOCHa), 3.74 (dd, J1 =10.3, J2 =2.7 Hz, 1H; SiOCHb), 3.19 (m, 1H; H-
5), 2.76 (ddd, J1 =13.9, J2 =J3 =9.0 Hz, 1H; H-4a), 1.85 (ddd, J1 =13.9,
J2 =J3 =7.7 Hz, 1H; H-4b), 1.02 ppm (s, 9H; SiCH3); 13C NMR (63MHz,
CDCl3): d=188.6 (CH=O), 156.8 (d, J(C,F)=27 Hz, C4’), 150.6 (C2’),
149.5 (C1), 146.8 (C2), 140.9 (d, J(C,F)=241 Hz, C5’), 135.6/135.4/133.1/
132.8/129.9/127.78/127,76 (all Ph), 124.8 (d, J(C,F)=33 Hz, C6’), 62.9
(CH2OSi), 59.8 (C3), 44.3 (C5), 33.3 (C4), 26.9 ((CH3)3CSi), 19.3ppm
ꢁ
ꢁ
IR (ATR): n˜ =3272/3060 (w, N H), 2954/2864 (m, C H), 1740 (s, C=O);
1685 (s, C=O), 1617 (s, C=C), 1586 (s), 1490 (s), 1374 (s), 1334 (s), 1280
ꢁ1
ꢁ
(s, C O), 1214 (s), 1186 (s), 1167 (s), 1059 (s), 1002 (s), 830 (s), 699 cm
(s).
(ꢁ)-(3S,5R)-Diphenylcarbamic acid 2’-acetylamino-9’-{4-[dimethyl-(1,1,2-
trimethylpropyl)-silanyloxymethyl]-3-formyl-cyclopent-2-enyl}-9H-purin-
6’-yl ester (ent-23 f): When the general hydrolysis/silylation procedure
was followed, ent-10 f (1.104 g, 2 mmol) afforded the aldehyde ent-23 f
(877 mg, 67%) as a light-yellow solid. [a]2D0 =ꢁ7.0 (c=0.60 in CHCl3),
[a]25046 =ꢁ7.4.
(+)-(3R,5S)-3-(6’-Aminopurin-9’-yl)-5-[dimethyl-(1,1,2-trimethylpropyl)-
silanyloxymethyl]-cyclopent-1-enecarbaldehyde (23g): When the modi-
fied protocol for the hydrolysis/silylation procedure was followed, 10g
(150 mg, 0.5 mmol) afforded the aldehyde 23g (79 mg, 40%) as a yellow
solid. M.p. 148–1528C; Rf =0.43(EtOAc/CyHex 4:1); [ a]2D0 =+40.8 (c=
0.40 in MeOH), [a]25406 =+50.1; 1H NMR (250 MHz, CDCl3): d=9.86 (s,
1H; HC=O), 8.30 (s, 1H; H-2’), 7.93(s, 1H; H-8 ’), 6.75 (dd, J1 =J2 =
2.2 Hz, 1H; H-2), 6.40 (s, 2H; NH2), 5.84 (dddd, J1 =9.1, J2 =6.8, J3 =J4 =
2.2 Hz, 1H; H-3), 4.14 (dd, J1 =10.0, J2 =3.8 Hz, 1H; SiOCHa), 3.66 (dd,
J1 =10.0, J2 =2.4 Hz, 1H; SiOCHb), 3.24 (m, 1H; H-5), 2.89 (ddd, J1 =
14.0, J2 =J3 =9.1 Hz, 1H; H-4a), 2.10 (ddd, J1 =14.0, J2 =J3 =6.8 Hz, 1H;
H-4b), 1.53(septet, J=6.8 Hz, 1H; Me2CH), 0.78 (d, J=6.8 Hz, 6H;
(CH3)2CH), 0.77 (s, 6H; C(CH3)2), 0.02 ppm (s, 6H; CH3Si); 13C NMR
(63MHz, CDCl 3): d=189.2 (CH=O), 155.7 (C4’), 152.8 (C2’), 149.5 (C1),
149.5 (C6’), 147.4 (C2), 138.5 (C8’), 119.2 (C5’), 62.2 (CH2OSi), 57.5 (C3),
ꢁ
ꢁ
(Me2CSi); IR (ATR): n˜ =3181/3166 (w, N H), 3065 (m, N H), 2952/2927
ꢁ
ꢁ
(m, C H), 1714 (s, C=O), 1683(s, C =O), 1243(s, C O), 1107 (s),
702 cmꢁ1 (s); MS (EI, 70 eV): m/z (%): 1023(2) [2 M+K]+, 1007 (1)
[2M+Na]+, 547 (100), 515 (14) [M+Na]+, 493(2) [ M+H]+.
(+)-(3R,5S)-3-(5’-Bromo-2’,4’-dioxo-3’,4’-dihydro-2H-pyrimidin-1’-yl)-5-
(tert-butyldiphenylsilanyloxymethyl)-cyclopent-1-enecarbaldehyde (23j):
When the general protocol for the hydrolysis/silylation procedure was
followed, 10c (71 mg, 0.2 mmol) afforded the aldehyde 23j (55 mg, 50%)
as a white solid (76% yield was achieved in a racemic version of the re-
action on a 1 mmol scale). M.p. 121–1238C; Rf =0.53(EtOAc/CyHex
4:1); [a]2D0 =+101.4 (c=0.31 in CHCl3), [a]25406 =+122.4. 1H NMR
(250 MHz, CDCl3): d=9.90 (s, 1H; HC=O), 8.50 (brs, 1H; NH), 7.59–
7.32 (m, 10H; Ph), 7.46 (s, 1H; H-6’), 6.62 (dd, J1 =J2 =2.1 Hz, 1H; H-2),
5.81 (dddd, J1 =J2 =2.5, J3 =J4 =8.4 Hz, 1H; H-3), 4.20 (dd, J1 =10.3, J2 =
4.4 Hz, 1H; SiOCHa), 3.74 (dd, J1 =10.3, J2 =2.6 Hz, 1H; SiOCHb), 3.18
(m, 1H; H-5), 2.74 (ddd, J1 =13.4, J2 =J3 =8.7 Hz, 1H; H-4a), 1.85 (ddd,
J1 =13.6, J2 =J3 =8.2 Hz, 1H; H-4b), 1.03ppm (s, 9H; SiC H3); 13C NMR
(63MHz, CDCl 3): d=188.8 (CH=O), 159.3(C4 ’), 150.40/150.35 (C1,
C2’), 147.1 (C2), 139.9 (C6’), 135.5/135.3/133.0/132.8/129.8/129.4/127.7/
127.6 (all Ph), 97.8 (C5’), 62.5 (CH2OSi), 60.1 (C3), 44.3 (C5), 34.0 (C4),
26.9 ((CH3)3CSi), 19.3ppm (Me 2CSi); IR (ATR): n˜ =3177/3067/3048 (w,
44.7 (C5), 35.1 (C4), 34.0 (Me2CH), 25.3(Me CSi), 20.3/20.2 ((CH3)2CH),
2
ꢁ
ꢁ
N H), 2953/2928/2888 (m, C H), 1704 (s, C=O), 1683(s, C =O), 1619 (m,
18.4/18.4 ((CH3)2CSi), ꢁ3.6 ppm (CH3Si); IR (ATR): n˜ =3318/3168 (w,
C=C), 1110 cmꢁ1 (s).
ꢁ
ꢁ
N H), 2953/2864 (m, C H), 1683(s, C =O), 1645 (s, C=C), 1598 (s),
(+)-(3R,5S)-N-{1-[4-(tert-Butyldiphenylsilanyloxymethyl)-3-formyl-cyclo-
pent-2-enyl]-2’-oxo-1’,2’-dihydro-pyrimidin-4’-yl}-benzamide (23k): When
the general hydrolysis/silylation procedure was followed, 10e (64 mg,
0.16 mmol, 94% purity) afforded the aldehyde 23k (52 mg, 57%) as a
+
1250 cmꢁ1 (s, C O); MS (EI, 70 eV): m/z (%): 401 (2) [M] , 316 (100)
ꢁ
[M+C6H13]+; HRMS (ESI): calcd for C20H31N5O2Si: 402.2325 [M+H]+;
found: 402.2327.
(ꢁ)-(3S,5R)-3-(6’-Aminopurin-9’-yl)-5-[dimethyl-(1,1,2-trimethylpropyl)-
silanyloxymethyl]-cyclopent-1-enecarbaldehyde (ent-23g): When the the
modified protocol for the hydrolysis/silylation procedure was followed,
ent-10g (239 mg, 0.8 mmol) afforded the aldehyde ent-23g (123mg,
38%) as a yellow solid. [a]2D0 =ꢁ25 (c=0.30 in MeOH), [a]25406 =ꢁ30.
pale-yellow solid. M.p. 104–1088C; Rf =0.25 (EtOAc/CyHex 4:1); [a]D20
=
+45.1 (c=0.32 in CHCl3), [a]25406 =+52.6; 1H NMR (250 MHz, CDCl3):
d=9.89 (s, 1H; HC=O), 7.88 (d, J=7.2 Hz, 2H; H-6’, 1H-Ph), 7.63(d,
J=7.4 Hz, 1H; H-5’), 7.60–7.33 (m, 14H; Ph), 6.66 (s, 1H; H-2), 6.07 (m,
1H; H-3), 4.28 (dd, J1 =10.3, J2 =3.9 Hz, 1H; SiOCHa), 3.74 (dd, J1 =
10.1, J2 =2.7 Hz, 1H; SiOCHb), 3.24 (m, 1H; H-5), 2.92 (ddd, J1 =14.2,
J2 =J3 =9.3Hz, 1H; H-4a), 1.90 (ddd, J1 =14.2, J2 =J3 =7.1 Hz, 1H; H-
4b), 1.04 ppm (s, 9H; SiCH3); 13C NMR (63MHz, CDCl 3): d=188.8
(CH=O), 161.9 (NHC=O), 150.4 (C2’), 147.7 (C6’) 145.7 (C2), 135.6/
135.4/135.2/133.3/133.2/132.8/130.3/130.0/129.1/128.0/127.8/127.6 (all Ph),
97.8 (C5’), 63.2 (CH2OSi), 60.8 (C3), 44.5 (C5), 34.4 (C4), 27.0
(SiC(CH3)3), 19.4 ppm (SiC(CH3)3).
(+)-(3R,5S)-3-(6’-Chloropurin-9’-yl)-5-[dimethyl-(1,1,2-trimethylpropyl)-
silanyloxymethyl]-cyclopent-1-enecarbaldehyde (23h): When the general
protocol for the hydrolysis/silylation procedure was followed, 10h
(638 mg, 2 mmol) afforded the aldehyde 23h (628 mg, 72%) as a pale-
yellow solid. M.p. 130–1318C; Rf =0.67 (EtOAc); [a]2D0 =+43.9 (c=0.65
in MeOH), [a]25406 =+53.8; 1H NMR (250 MHz, CDCl3): d=9.91 (s, 1H;
HC=O), 8.74 (s, 1H; H-2’), 8.29 (s, 1H; H-8’), 6.76 (dd, J1 =J2 =2.1 Hz,
1H; H-2), 5.96 (dddd, J1 =9.3, J2 =6.9, J3 =J4 =2.1 Hz, 1H; H-3), 4.22
(dd, J1 =10.0, J2 =3.8 Hz, 1H; SiOCHa), 3.66 (dd, J1 =10.0, J2 =2.6 Hz,
1H; SiOCHb), 3.30 (m, 1H; H-5), 2.94 (ddd, J1 =14.0, J2 =J3 =9.1 Hz,
1H; H-4a), 2.16 (ddd, J1 =14.0, J2 =J3 =6.8 Hz, 1H; H-4b), 1.55 (septet,
J=6.9 Hz, 1H; Me2CH), 0.80 (d, J=6.8 Hz, 6H; (CH3)2CH), 0.79 (s, 6H;
C(CH3)2), 0.05 ppm (s, 6H; CH3Si); 13C NMR (63MHz, CDCl 3): d=
188.9 (CH=O), 151.9 (C2’), 151.4/151.2/150.1 (C4’, C6’, C3), 146.1 (C2),
143.5 (C8’), 131.5 (C5’), 62.1 (CH2OSi), 58.2 (C1), 44.8 (C4), 34.9 (C5),
34.0 (Me2CH), 25.4 (Me2CSi), 20.4/20.3(( CH3)2CH), 18.4 ((CH3)2CSi),
(+)-(3R,5S)-Diphenylcarbamic acid 2’-acetylamino-9’-[4-(tert-butyldiphe-
nylsilanyloxymethyl)-3-formyl-cyclopent-2-enyl]-9H-purin-6’-yl
ester
(23l): When the general hydrolysis/silylation procedure was followed,
10 f (228 mg, 0.4 mmol) afforded the aldehyde 23l (112 mg, 37%) as a
white solid. Rf =0.41 (EtOAc/CyHex 4:1); [a]2D0 =+12.1 (c=0.75 in
CHCl3), [a]25406 =+13.7; 1H NMR (250 MHz, CDCl3): d=9.84 (s, 1H;
HC=O), 8.46 (s, 1H; NH), 7.92 (s, 1H; H-8’), 7.99 (s, 1H; NH), 7.56–7.18
(m, 20H; 4ꢁPh), 6.76 (s, 1H; H-2), 5.74 (m, 1H; H-3), 4.05 (dd, J1 =10.3,
J2 =6.0 Hz, 1H; SiOCHa), 3.85 (dd, J1 =10.1, J2 =3.2 Hz, 1H; SiOCHb),
3.25 (m, 1H; H-5), 2.85 (ddd, J1 =13.7, J2 =J3 =8.5 Hz, 1H; H-4a), 2.43
(s, 3H; CH3CO), 2.06 (ddd, J1 =13.2, J2 =J3 =5.8 Hz, 1H; H-4b),
1.00 ppm (s, 9H; SiCH3); 13C NMR (63MHz, CDCl 3): d=188.9 (CH=O),
170.5 (CH3C=O), 156.2 (C4’), 154.6/152.1/150.3(C2 ’, C6’, Ph2NC=O),
149.4 (C1), 146.7 (C2), 141.75 (C8’), 141.64/135.5/135.3/133.1/132.9/129.75/
ꢁ
ꢁ3.5 ppm (CH3Si); IR (ATR): n˜ =2954/2868 (m, C H), 1674 (s, C=O),
ꢁ1
1589 (s), 1563(s), 1396 (m), 1205 (m), 1109 (s), 826 cm
(s); MS (EI,
70 eV): m/z (%): 420 (7) [M]+, 335 (82) [MꢁC6H13]+, 243(24), 181 (53),
167 (16), 151 (16), 75 (100); HRMS (EI): calcd for C20H29ClN4O2Si:
335.073 [MꢁC6H13]+; found: 335.073; elemental analysis: calcd (%) for
5104
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5087 – 5110

Carbocyclic Nucleoside Analogues
5087 – 5110
129.772/129.1/127.65/127.60/126.9 (br, all 4ꢁPh), 120.6 (C5’), 63.2
(CH2OSi), 58.2 (C3), 44.7 (C5), 35.3 (C4), 26.9 (SiC(CH3)3), 25.0 (CH3C=
yellow solid. M.p. 165–1678C; [a]2D0 =+71.1 (c=0.68 in CHCl3), [a]25046
+88.3.
=
ꢁ
O), 19.2 ppm (SiC(CH3)3); IR (ATR): n˜ =3217/3064 (w, N H), 2929/2854
(ꢁ)-(1’R,4’S)-5-Bromo-1-{4’-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy-
methyl]-3’-hydroxymethyl-cyclopent-2’-enyl}-1H-pyrimidine-2,4-dione
(9c): When the general protocol for the reduction was followed, 23c
(92 mg, 0.2 mmol) afforded the alcohol 9c (92 mg, 99%) as a yellow
solid. M.p. 79–828C; Rf =0.39 (EtOAc/CyHex 4:1); [a]2D0 =ꢁ25 (c=0.30
in CHCl3); 1H NMR (250 MHz, CDCl3): d=9.01 (brs, 1H; NH), 7.55 (s,
1H; H-6), 5.59 (dddd, J1 =8.6, J2 =7.3, J3 =J4 =2.0 Hz, 1H; H-1’), 5.55 (d,
J=1.7 Hz, 1H; H-2’), 4.29 (brs, 2H; CH2OH), 3.78 (dd, J1 =10.6, J2 =
3.7 Hz, 1H; SiOCHa), 3.52 (dd, J1 =10.0, J2 =5.8 Hz, 1H; SiOCHb), 2.87
(m, 1H; H-4’), 2.69 (ddd, J1 =13.4, J2 =J3 =8.2 Hz, 1H; H-5’a), 1.68 (brs,
1H; OH), 1.60 (septet, J=6.8 Hz, 1H; Me2CH), 1.40 (ddd, J1 =13.4, J2 =
J3 =7.6 Hz, 1H; H-5’b), 0.86 (d, J=6.8 Hz, 6H; (CH3)2CH), 0.84 (s, 6H;
C(CH3)2), 0.12/0.10 ppm (2s, 6H; CH3Si); 13C NMR (63MHz, CDCl 3):
d=159.1 (C4), 153.6 (C3’), 150.3(C2), 140.4 (C6), 124.0 (C2 ’), 96.7 (C5),
63.8 (CH2OSi), 60.5 (CH2OH), 60.4 (C1’), 46.9 (C4’), 34.3 (C5’), 34.0
(Me2CH), 25.2 (Me2CSi), 20.3/20.2 ((CH3)2CH), 18.4 ((CH3)2CSi), ꢁ3.4/
ꢁ
(w, C H), 1741 (s, C=O); 1684 (s, C=O), 1617 (s, C=C), 1281 (s), 1213
(s), 1185 (s), 1167 (s), 700 cmꢁ1 (s); MS (ESI, 70 eV): m/z (%): 773(47)
[M+Na]+, 411 ppm (100); HRMS (ESI): calcd for C43H42N6NaO5Si:
773.288 [M+Na]+; found: 773.288.
General procedure for the reduction of aldehydes of type 23: A mixture
of MeOH (6 mL) and CH2Cl2 (12 mL) was added to NaBH4 (76 mg,
2 mmol) and the resulting mixture was stirred at RT for 3min and then
cooled to ꢁ788C. A solution of 23 (200 mmol) in CH2Cl2 (2 mL) was
added dropwise. After the mixture was stirred at ꢁ788C for 1 h, acetone
(5 mL) was added and the mixture was allowed to warm to RT and stir-
red for 30 min. The mixture was poured through a plug of silica and
washed with EtOAc. The solvents were then removed under reduced
pressure to give the allylic alcohols of type 9 in a high purity according to
1H NMR spectroscopy and TLC.
(ꢁ)-(1’R,4’S)-1-{4’-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3’-hydroxymethyl-cyclopent-2’-enyl}-1H-pyrimidine-2,4-dione (9a): When
the general protocol for the reduction was followed, 23a (76 mg,
0.2 mmol) afforded the alcohol 9a (59 mg, 78%) as a white solid. M.p.
60–628C; Rf =0.17 (EtOAc/CyHex 4:1); [a]2D0 =ꢁ84.6 (c=0.33 in CHCl3),
[a]25046 =ꢁ101.3; 1H NMR (250 MHz, CDCl3): d=9.00 (brs, 1H; NH), 7.34
(d, J=8.0 Hz, 1H; H-6), 5.67 (dd, J1 =8.0, J2 =2.2 Hz, H-5), 5.62 (ddd,
J1 =8.5, J2 =J3 =1.9 Hz, 1H; H-1’), 5.52 (s, 1H; H-2’), 4.26 (s, 2H;
CH2OH), 3.79 (dd, J1 =10.5, J2 =3.6 Hz, 1H; SiOCHa), 3.52 (dd, J1 =
10.5, J2 =6.1 Hz, 1H; SiOCHb), 2.86 (m, 1H; H-4’), 2.71 (ddd, J1 =13.5,
J2 =J3 =8.5 Hz, 1H; H-5’a), 1.59 (septet, J=6.8 Hz, 2H; OH, Me2CH),
1.39 (ddd, J1 =13.5, J2 =J3 =6.9 Hz, 1H; H-5’b), 0.85 (d, J=6.8 Hz, 6H;
(CH3)2CH), 0.83(s, 6H; C(C H3)2), 0.10/0.09 ppm (2s, 6H; CH3Si);
13C NMR (63MHz, CDCl 3): d=163.3 (C4), 152.7 (C3’), 151.0 (C2), 141.2
(C6), 124.7 (C2’), 102.4 (C5), 64.1 (CH2OSi), 60.5 (CH2OH), 59.6 (C1’),
46.9 (C4’), 34.1 (C5’), 34.0 (Me2CH), 25.3(Me 2CSi), 20.3/20.2
((CH3)2CH), 18.5/18.4 ((CH3)2CSi), ꢁ3.49/ꢁ3.51 ppm (CH3Si); IR (ATR):
ꢁ
ꢁ
ꢁ3.5 ppm (CH3Si); IR (ATR): n˜ =3427 (w, O H), 3171/3048 (w, N H),
ꢁ
2953/2862 (m, C H), 1693(s, C =O), 1682 (s, C=O), 1615 (m, C=C),
1249 cmꢁ1 (m, C O); MS (EI, 70 eV): m/z (%): 375 (48), 373 (58), 183
ꢁ
(100); HRMS (EI): calcd for C13H18BrN2O4Si: 373.022 [MꢁC6H13]+;
found: 373.020.
(+)-(1’S,4’R)-5-Bromo-1-{4’-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy-
methyl]-3’-hydroxymethyl-cyclopent-2’-enyl}-1H-pyrimidine-2,4-dione
(ent-9c): When the general protocol for the reduction was followed, ent-
23c (92 mg, 0.2 mmol) afforded the alcohol ent-9c (85 mg, 93%) as a
yellow solid. [a]D20 =+20.7 (c=0.34 in CHCl3), [a]25406 =+26.1.
(ꢁ)-(1’R,4’S)-1-{4’-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3’-hydroxymethyl-cyclopent-2’-enyl}-5-methyl-1H-pyrimidine-2,4-dione
(9d): When the general protocol for the reduction was followed, 23d
(78 mg, 0.2 mmol) afforded the alcohol 9d (69 mg, 88%) as a white solid.
M.p. 108–1098C; Rf =0.21 (EtOAc/CyHex 4:1); [a]2D0 =ꢁ67.9 (c=0.50 in
CHCl3), [a]25406 =ꢁ83.6; 1H NMR (250 MHz, CDCl3): d=8.62 (brs, 1H;
NH), 7.05 (d, J=1.2 Hz, 1H; H-6), 5.59 (dddd, J1 =7.8, J2 =7.6, J3 =J4 =
2.1 Hz, 1H; H-1’), 5.53(s, 1H; H-2 ’), 4.27 (d, J=5.8 Hz, 2H; CH2OH),
3.77 (dd, J1 =10.3, J2 =3.7 Hz, 1H; SiOCHa), 3.52 (dd, J1 =10.3, J2 =
6.3Hz, 1H; SiOC Hb), 2.87 (m, 1H; H-4’), 2.65 (ddd, J1 =13.3, J2 =J3 =
8.4 Hz, 1H; H-5’a), 1.88 (d, J=1.2 Hz, 3H; CH3), 1.67 (brs, 1H; OH),
1.60 (septet, J=6.9 Hz, 1H; Me2CH), 1.35 (ddd, J1 =13.6, J2 =J3 =7.7 Hz,
1H; H-5’b), 0.86 (d, J=6.9 Hz, 6H; (CH3)2CH), 0.83(s, 6H; C(C H3)2),
0.11/0.10 ppm (2s, 6H; CH3Si); 13C NMR (63MHz, CDCl 3): d=163.8
(C4), 152.3(C3 ’), 150.1 (C2), 136.6 (C6), 125.2 (C2’), 110.1 (C5), 64.1
(CH2OSi), 60.6 (CH2OH), 59.4 (C1’), 46.7 (C4’), 34.2 (C5’), 34.1
(Me2CH), 25.2 (Me2CSi), 20.2 ((CH3)2CH), 18.5 ((CH3)2CSi), 12.4 (CH3),
ꢁ
ꢁ
ꢁ
ꢁ
n˜ =3406 (w, O H), 3178 (w, N H), 3043 (m, N H), 2951/2862 (m, C H),
1693(s, C =O), 1687 (s, C=O), 1666 (s, C=N), 1651 (m, C=C), 1461 (s),
ꢁ1
ꢁ
1248 (s, C O), 828 (s), 775 cm (s); MS (EI, 70 eV): m/z (%): 295 (10)
[MꢁC6H13]+, 91 (100); HRMS (ESI): calcd for C19H32N2NaO4Si: 403.203
[M+Na]+; found: 403.204.
(+)-(1’S,4’R)-1-{4’-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3’-hydroxymethyl-cyclopent-2’-enyl}-1H-pyrimidine-2,4-dione
When the general protocol for the reduction was followed, ent-23a
(76 mg, 0.2 mmol) afforded the alcohol ent-9a (72 mg, 95%) as a white
solid. [a]2D0 =+61 (c=0.26 in CHCl3), [a]25406 =+76.
(ent-9a):
(ꢁ)-(1’R,4’S)-5-Fluoro-1-{4’-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy-
methyl]-3’-hydroxymethyl-cyclopent-2’-enyl}-1H-pyrimidine-2,4-dione
(9b): When the general protocol for the reduction was followed, 23b
(48 mg, 0.1 mmol) afforded the alcohol 9b (48 mg, 99%) as a colorless
oil. Rf =0.40 (EtOAc/CyHex 4:1); [a]2D0 =ꢁ77.0 (c=0.46 in CHCl3),
[a]25046 =ꢁ95.3; 1H NMR (250 MHz, CDCl3): d=9.92 (brs, 1H; NH), 7.42
(d, J(H,F)=5.9 Hz, 1H; H-6), 5.62 (m, 1H; H-1’), 5.53(s, 1H; H-2 ’), 4.31
(d, J=14.6 Hz, 1H; CHaOH), 4.23(d, J=15.0 Hz, 1H; CHbOH), 3.80
(dd, J1 =10.4, J2 =3.4 Hz, 1H; SiOCHa), 3.53 (dd, J1 =10.4, J2 =5.2 Hz,
1H; SiOCHb), 2.86 (m, 1H; H-4’), 2.70 (ddd, J1 =13.6, J2 =J3 =8.6 Hz,
1H; H-5’a), 1.58 (septet, J=6.8 Hz, 1H; Me2CH), 1.43(ddd, J1 =13.7,
J2 =J3 =6.6 Hz, 1H; H-5’b), 0.84 (d, J=7.0 Hz, 6H; (CH3)2CH), 0.82 (s,
6H; C(CH3)2), 0.10/0.08 ppm (2s, 6H; CH3Si); 13C NMR (63MHz,
CDCl3): d=157.1 (d, J(C,F)=26 Hz, C4), 153.2 (C3’), 149.8 (C2), 140.6
(d, J(C,F)=236 Hz, C6), 125.3 (d, J(C,F)=32 Hz, C5), 124.2 (C2’), 63.7
(CH2OSi), 60.4 (CH2OH), 60.1 (C1’), 46.8 (C4’), 34.0 (Me2CH), 33.7
(C5’), 25.3(Me 2CSi), 20.3/20.1 ((CH3)2CH), 18.41/18.36 ((CH3)2CSi),
ꢁ
ꢁ
ꢁ3.5/ꢁ3.6 ppm (CH3Si); IR (ATR): n˜ =3404 (w, O H), 3173/3042 (w, N
ꢁ
ꢁ
H), 2953/2863 (m, C H), 1681 (s, C=O), 1249 (s), 1222 (m, C O),
829 cmꢁ1 (s); MS (EI, 70 eV): m/z (%): 216 (87), 183(34), 105 (100), 91
(28), 77 (29), 75 (50), 73(30); HRMS (ESI): calcd for C 20H34N2NaO4Si:
417.2186 [M+Na]+; found: 417.219.
(+)-(1’S,4’R)-1-{4’-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3’-hydroxymethyl-cyclopent-2’-enyl}-5-methyl-1H-pyrimidine-2,4-dione
(ent-9d): When the general protocol for the reduction was followed, ent-
23d (78 mg, 0.2 mmol) afforded the alcohol ent-9d (79 mg, 99%) as a
white solid. [a]D20 =+70 (c=0.16 in CHCl3), [a]25406 =+87.
(+)-(1’R,4’S)-4-Amino-1-{4’-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy-
methyl]-3’-hydroxymethyl-cyclopent-2’-enyl}-1H-pyrimidin-2-one
(ent-
9e): When the general protocol for the reduction was followed, ent-23e
(96 mg, 0.2 mmol) afforded the corresponding protected alcohol (97 mg,
99%; Rf =0.55, EtOAc/CyHex 4:1) as a yellow foam. The resulting inter-
mediate (48 mg, 100 mmol) was treated under argon with a 2m solution of
ammonia in MeOH (2 mL, 4 mmol) and the resulting mixture was stirred
for 16 h at RT. The solvent and the ammonia were evaporated and the
residue was purified by flash chromatography (EtOAc/CyHex 4:1, then
EtOAc/MeOH 4:1). The product ent-9e was obtained as a yellow oil
(36 mg, 95%). Rf =0.27 (EtOAc/MeOH 4:1); [a]2D0 =+91.6 (c=0.31 in
MeOH), [a]25406 =+112.1; 1H NMR (250 MHz, [D4]MeOH): d=7.49 (d,
J=6.0 Hz, 1H; H-6), 5.79 (d, J=6.0 Hz, 1H; H-5), 5.50 (brs, 2H; NH2),
4.25 (d, J=13.0 Hz, 1H; CHaOH), 4.10 (d, J=13.0 Hz, 1H; CHbOH),
3.71 (dd, J1 =8.8, J2 =3.5 Hz, 1H; SiOCHa), 3.51 (m, 1H; SiOCHb), 3.29
ꢁ
ꢁ
ꢁ3.5/ꢁ3.6 ppm (CH3Si); IR (ATR): n˜ =3416 (w, O H), 3178/3056 (w, N
ꢁ
ꢁ
H), 2954/2864 (m, C H), 1692 (s, C=O), 1659 (s, C=C), 1239 (s, C O),
830 cmꢁ1 (s); MS (ESI, 70 eV): m/z (%): 835 (4) [2M+K]+, 819 (4)
[2M+Na]+, 421 (100) [M+Na]+, 399 (2) [M+H]+; HRMS (ESI): calcd
for C19H31FN2NaO4Si: 421.194 [M+Na]+; found: 421.194.
(+)-(1’S,4’R)-5-Fluoro-1-{4’-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy-
methyl]-3’-hydroxymethyl-cyclopent-2’-enyl}-1H-pyrimidine-2,4-dione
(ent-9b): When the general protocol for the reduction was followed, ent-
23b (48 mg, 0.1 mmol) afforded the alcohol ent-9b (45 mg, 94%) as a
Chem. Eur. J. 2004, 10, 5087 – 5110
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5105

H.-G. Schmalz et al.
FULL PAPER
(s, 1H; H-2’), 3.23 (m, 1H; H-1’), 2.81 (m, 1H; H-4’), 2.64 (ddd, J1 =11.5,
J2 =J3 =7.3Hz, 1H; H-5 ’a), 1.54 (septet, J=5.5 Hz, 1H; Me2CH), 1.46
(ddd, J1 =11.5, J2 =J3 =5.5 Hz, 1H; H-5’b), 0.80 (d, J=5.5 Hz, 6H;
(CH3)2CH), 0.78 (s, 6H; C(CH3)2), 0.03/0.01 ppm (2s, 6H; CH3Si);
13C NMR (63MHz, [D 4]MeOH): d=167.3(C4), 158.9 (C2), 154.1 (C3 ’),
143.8 (C6), 124.9 (C2’), 96.0 (C5), 64.4 (CH2OSi), 62.2 (C1’), 60.9
(CH2OH), 48.0 (C4’), 35.9 (C5’), 35.4 (Me2CH), 26.3(Me 2CSi), 21.0/20.8
((CH3)2CH), 19.05/18.98 ((CH3)2CSi), ꢁ3.3 ppm (CH3Si); IR (ATR): n˜ =
(+)-(1’S,4’R)-9-{4’-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3’-hydroxymethyl-cyclopent-2’-enyl}-9H-purin-6-ylamine (ent-9g): When
the general protocol for the reduction was followed, ent-23g (40 mg,
0.1 mmol) afforded the alcohol ent-9g (40 mg, 99%) as a yellow solid.
[a]2D0 =+16 (c=0.20 in MeOH), [a]52406 =+18.
(ꢁ)-(1’R,4’S)-9-{4’-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3’-hydroxymethyl-cyclopent-2’-enyl}-9H-6-chloropurine (9h): When the
general protocol for the reduction was followed, 23h (422 mg, 1 mmol)
afforded the alcohol 9h (412 mg, 97%) as a white solid. M.p. 112–1138C;
Rf =0.48 (EtOAc); [a]D20 =ꢁ50.8 (c=0.665 in CHCl3), [a]25406 =ꢁ62.1;
1H NMR (250 MHz, CDCl3): d=8.71 (s, 1H; H-2), 8.18 (s, 1H; H-8),
5.80 (m, 1H; H-2’), 5.73(m, 1H; H-1 ’), 4.37 (d, J=15.0 Hz, 1H;
CHaOH), 4.32 (d, J=15.0 Hz, 1H; CHbOH), 3.76 (dd, J1 =10.3, J2 =
4.1 Hz, 1H; SiOCHa), 3.57 (dd, J1 =10.3, J2 =6.6 Hz, 1H; SiOCHb), 3.01
(m, 1H; H-4’), 2.88 (ddd, J1 =13.5, J2 =J3 =8.5 Hz, 1H; H-5’a), 2.74 (s,
1H; OH), 1.85 (ddd, J1 =13.5, J2 =J2 =6.4 Hz, 1H; H-5’b), 1.57 (septet,
J=6.9 Hz, 1H; (CH3)2CH), 0.83(d, J=6.9 Hz, 6H; (CH3)2CH), 0.81 (s,
6H; C(CH3)2), 0.09/0.07 ppm (2s, 6H; CH3Si); 13C NMR (63MHz,
CDCl3): d=153.3 (C3’), 151.7 (C2), 151.5/150.9 (C4, C6), 143.4 (C8),
131.8 (C5), 123.5 (C2’), 64.5 (CH2OSi), 60.5 (CH2OH), 58.6 (C1’), 47.4
(C4’), 35.6 (C5’), 34.0 ((CH3)2CH), 25.2 (Me2CSi), 20.3/20.2 ((CH3)2CH),
ꢁ
ꢁ
ꢁ
3330 (brm, O H), 3199 (m, N H), 2954/2863(m, C H), 1714 (w, C=O),
1640 (s, C=N), 1613(s, C =C), 1250 cmꢁ1 (m, C O); MS (ESI, 70 eV): m/z
ꢁ
(%): 402 (100) [M+Na]+, 134 (39), 112 (43); HRMS (ESI): calcd for
C19H33N3O3NaSi: 402.219 [M+Na]+; found: 402.218.
(ꢁ)-(1’S,4’R)-4-Amino-1-{4’-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy-
methyl]-3’-hydroxymethyl-cyclopent-2’-enyl}-1H-pyrimidin-2-one
(9e):
When the general protocol for the reduction was followed, 23e (96 mg,
0.2 mmol) afforded a mixture of the protected and the deprotected alco-
hols. This mixture was used directly for the deprotecting step. By follow-
ing the deprotection method described for ent-9e, the product 9e was ob-
tained as a white solid (59 mg, 85% yield). M.p. 189–1938C; [a]2D0 =ꢁ97.9
(c=0.33 in MeOH), [a]25406 =ꢁ120.6.
(ꢁ)-(1’R,4’S)-2-Amino-9-{4’-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy-
methyl]-3’-hydroxymethyl-cyclopent-2’-enyl}-1,9-dihydro-purin-6-one
(9 f): Alcohol 9 f (97 mg, 99% yield) was obtained as a white solid from
23 f (65 mg, 0.1 mmol) by following the general procedure for the reduc-
tion, except that the solvents were evaporated and the residue was direct-
ꢁ
18.43/18.41 ((CH3)2CSi), ꢁ3.5 ppm (CH3Si); IR (ATR): n˜ =3382 (s, O
ꢁ
H), 2953/2863 (m, C H), 1588 (s), 1557 (s), 1395 (m), 1194 (s), 831 (s),
777 cmꢁ1 (s); MS (EI, 70 eV): m/z (%): 318 (28) [M C6H13] , 136 (100);
+
ꢁ
HRMS (ESI): calcd for C20H31ClN4O2Si: 445.180 [M+Na]+; found:
445.181; elemental analysis: calcd (%) for C20H31ClN4O2Si: C 56.78, H
7.39, N 13.24; found: C 56.63, H 7.41, N 13.18.
ly subjected to the ammonolysis as described for ent-9e. M.p. 2308C;
20
546
Rf =0.58 (EtOAc/MeOH 4:1); [a]2D0 =ꢁ55.4 (c=0.31 in MeOH), [a]
=
ꢁ66.7; 1H NMR (250 MHz, [D4]MeOH): d=7.66 (s, 1H; H-8), 5.80 (s,
1H; H-2’), 5.42 (m, 1H; H-1’), 4.37 (d, J=15.0 Hz, 1H; CHaOH), 4.21
(d, J=15.0 Hz, 1H; CHbOH), 3.77 (dd, J1 =10.3, J2 =4.9 Hz, 1H;
SiOCHa), 3.66 (dd, J1 =10.2, J2 =4.4 Hz, 1H; SiOCHb), 2.95 (m, 1H; H-
4’), 2.76 (ddd, J1 =13.7, J2 =J3 =8.5 Hz, 1H; H-5’a), 1.83(ddd, J1 =13.6,
J2 =J2 =5.9 Hz, 1H; H-5’b), 1.60 (septet, J=6.9 Hz, 1H; Me2CH), 0.87
(d, J=6.9 Hz, 6H; (CH3)2CH), 0.84 (s, 6H; C(CH3)2), 0.08/0.07 ppm (2s,
6H; CH3Si); 13C NMR (63MHz, [D 4]MeOH): d=159.4 (C6), 155.2 (C2),
153.8 (C4), 152.7 (C3’), 137.3 (C8), 128.8 (C5), 124.4 (C2’), 64.8
(CH2OSi), 60.9 (CH2OH), 59.3(C1 ’), 48.6 (C4’), 36.7 (C5’), 35.5
(Me2CH), 26.3(Me 2CSi), 20.93/20.84 ((CH3)2CH), 19.00/18.96
(ꢁ)-(1’R,4’S)-5-Fluoro-1-[4’-(tert-butyldiphenylsilanyloxymethyl)-3’-hy-
droxymethyl-cyclopent-2’-enyl]-1H-pyrimidine-2,4-dione (9i): When the
general protocol for the reduction was followed, 23i (25 mg, 50 mmol) af-
forded the alcohol 9i (25 mg, 99%) as a colorless oil. Rf =0.43(EtOAc/
CyHex 4:1); [a]D20 =ꢁ42.1 (c=0.44 in CHCl3), [a]25406 =ꢁ51.5; 1H NMR
(250 MHz, CDCl3): d=9.20 (brs, 1H; NH), 7.64–7.58 (m, 4H; Ph), 7.46–
7.35 (m, 6H; Ph), 7.31 (d, J(H,F)=5.9 Hz, 1H; H-6), 5.56 (m, 2H; H-1’,
H-2’), 4.35 (d, J=14.7 Hz, 1H; CHaOH), 4.25 (d, J=14.8 Hz, 1H;
CHbOH), 3.73 (dd, J1 =10.5, J2 =4.4 Hz, 1H; SiOCHa), 3.64 (dd, J1 =
10.5, J2 =5.9 Hz, 1H; SiOCHb), 2.88 (m, 1H; H-4’), 2.63(ddd, J1 =14.0,
J2 =J3 =8.7 Hz, 1H; H-5’a), 1.37 (ddd, J1 =14.0, J2 =J3 =7.3Hz, 1H; H-
5’b), 1.06 ppm (s, 9H; (CH3)CSi); 13C NMR (63MHz, CDCl 3): d=153.6
(C3’), 149.5 (C2), 135.54/135.48/132.6/130.11/130.08/128.0 (all Ph), 125.0
(d, J(C,F)=33 Hz, C6), 123.9 (C2’), 65.1 (CH2OSi), 60.7 (CH2OH), 60.3
(C1’), 46.8 (C4’), 34.0 (C5’), 26.9 (SiC(CH3)3), 19.2 ppm (SiC(CH3)3); IR
ꢁ
((CH3)2CSi), ꢁ3.4 ppm ((CH3)2Si); IR (ATR): n˜ =3364 (m, O H), 3191
ꢁ
ꢁ
(m, N H), 2954/2865 (m, C H), 1686 (s, C=O), 1638 (s, C=N), 1608 (m,
C=C), 1251 cmꢁ1 (m, C O); MS (ESI, 70 eV): m/z (%): 861 (55)
ꢁ
[2M+Na]+, 442 (100) [M+Na]+; HRMS (ESI): calcd for C20H33N5NaO3-
Si: 442.225 [M+Na]+; found: 442.225.
ꢁ
ꢁ
ꢁ
(ATR): n˜ =3399 (w, O H), 3176/3065 (m, N H), 2927/2890/2854 (m, C
ꢁ1
ꢁ
H), 1696 (s, C=O), 1659 (s, C=N), 1239 (s, C O), 1109 (s), 702 cm (s);
(+)-(1’S,4’R)-2-Amino-9-{4’-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy-
methyl]-3’-hydroxymethyl-cyclopent-2’-enyl}-1,9-dihydro-purin-6-one
(ent-9 f): When the protocol for the reduction and deprotection as de-
scribed for 9 f was followed, ent-23 f (65 mg, 0.1 mmol) afforded the alco-
hol ent-9 f (32 mg, 76%) as a white solid. [a]2D0 =+68.1 (c=0.42 in
MeOH).
MS (EI, 70 eV): m/z (%): 437 (14) [MꢁC4H9]+, 229 (41), 199 (100);
HRMS (EI): calcd for C23H22FN2O4Si: 437.133 [MꢁC4H9]+; found:
437.133.
(+)-(1’R,4’S)-5-Bromo-1-[4’-(tert-butyldiphenylsilanyloxymethyl)-3’-hy-
droxymethyl-cyclopent-2’-enyl]-1H-pyrimidine-2,4-dione (9j): When the
general protocol for the reduction was followed, 23j (55 mg, 0.1 mmol)
(ꢁ)-(1’R,4’S)-9-{4’-[Dimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl]-
3’-hydroxymethyl-cyclopent-2’-enyl}-9H-purin-6-ylamine (9g): When the
general protocol for the reduction was followed, 23g (40 mg, 0.1 mmol)
afforded the alcohol 9g (37 mg, 93%) as a pale-yellow solid. M.p. 203–
2058C; Rf =0.33 (EtOAc/MeOH 4:1); [a]2D0 =ꢁ27.2 (c=0.34 in MeOH),
[a]25046 =ꢁ31.4; 1H NMR (250 MHz, [D4]MeOH): d=8.21 (s, 1H; H-2),
8.06 (s, 1H; H-8), 5.85 (dd, J1 =J2 =1.8 Hz, 1H; H-2’), 5.59 (m, 1H; H-
afforded the alcohol 9j (56 mg, 99%) as
a colorless oil. Rf =0.39
(EtOAc/CyHex 4:1); [a]D20 =+18.5 (c=0.52 in CHCl3), [a]25406 =+21.7;
1H NMR (250 MHz, CDCl3): d=9.74 (s, 1H; NH), 7.64–7.58 (m, 4H;
Ph), 7.52 (s, 1H; H-6), 7.43–7.34 (m, 6H; Ph), 5.58 (d, J=1.7 Hz, 1H; H-
2’), 5.55 (dd, J1 =J2 =8.2 Hz, 1H; H-1’), 4.37 (d, J=14.6 Hz, 1H;
CHaOH), 4.27 (d, J=14.7 Hz, 1H; CHbOH), 3.71 (dd, J1 =10.5, J2 =
4.6 Hz, 1H; SiOCHa), 3.63 (dd, J1 =10.5, J2 =6.0 Hz, 1H; SiOCHb), 2.87
(m, 2H; H-4’, OH), 2.61 (ddd, J1 =13.7, J2 =J3 =8.2 Hz, 1H; H-5’a), 1.33
(ddd, J1 =13.6, J2 =J3 =7.4 Hz, 1H; H-5’b), 1.06 ppm (s, 9H; (CH3)3CSi);
13C NMR (63MHz, CDCl 3): d=159.2 (C4), 153.6 (C3’), 150.4 (C2), 140.3
(C6), 135.50/135.48/132.61/132.58/130.07/130.03/127.9 (all Ph), 123.7 (C2’),
96.7 (C5), 65.0 (CH2OSi), 61.0 (CH2OH), 60.6 (C1’), 46.8 (C4’), 34.5
(C5’), 26.9 ((CH3)3CSi), 19.2 ppm ((CH3)3CSi); IR (ATR): n˜ =3425 (w,
1’), 4.38 (d, J=15.3Hz, 1H; C HaOH), 4.23(d,
J=15.3Hz, 1H;
CHbOH), 3.76 (dd, J1 =10.3, J2 =4.7 Hz, 1H; SiOCHa), 3.66 (dd, J1 =
10.3, J2 =4.1 Hz, 1H; SiOCHb), 2.99 (m, 1H; H-4’), 2.84 (ddd, J1 =13.4,
J2 =J3 =8.6 Hz, 1H; H-5’a), 1.85 (ddd, J1 =13.4, J2 =J2 =5.4 Hz, 1H; H-
5’b), 1.57 (septet, J=6.8 Hz, 1H; (Me2CH), 0.84 (d, J=6.8 Hz, 6H;
(CH3)2CH), 0.82 (s, 6H; C(CH3)2), 0.06/0.04 ppm (2s, 6H; CH3Si);
13C NMR (63MHz, [D 4]MeOH): d=155.2/153.7/152.7 (C2, C4, C6), 152.0
(C3’), 137.3 (C8), 136.68/136.64/134.50/134.42/131.00/130.96 (all Ph), 124.4
(C2’), 117.9 (C5), 66.2 (CH2OSi), 61.0 (CH2OH), 59.9 (C1’), 48.5 (C4’),
36.7 (C5’), 35.4 ((CH3)2CH), 26.3(Me 2CSi), 20.95/20.83(( CH3)2CH),
ꢁ
ꢁ
ꢁ
ꢁ
O H), 3173 (w, N H), 3065 (m, N H), 2927/2854 (m, C H), 1691 (s, C=
O), 1683(s, C =O), 1615 (m, C=C), 702 cmꢁ1 (s); MS (ESI, 70 eV): m/z
(%): 583(100), 581 (92), 579 (46), 577 (42) [ M+Na]+, 501 (67); HRMS
(ESI): calcd for C27H31BrN2NaO4Si: 577.113[ M+Na]+; found: 577.114.
ꢁ
18.99/18.93(( CH3)2CSi), ꢁ3.4 ppm (CH3Si); IR (ATR): n˜ =3357 (s, O
ꢁ
ꢁ
H), 3304 (s, N H), 2956/2865 (m, C H), 1643(m, C =C), 1606 (s),
(ꢁ)-(1’R,4’S)-4-Amino-1-[4’-(tert-butyldiphenylsilanyloxymethyl)-3’-hy-
droxymethyl-cyclopent-2’-enyl]-1H-pyrimidin-2-one (9k): When the gen-
eral protocol for the reduction was followed, 23k (29 mg, 50 mmol) af-
forded the corresponding protected alcohol (23mg, 79%) as a light-
+
1250 cmꢁ1 (m, C O); MS (EI, 70 eV): m/z (%): 318 (28) [MꢁC6H13] ,
ꢁ
136 (100); HRMS (ESI): calcd for C20H33N5O2Si: 404.248 [M+H]+;
found: 404.248.
5106
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5087 – 5110

Carbocyclic Nucleoside Analogues
5087 – 5110
yellow solid (m.p. 190–1938C; Rf =0.54, EtOAc/MeOH 4:1). By using the
ammonolysis method described for ent-9e, the protected alcohol (20 mg,
35 mmol) was converted into the alcohol 9k (16 mg, 96%), which was ob-
tained as a white solid. M.p. 198–2018C; Rf =0.33 (EtOAc/MeOH 4:1);
[a]D20 =ꢁ54.5 (c=0.31 in MeOH), [a]52406 =ꢁ67.6; 1H NMR (250 MHz,
CDCl3): d=7.60–7.56 (m, 4H; Ph-H), 7.42–7.33 (m, 7H; H-6, Ph-H),
5.61–5.48 (m, 3H; H-1’, H-2’, H-5), 4.34 (d, J=14.6 Hz, 1H; CHaOH),
4.24 (d, J=14.6 Hz, 1H; CHbOH), 3.74–3.52 (m, 4H; SiOCH2, NH2),
2.84 (m, 1H; H-4’), 2.64 (m, 1H; H-5’a), 1.28 (m, 1H; H-5’b), 1.03ppm
(s, 9H; Si(CH3)3); 13C NMR (63MHz, CDCl 3): d=153.4 (C3’), 142.8
(C6), 135.53/135.48/132.9/132.6/130.06/129.94/127.89/127.83 (all Ph), 125.1
(C2’), 94.6 (C5), 65.5 (CH2OSi), 61.7 (C1’), 60.8 (CH2OH), 46.9 (C4’),
34.8 (C5’), 26.9 (SiC(CH3)3), 19.2 ppm (SiC(CH3)3); IR (ATR): n˜ =3338
2.0 Hz, 1H; H-3), 5.89 (tdd, J1 =17.1, J2 =10.3, J3 =6.3Hz, 1H; C H=
CH2), 5.37 (s, 1H; H-8), 5.26 (ddd, J1 =17.1, J2 =1.5, J3 =1.2 Hz, 1H;
ꢁ
ꢁ
CH=CH Htrans), 5.17 (ddd, J1 =10.3, J2 =J3 =1.2 Hz, 1H; CH=CH Hcis),
ꢁ
4.20 (dd, J1 =J2 =7.8 Hz, 1H; H-6a), 4.18 (m, 1H; CHHa CH=CH2),
ꢁ
3.99 (dd, J1 =12.2, J2 =6.3Hz, 1H; CH Hb CH=CH2), 3.43 (d, J=0.7 Hz,
3H; CH3O), 3.40 (dd, J1 =J2 =7.3 Hz, 1H; H-6b), 3.31 (m, 1H; H-5), 3.00
(ddd, J1 =12.7, J2 =J3 =6.6 Hz, 1H; H-4a), 1.27 (ddd, J1 =12.2, J2 =J3 =
8.1 Hz, 1H; H-4b), 0.03ppm (s, 9H; SiCH 3); 13C NMR (63MHz, CDCl 3):
d=177.3( C=O), 159.1 (C1), 135.0 (C2), 134.1 (CH=CH2), 131.6/129.7/
128.5/127.6 (all Ph), 123.4 (d, J(C,F)=289 Hz, CF3), 118.0 (CH=CH2),
97.0 (C8), 91.5 (C3), 84.9 (d, J(C,F)=27 Hz, CF3C), 71.7 (C6), 68.4
(CH2CH=CH2), 55.2 (OCH3), 46.7 (C5), 40.1 (C4), ꢁ1.1 ppm (SiC); IR
ꢁ
(ATR): n˜ =2945/2891/2851 (m, C H), 1742 (C=O), 1662 (m, C=C), 1268
ꢁ
ꢁ
ꢁ
(brs, O H/N H), 2953/2928/2854 (m, C H), 1714 (w, C=O), 1640 (s, C=
N), 1486 (s), 778 (s), 738 cmꢁ1 (s); MS (ESI, 70 eV): m/z (%): 973(14)
[2M+Na]+, 951 (3) [2M+H]+, 498 (100) [M+Na]+; HRMS (ESI): calcd
for C27H33N3NaO3Si: 498.219 [M+Na]+; found: 498.219.
(s), 1248 (s), 1167 (s), 1117 (s), 1077 (s), 1021 (s), 941 (s), 838 (s), 762 (s),
721 (s), 697 cmꢁ1 (s); MS (EI, 70 eV): m/z (%): 455 (2) [MꢁCH3]+, 189
+
(100) [CF3C(Ph)OMe]+, 170 (64), 126 (42), 83(87), 77 (29) [Ph]
.
(ꢁ)-(2S,3’R,5’S,8’R)-3,3,3-Trifluoro-2-methoxy-2-phenyl propionic acid
(8’-allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl) ester (25a): Ester 25a
(53mg, 67%) was obtained from alcohol 20 (36 mg, 200 mmol) as a color-
less oil by using the DCC method described for the preparation of 24a.
(ꢁ)-(1’R,4’S)-2-Amino-9-[4’-(tert-butyldiphenylsilanyloxymethyl)-3’-hy-
droxymethyl-cyclopent-2’-enyl]-1,9-dihydro-purin-6-one (9l): When the
one-pot procedure described for 9 f was followed, 23l (38 mg, 50 mmol)
afforded the alcohol 9l (26 mg, 99% over 2 steps) as a white solid. M.p.
>2608C (decomp.); Rf =0.50 (EtOAc/MeOH 4:1); [a]2D0 =ꢁ34.8 (c=0.72
Rf =0.59 (EtOAc/CyHex 1:1); [a]2D0 =ꢁ123.1 (c=0.99 in CHCl3), [a]25046
=
ꢁ146.5; 1H NMR (250 MHz, CDCl3): d=7.51 (m, 2H; Ph), 7.39 (m, 3H;
Ph), 6.18 (dddd, J1 =J2 =7.1, J3 =6.6, J4 =1.5 Hz, 1H; H-3), 5.89 (dddd,
J1 =17.1, J2 =10.3, J3 =5.9, J4 =5.4 Hz, 1H; CH=CH2), 5.71 (s, 1H; H-2),
20
1
in MeOH), [a] =ꢁ40.6; H NMR (250 MHz, [D4]MeOH): d=7.60–7.32
546
(m, 11H; Ph, H-8), 5.84 (s, 1H; H-2’), 5.39 (m, 1H; H-1’), 4.37 (d, J=
15.6 Hz, 1H; CHaOH), 4.19 (d, J=15.7 Hz, 1H; CHbOH), 3.79 (dd, J1 =
10.3, J2 =4.9 Hz, 1H; SiOCHa), 3.69 (dd, J1 =10.3, J2 =5.7 Hz, 1H;
SiOCHb), 2.99 (m, 1H; H-4’), 2.72 (ddd, J1 =13.7, J2 =J3 =8.5 Hz, 1H;
H-5’a), 1.81 (ddd, J1 =13.3, J2 =J2 =6.2 Hz, 1H; H-5’b), 1.02 ppm (s, 9H;
Si(CH3)3); 13C NMR (63MHz, [D 4]MeOH): d=155.2/153.7/152.7 (C2,
C4, C6), 152.0 (C3’), 137.1 (C8), 136.68/136.64/134.50/134.42/131.00/
130.96 (all Ph), 124.4 (C2’), 117. 9 (C5), 66.2 (CH2OSi), 61.0 (CH2OH),
59.9 (C1’), 48.5 (C4’), 36.7 (C5’), 27.4 (SiC(CH3)3), 20.1 ppm (SiC(CH3)3);
ꢁ
5.40 (s, 1H; H-8), 5.27 (ddt, J1 =17.1, J2 =1.7, J3 =1.5 Hz, 1H; CH=CH
ꢁ
Htrans), 5.17 (ddt, J1 =10.3, J2 =1.5, J3 =1.2 Hz, 1H; CH=CH Hcis), 4.25
(dd, J1 =J2 =7.6 Hz, 1H; H-6a), 4.18 (ddt, J1 =12.7, J2 =5.4, J3 =1.5 Hz,
ꢁ
1H; CHHa CH=CH2), 4.01 (ddt, J1 =6.1, J2 =2.7, J3 =1.5 Hz, 1H;
ꢁ
CHHb CH=CH2), 3.52 (d, J=1.0 Hz, 3H; CH3O), 3.45 (dd, J1 =J2 =
7.6 Hz, 1H; H-6b), 3.36 (m, 1H; H-5), 2.87 (ddd, J1 =12.9, J2 =J3 =
6.8 Hz, 1H; H-4a), 1.62 ppm (ddd, J1 =12.7, J2 =J3 =7.6 Hz, 1H; H-4b);
13C NMR (63MHz, CDCl 3): d=166.0 (C=O), 151.1 (C1), 134.1 (CH=
CH2), 132.0/129.6/128.4/127.3 (all Ph), 123.2 (d, J(C,F)=289 Hz, CF3),
121.3(C2), 117.5 (CH =CH2), 96.6 (C8), 86.1 (C3), 84.3 (CF3C), 72.2 (C6),
68.1 (CH2CH=CH2), 55.4 (OCH3), 45.0 (C5), 38.7 ppm (C4); IR (ATR):
ꢁ
ꢁ
ꢁ
IR (ATR): n˜ =3350 (m, O H), 3317/3191 (m, N H), 2934/2891 (m, C
H), 1683(s, C =O), 1603(m, C =C), 701 cmꢁ1 (s); MS (ESI, 70 eV): m/z
(%): 339 (100).
(ꢁ)-(2S,3’R,5’S,8’R)-3,3,3-Trifluoro-2-methoxy-2-phenyl propionic acid
ꢁ
ꢁ
n˜ =2977/2926/2848 (w, C H), 1743(s, C =O), 1664 (w, C=C), 1251 (s, C
O), 1166 (s), 1018 (s), 993cm ꢁ1 (s); MS (EI, 70 eV): m/z (%): 398 (2)
[M]+, 190 (42), 189 (100) [CF3C(Ph)OMe]+, 170 (45), 105 (51), 83(91),
77 [Ph]+ (35).
(8’-allyloxy-2’-trimethylsilyl-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)
ester
(24a): A solution of DCC (46 mg, 220 mmol) in dry CH2Cl2 (0.5 mL) was
added at 08C to a solution of alcohol 18 (51 mg, 200 mmol), (S)-MTPA
(52 mg, 97% ee, 220 mmol), and DMAP (3mg, 98%, 24 mmol) in dry
CH2Cl2 (0.5 mL). The formation of a white suspension was observed. The
mixture was allowed to warm to RT and was stirred for 16 h. The mixture
was purified directly by flash chromatography (EtOAc/CyHex 1:9) to
afford the ester 24a as a colorless oil (84 mg, 89%). Rf =0.72 (EtOAc/
(+)-(2S,3’S,5’R,8’S)-3,3,3-Trifluoro-2-methoxy-2-phenyl propionic acid
(8’-allyloxy-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl) ester (25b): Ester 25b
(57 mg, 72%) was obtained from alcohol ent-20 (36 mg, 200 mmol) as a
colorless oil by using the DCC method described for preparation of 24a.
Rf =0.48 (EtOAc/CyHex 1:1); [a]2D0 =+33.2 (c=1.05 in CHCl3), [a]25046
=
1
CyHex 1:1); [a]2D0 =ꢁ154.6 (c=0.875 in CHCl3), [a]25406 =ꢁ184.4; H NMR
+39.4; 1H NMR (250 MHz, CDCl3): d=7.50 (m, 2H; Ph), 7.39 (m, 3H;
Ph), 6.18 (dddd, J1 =J2 =6.8, J3 =J4 =1.5 Hz, 1H; H-3), 5.90 (ddt, J1 =
17.3, J2 =10.5, J3 =6.1 Hz, 1H; CH=CH2), 5.78 (s, 1H; H-2), 5.41 (s, 1H;
(250 MHz, CDCl3): d=7.53(m, 2H; Ph), 7.37 (m, 3H; Ph), 6.08 (tdd,
J1 =7.8, J2 =5.9, J3 =1.7 Hz, 1H; H-3), 5.89 (tdd, J1 =16.8, J2 =10.3, J3 =
J4 =6.6 Hz, 1H; CH=CH2), 5.38 (s, 1H; H-8), 5.26 (ddd, J1 =17.1, J2 =1.7,
ꢁ
H-8), 5.27 (ddd, J1 =17.3, J1 =1.7, J3 =1.5 Hz, 1H; CH=CH Htrans), 5.18
ꢁ
J3 =1.5 Hz, 1H; CH=CH Htrans), 5.17 (tdd, J1 =10.3, J2 =1.7, J3 =1.0 Hz,
ꢁ
(tdd, J1 =10.3, J2 =J3 =1.2 Hz, 1H; CH=CH Hcis), 4.24 (dd, J1 =J2 =
ꢁ
1H; CH=CH Hcis), 4.22 (dd, J1 =J2 =8.1 Hz, 1H; H-6a), 4.12 (ddd, J1 =
ꢁ
7.6 Hz, 1H; H-6a), 4.19 (ddt, J1 =12.7, J2 =5.4, J3 =1.5 Hz, 1H; CHHa
CH=CH2), 4.01 (ddt, J1 =12.7, J2 =6.1, J3 =1.5 Hz, 1H; CHHb CH=
ꢁ
12.5, J2 =5.4, J3 =1.2 Hz, 1H; CHHa CH=CH2), 3.99 (ddd, J1 =12.5, J2 =
6.6, J3 =1.2 Hz, 1H; CHHb CH=CH2), 3.58 (d, J(H,F)=1.5 Hz, 3H;
ꢁ
ꢁ
CH2), 3.54 (d, J(H,F)=1.2 Hz, 3H; CH3O), 3.42 (dd, J1 =J2 =7.1 Hz, 1H;
H-6b), 3.36 (m, 1H; H-5); 2.83 (ddd, J1 =12.9, J2 =J3 =6.8 Hz, 1H; H-
4a), 1.52 ppm (ddd, J1 =12.7, J2 =J3 =7.6 Hz, 1H; H-4b); 13C NMR
(63MHz, CDCl 3): d=166.0 (C=O), 151.3(C1), 134.1 ( CH=CH2), 132.1/
129.7/128.5/127.2 (all Ph), 123.2 (d, J(C,F)=289 Hz, CF3), 121.2 (C2),
117.5 (CH=CH2), 96.6 (C8), 86.2 (C3), 84.5 (d, J(C,F)=28 Hz, CF3C),
72.2 (C6), 68.1 (CH2CH=CH2), 55.4 ppm (OCH3), 45.0 (C5), 38.5 (C4);
CH3O), 3.45 (dd, J1 =J2 =7.8 Hz, 1H; H-6b), 3.33 (m, 1H; H-5), 3.03
(ddd, J1 =12.2, J2 =6.8, J3 =5.9 Hz, 1H; H-4a), 1.40 (ddd, J1 =12.2, J2 =
J3 =8.5 Hz, 1H; H-4b), ꢁ0.14 ppm (s, 9H; SiCH3); 13C NMR (63MHz,
CDCl3): d=177.5 (C=O), 158.8 (C1), 135.4 (C2), 134.1 (CH=CH2), 132.4/
129.5/128.3/126.9 (all Ph), 123.3 (d, J(C,F)=289 Hz, CF3), 118.0 (CH=
CH2), 97.0 (C8), 91.3(C3), 84.7 (d, J(C,F)=28 Hz, CF3C), 71.7 (C6), 68.4
(CH2CH=CH2), 55.7 (OCH3), 46.8 (C5), 40.7 (C4), ꢁ1.4 ppm (SiC); IR
ꢁ
ꢁ
IR (ATR): n˜ =2976/2944/2848 (w, C H), 1743(s, C =O), 1250 (s, C O),
1180 (s), 1166 (s), 1018 (s), 993cm ꢁ1 (s); MS (EI, 70 eV): m/z (%): 341
(19) [MꢁC3H5O]+, 189 (100) [CF3C(Ph)OMe]+, 119 (55), 105 (41), 91
(42), 79 (49), 77 (34) [Ph]+.
ꢁ
ꢁ
(ATR): n˜ =2947 (s, C H), 2892/2849 (w, C H), 1742 (C=O), 1662 (w, C=
ꢁ
C), 1268 (s), 1246 (s, C O), 1165 (s), 1118 (s), 1077 (s), 1020 (s), 987 (s),
941 (s), 837 (s), 762 (s), 720 (s), 696 cmꢁ1 (s); MS (EI, 70 eV): m/z (%):
189 (41) [CF3C(Ph)OMe]+, 91 (100), 77 (11) [Ph]+; GC (HP-5 column,
50!3008C over 2 min, gradient: 258Cminꢁ1): Rt =9.20 min.
(ꢁ)-(1’R,4’S)-2-Amino-9-[3’,4’-bis(hydroxymethyl)-2’-cyclopenten-1’-yl]-
9H-purine-6-one (26a): A 1m solution of TBAF in THF (150 mL) was
added to a solution of alcohol 9 f (33 mg, 75 mmol) in THF (0.5 mL) at
RT and the mixture was stirred for 16 h. The solvent was evaporated and
the residue purified by flash chromatography (EtOAc!EtOAc/MeOH
4:1!3:2 !2:3). The diol 26a was obtained as a white solid (14 mg, 67%
yield over 3steps from aldehyde 23 f). Rf =0.22 (EtOAc/MeOH 1:1);
[a]2D0 =ꢁ11.8 (c=0.34 in H2O; literature value:[57a] [a]2D0 =ꢁ12.8 (c=0.25
(+)-(2S,3’S,5’R,8’S)-3,3,3-Trifluoro-2-methoxy-2-phenyl propionic acid
(8’-allyloxy-2’-trimethylsilyl-7’-oxa-[3.3.0]-bicyclooct-1’-ene-3’-yl)
ester
(24b): Ester 24b (89 mg, 95%) was obtained from the alcohol ent-18
(51 mg, 200 mmol) as a colorless oil, by using the DCC method described
for the preparation of 24a. Rf =0.56 (EtOAc/CyHex 1:1); [a]2D0 =+106.1
1
(c=0.90 in CHCl3), [a]25406 =+125.7; H NMR (250 MHz, CDCl3): d=7.48
(m, 2H; Ph), 7.39 (m, 3H; Ph), 6.16 (dddd, J1 =J2 =7.6, J3 =5.9, J4 =
Chem. Eur. J. 2004, 10, 5087 – 5110
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5107

H.-G. Schmalz et al.
FULL PAPER
in H2O)); the spectral data were in accordance with those reported in the
literature.[57a]
again and the ECL (enhanced chemiluminescence) system from Amer-
sham Buchler (Braunschweig, Germany) was used to visualize the pro-
tein bands in question.
(ꢁ)-(1’R,4’S)-9-[3’,4’-Bis(hydroxymethyl)-2’-cyclopenten-1’-yl]-9H-
purine-6-ylamine (26b): When the desilylation procedure described for
the preparation of 26a was followed, 9g (10.5 mg, 25 mmol) afforded the
diol 26b (6.5 mg, 99%) as a white solid. For purification, flash chroma-
tography (EtOAc/MeOH 4:1) was used. Rf =0.40 (EtOAc/MeOH 1:1);
[a]2D0 =ꢁ30.3 (c=0.33 in H2O; literature value:[57a] [a]2D0 =ꢁ25.8 (c=0.66
in H2O)); the spectral data were in accordance with those reported in the
literature.[57a]
Acknowledgment
This work was supported by the Fond der Chemischen Industrie (Fonds
Stipendium to A.L.). We also thank Dr. D. Blunk, Dr. H. Schmickler, Dr.
J. Neudörfl, and Dr. M. Schäfer for their support in the application of ad-
vanced CD spectroscopy, NMR spectroscopy, X-ray crystallography, and
MS techniques. Generous gifts of chemicals from Chemetall AG and De-
gussa AG are highly appreciated. A.P. and T.W. thank the Deutsche JosØ
Carreras Leukämie-Stiftung, the Verein zur Förderung der Tagesklinik,
and the Berliner Krebsgesellschaft for support. The authors would also
like to thank Dr. P. T. Daniel for kindly providing BJAB cells and labora-
tory equipment. Technical assistance by A. Richter in the performance of
cell assays is gratefully acknowledged.
Materials and methods for the biological investigations
Materials: Polyclonal rabbit anti-human-caspase-3antibody (developed
against the human recombinant protein) was from PharMingen (Ham-
burg, Germany), murine monoclonal anti-human-caspase-8 antibody has
been described previously,[58] and polyclonal goat anti-human-caspase-9
antibody was from R&D Systems (Wiesbaden, Germany). Primary anti-
bodies were used at 1:2000. Secondary anti-mouse and anti-rabbit anti-
bodies conjugated with horseradish peroxidase (HRP) were from Prome-
ga (Mannheim, Germany) and secondary anti-goat HRP-conjugated anti-
bodies were from Santa Cruz (Heidelberg, Germany) and were used at
1:5000. RNase A was from Roth (Karlsruhe, Germany).
Cell culture: Leukemic lymphoblasts were obtained from bone marrow
aspirations of patients with childhood acute lymphoblastic leukemia
(ALL) and were separated by centrifugation over Ficoll (Biochrom KG,
Berlin, Germany). ALL cells or BJAB cells were grown in RPMI 1640
medium (RPMI=Rosewell Park Memorial Institute) supplemented with
10% fetal calf serum, 0.56 gLꢁ1 l-glutamine, 100000 ULꢁ1 penicillin, and
0.1 gLꢁ1 streptomycin. Media and culture reagents were from Life Tech-
nologies GmbH (Karlsruhe, Germany). BJAB cells were subcultured
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every 3–4 days by dilution of the cells to
a concentration of 1ꢁ
105 cellsmLꢁ1
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centrifuged for 5 min at 200 g. The cytospins were Haemalaun–Eosin
stained and then analyzed under a microscope.
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Measurement of cell death: Cytotoxicity was measured by release of
LDH as described previously.[58] After incubation with different concen-
trations of the nucleosides, LDH activity released by BJAB cells was
measured in the cell-culture supernatants by using a Cytotoxicity Detec-
tion Kit from Boehringer-Mannheim (Mannheim, Germany). The super-
natants were centrifuged at 300 g for 5 min. Cell-free supernatants
(20 mL) were diluted with phosphate-buffered saline (PBS, 80 mL) and a
reaction mixture containing 2-[4-iodophenyl]-3-[4-nitrophenyl]-5-phenyl-
tetrazolium chloride (INT), sodium lactate, oxidized nicotinamide ade-
nine dinucleotide (NAD+), and diaphorase (100 mL) was added. Time-
dependent formation of the reaction product was then quantified photo-
metrically at 490 nm. The maximum amount of LDH activity released by
the cells was determined by lysis of the cells by using 0.1% Triton X-100
in culture medium; this value was set as 100% cell death.
Measurement of DNA fragmentation: DNA fragmentation was measured
essentially as described.[60] After treatment with different concentrations
of the nucleosides for 48 h, cells were collected by centrifugation at 300 g
for 5 min. Cells were washed with PBS at 48C. Cells were fixed in 0.74%
formaldehyde in PBS on ice for 30 min, pelleted, incubated with ethanol/
PBS (2:1) for 15 min, pelleted, and resuspended in PBS containing
40 mgmLꢁ1 RNase A. The RNA was digested for 30 min at 378C. Cells
were pelleted again and finally resuspended in PBS containing
50 mgmLꢁ1 propidium iodide. Nuclear DNA fragmentation was quanti-
fied by flow-cytometric determination of hypodiploid DNA (Fluores-
cence-activated cell sort, FACS). Data were collected and analyzed by
using a FACScan (Becton Dickinson; Heidelberg, Germany) apparatus
equipped with CELLQuest software. Data are given in %hypoploidy
(subG1), a value which reflects the number of apoptotic cells.
Western blot analysis: Cytosolic protein (15 mg) was loaded in each lane
and was separated by sodium dodecylsulfate (SDS) PAGE as previously
described in detail.[61] After blotting of proteins onto nitrocellulose mem-
branes (Schleicher and Schuell, Dassel, Germany), the membrane was
blocked for 1 h in PBST (PBS containing 0.05% Tween-20) containing
3% nonfat dry milk and incubated with primary antibody for 1 h. After
the membrane had been washed three times in PBST, secondary antibody
in PBST was applied for 1 h. Finally, the membrane was washed in PBST
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b=9.699(1), c=12.492(1) Š, b=100.61(1)8, V=1725.8(3) Š3, T=
293(2) K, space group P21/n, Z=4,
d
calcd =1.141 gcmꢁ3
,
m=
0.145 mmꢁ1. A total of 3575 reflections were measured, of which
2585 (Rint =0.0738) were unique. Final residuals were R1=0.0612
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ꢁ3
279 parameters) with GOF 1.009, largest residual peak 0.224 eŠ
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b=8.875(1), c=12.135(1) Š, a=109.05(1)8, b=93.46(1)8, g=
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d
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Chem. Eur. J. 2004, 10, 5087 – 5110
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H.-G. Schmalz et al.
FULL PAPER
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Received: January 23, 2004
Revised: June 8, 2004
Published online: September 2, 2004
5110
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www.chemeurj.org
Chem. Eur. J. 2004, 10, 5087 – 5110