Synthesis and biological evaluation of potent bisubstrate inhibitors of the enzyme catechol O-methyltransferase (COMT) lacking a nitro group

Article abstract of DOI:10.1002/hlca.200690179

Inhibition of the enzyme catechol O-methyltransferase (COMT) represents a viable strategy for regulation of the catabolism of catecholamine neurotransmitters or their precursors, and is of considerable interest in the therapy of Parkinson's, disease. Here

Full text of DOI:10.1002/hlca.200690179

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Helvetica Chimica Acta – Vol. 89 (2006)
Synthesis and Biological Evaluation of Potent Bisubstrate Inhibitors of the
Enzyme Catechol O-Methyltransferase (COMT)Lacking a Nitro Group
by Ralph Paulinia), Christian Lernera), FranÅois Diederich*a), Roland Jakob-Roetneb), Gerhard
Zürcherb), and Edilio Borronib)
a) Laboratorium für Organische Chemie, ETH-Zürich, Hçnggerberg, HCI, CH-8093 Zürich
(e-mail: diederich@org.chem.ethz.ch)
b) Pharma Division, Präklinische Forschung, F. Hoffmann-La Roche AG, CH-4070 Basel
Inhibition of the enzyme catechol O-methyltransferase (COMT) represents a viable strategy for reg-
ulation of the catabolism of catecholamine neurotransmitters or their precursors, and is of considerable
interest in the therapy of Parkinsonꢀs disease. Herein, we report the development of a new generation of
potent bisubstrate inhibitors of COMT derived from nitro-substituted ligand 1 (Ki =28n M, Table 1),
which achieve high biological activity despite the lack of a NO2 substituent on the catechol moiety.
Their synthesis takes advantage of a convergent approach, in which a series of functionalized catechol
intermediates is prepared (Schemes 2–7) and coupled to a common adenosine-derived allylic amine
building block (Scheme 8). Biological activities of the newly synthesized inhibitors, determined by in
vitro enzymatic assay and kinetic studies, clearly demonstrate that high inhibitory potency of the bisub-
strate inhibitors is not correlated with the pKa of the catechol OH groups. Aromatic residues, connected
to the catechol via a biaryl-type linkage, were found to maximally benefit from additional favorable
hydrophobic interactions with the enzyme and thus to be preferred replacements of the NO2 group in
1. A competitive kinetic inhibition mechanism (Fig. 2) with respect to the cofactor binding site was con-
firmed in all cases, supporting a bisubstrate inhibition mode for inhibitors 2–19.
1. Introduction. – Catechol O-methyltransferase (COMT) is an important enzyme
involved in catecholamine catabolism, which, in the presence of Mg2+ ions, catalyzes
the O-methylation of biologically active catechols such as dopamine or its precursor
L-Dopa [1] (for a crystal structure of COMT, see [1d]). Thus, inhibition of COMTallows
for regulation of catechol-based neurotransmitter levels and offers an important ther-
apeutic approach to the treatment of central nervous system (CNS) disorders such as
Parkinsonꢀs disease [2] and possibly schizophrenia [2d][3] and depression [4]. Nitro-
substituted catechols are potent COMT inhibitors, and two of them (tolcapone
(Tasmarꢁ) [5] and entacapone (Comtanꢁ) [6]) have been developed as therapeutic
adjuncts to the L-Dopa-based treatment of Parkinsonꢀs disease, reducing the peripheral
metabolic degradation and significantly prolonging the beneficial effects of L-Dopa.
However, adverse effects of hepatotoxicity1) associated in rare cases with the use of tol-
capone [7] have been related to the NO2 substituent of the catechol (=benzene-1,2-
diol) structural unit [8]. Therefore, the development of potent COMT inhibitors lack-
ing this functional group is desirable. Such an endeavor faces the challenge of replacing
1
)
For a controversial discussion on entacapone-induced hepatotoxicity, see [7b]; however, hepatotox-
icity is believed not to be a class effect of nitrocatechols [7d].
ꢂ 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
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Fig. 1. a) Computer model (MOLOC) of bisubstrate inhibitor 3 complexed in the active site of COMT
in the presence of a Mg2+ ion. The Connolly surface of the inhibitor is shown. b) Detailed view of the
catechol binding site. Inhibitor skeleton: green, C-atoms: gray, O-atoms: red, N-atoms: blue, S-atoms:
yellow, Mg-atom: black. Distances are given in Š.
a structural element, which, by its electron-withdrawing effect, ensures both high bind-
ing affinity and reduced O-methylation of the respective inhibitors. In fact, the NO2
group has been regarded key element for tight and reversible binding to the substrate
pocket of the active site [5a].
Recently, we described the synthesis of potent bisubstrate inhibitor 1 (Table 1;
IC50 =9 nM; IC50 =concentration of inhibitor at which 50% maximal initial velocity is
observed) and demonstrated its ability to block both the SAM and catechol binding
sites of COMT by kinetic studies and X-ray crystal structure analysis [9] (for modifica-
tions of the ribose unit of 1, see [9c,d]. Guided by molecular modeling results2), we
designed compounds 2–19 (Table 1) to take advantage of a hydrophobic cleft at the
enzyme surface [2c][11], located in proximity of the NO2 group of 1. We hypothesized
that bisubstrate inhibitors featuring suitable substituents connected to position 5 of the
catechol could undergo favorable apolar interactions with the lipophilic side chains of
the amino acid residues Trp38, Leu198, Val173, and Pro174 of COMT (Fig. 1). Here, we
report the synthesis and biological evaluation of this new generation of highly active
bisubstrate inhibitors that eliminate the need for NO2 substitution of the catechol struc-
tural unit (for a preliminary communication of parts of this work, see [12]).
2. Results and Discussion. – 2.1. Synthesis. In analogy to the synthesis of 1 [9a,b], we
envisioned bisubstrate inhibitors 2–19 arising in a highly convergent manner from
amide coupling of previously described allylic amine 20 [9a,b] with adequately func-
tionalized catechol N-hydroxysuccinimide esters, derived from the corresponding car-
boxylic acids 21–38 (Scheme 1). To this end, diphenylmethyldioxy or bis(4-methoxy-
phenyl)methyldioxy moieties were chosen to mask the catechol OH functionalities,
enabling the final one-pot acid-catalyzed deprotection of both catechol and ribose moi-
eties.
2
)
Computer simulations were performed using the molecular modeling package MOLOC [10].

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Helvetica Chimica Acta – Vol. 89 (2006)
Table 1. Structures of Inhibitors 1–19 and Catechol Carboxylic Acid Intermediates 21–38
R
Inhibitor
Catechol intermediate
1
2
–
21
3
4
22
23
5
6
7
24
25
26
8
9
27
28
10
29
11
12
13
30
31
32
14
15
33
34
16
17
35
36

Helvetica Chimica Acta – Vol. 89 (2006)
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Table 1 (cont.)
R
Inhibitor
Catechol intermediate
18
19
37
38
Scheme 1. Retrosynthetic Analysis of Inhibitors 2–19. R2 =H or MeO. For an explicit description of
the catechol substituents R1, see Table 1.
Key building block for the synthesis of protected catechol derivatives is 5-bromo
intermediate 39, obtained from 5-bromo-2,3-dihydroxybenzoic acid (40) by esterifica-
tion to give 41 (88%; Scheme 2) and protection with dichloro(diphenyl)methane
(76%).
Analogously, conversion of the known carboxylic acid 42 [13] to the corresponding
methyl ester 43, followed by ketal formation, yielded 5-Cl-substituted building block 44
in 42% overall yield. The ester functionalities of 39 and 44 were subsequently hydro-
lyzed under standard basic conditions to provide the corresponding carboxylic acids
25 and 31 in high yields (91 and 82%, resp.).
The 5-Br substituent of intermediates 39 and 25 additionally served as a handle for
further functionalization. Thus, generation of the dianion of 25 by sequential deproto-

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Scheme 2. Synthesis of Catechol Building Blocks 25 and 31
a) SOCl2, MeOH, D, 12 h; 80–88%. b) Ph2CCl2 (neat), 1608, 40 min; 52–76%. c) LiOH, THF/H2O
1:1, D, 4 h; 82–91%.
nation with MeOLi/MeOH and careful drying of the resulting lithium carboxylate
under high vacuum, followed by Br/Li exchange (t-BuLi/THF) and subsequent quench-
ing with the appropriate electrophile, gave rise to acylated building blocks 29 and 32,
and secondary alcohol 45 in moderate yields (25–38%; Scheme 3). Intermediate 45
was easily oxidized to give (pyridin-4-yl)carbonyl derivative 30 by treatment with
ortho-iodoxybenzoic acid (IBX; 95%). Alternatively, deprotonation of 25 with LiH/
THF, followed by Br/Li exchange (t-BuLi/THF), avoided the change of the solvent
medium, furnishing carbamoyl derivative 37 upon quenching with N,N-dimethylcarba-
moyl chloride (21%). Interestingly, attempts to generate the respective dianionic inter-
mediate by treatment of 25 with 2 equiv. or an excess of alkyllithium reagent led to
exclusive formation of the corresponding 5-unfunctionalized catechol 38 (replacement
of Br by H) upon reaction with electrophiles and aqueous workup.
Starting from intermediate 39, a variety of catechol building blocks could be
accessed using Pd0-catalyzed cross-coupling reactions. Thus, Suzuki cross-coupling of
39 with (4-fluorophenyl)- or (4-methylphenyl)boronic acid furnished the corresponding
biaryl carboxylates 46 and 47 (78and 79%, resp.; Scheme 4), which, after hydrolysis,
provided carboxylic acids 21 and 22 in high yields (89 and 93%, resp.). Heterocyclic
and benzylic residues could be introduced by one-pot Pd0-catalyzed conversion of Br
derivative 39 to the corresponding boronate, followed by Suzuki cross-coupling with
the desired aryl or benzyl (Bn) bromide to give biaryls 48–50 and 5-Bn carboxylate
51 (40–80% overall). Again, the methyl esters of these intermediates were subjected
to basic hydrolysis to furnish the corresponding carboxylic acids 23, 24, 26, and 35
(92–99%). Furthermore, (N,N-dimethylcarbamoyl)ethenyl-substituted intermediate
52 was obtained by Heck cross-coupling of 39 with N,N-dimethylacrylamide, using
Ph3
N
N
accelerated the conversion of 39 to 52. Subsequent hydrolysis provided carboxylic
acid 33 (77%).
Cross-coupling methodology was also used for the synthesis of 5-CN-functionalized
catechol building blocks 27 and 53 starting from 5-Br intermediates 39 and 54, respec-
tively [9d]. In this case, protection of the catechol OH groups as the corresponding
bis(4-methoxyphenyl)methyldioxy moieties was introduced to improve the outcome

Helvetica Chimica Acta – Vol. 89 (2006)
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Scheme 3. Synthesis of Catechol Intermediates 29, 30, 32, and 37
a) 1. MeOLi, MeOH, 208, 10 min; 2. t-BuLi, THF, À788, 30 min; 3. ethyl trifluoroacetate (! 29) or
N-methyl-N-(methoxy)cyclohexanecarboxamide (! 32) or pyridine-4-carbaldehyde (! 45), À788, 30
min, then 208, 2 h; 25–38%. b) ortho-Iodoxybenzoic acid (IBX), acetone/Me2SO 3 :1, 508, 3 h; 95%.
G
c) 1. LiH, THF, 208, 10 min; 2. t-BuLi, THF, À788, 30 min; 3. N,N-Dimethylcarbamoyl chloride,
À788, 30 min, then 208, 2 h; 21%.
of the final acid-catalyzed ketal hydrolysis (vide infra). Thus, Pd0-catalyzed reaction of
39 or 54 with KCN in benzene (or toluene)/DMF (3 :1) in the presence of 18-crown-6
provided intermediates 55 and 56 in moderate to good yields (76 and 48%, resp.). Inter-
estingly, the composition of the solvent mixture plays a decisive role in the outcome of
this transformation. Whereas an increase of the proportion of the aromatic solvent
component leads to a significant increase in reaction times and low conversions, exten-
sive decomposition of the starting 5-bromocatechol is observed when the proportion of
the polar solvent component is increased. Saponification of the methyl esters of 55 and
56, carried out under mild conditions to prevent hydrolysis of the newly introduced CN
group (LiOH/MeOH at ambient temperature), furnished carboxylic acids 27 and 53 in
high yields (92 and 93%, resp.).
The synthesis of (4-methylphenyl)sulfonyl-substituted catechol building block 34
started from known methyl 5-iodo-2,3-dimethoxybenzenecarboxylate (57) [14],
which was converted to sulfonyl derivative 58 by CuI-mediated coupling with sodium
p-toluenesulfinate (Scheme 5; 58%). Cleavage of methyl ester and ethers under
harsh acidic conditions (! 59), followed by re-esterification (! 60) and ketal forma-
tion, furnished methyl catechol-carboxylate 61, which was subjected to basic ester
hydrolysis to give intermediate 34 (26% overall).
In contrast to the usual functionalization route of 5-Br-catechol intermediates,
building blocks 36 and 28 were obtained by carboxylation of a corresponding 4-substi-

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Scheme 4. Synthesis of Catechol Building Blocks 21–24, 26, 27, 33, 35, and 53
a) (4-Fluorophenyl)- or (4-methylphenyl)boronic acid, [Pd(PPh3)4], Na2CO3, benzene/EtOH/H2O, D,
12 h; 78–79%. b) LiOH, THF/H2O 1:1, D, 4 h; 77–99%. c) KCN, [Pd(PPh3)4], 18-crown-6, toluene/
DMF 3 :1, 1008, 16 h; 48–76%. d) LiOH, MeOH, 208, 16 h; 92–93%. e) N,N-Dimethylacrylamide,
Pd(OAc)2, Na2CO3, Bu4NBr, P(OPh)3, N,N-dimethylacetamide (DMA), 1408, 72 h; 44%. f) ꢃPinacol
A
diboronꢀ, [Pd(PPh3)4], AcOK, toluene, D; 4 h. g) Aryl or benzyl bromide, [Pd(PPh3)4], Na2CO3, tolu-
ene/EtOH/H2O, D, 16 h; 40–80% (2 steps).
tuted catechol intermediate. Thus, 5-iPr-substituted 36 was derived from known pro-
tected 4-acetylcatechol 62 [15] by Wittig methenylation of the carbonyl group (! 63,
86%; Scheme 6) and catalytic hydrogenation of the disubstituted C=C bond (! 64,
94%), followed by ortho-lithiation and trapping of the aryllithium nucleophile with
methyl chloroformate to give methyl ester 65 (51%). The hydroxy functionalities of

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Scheme 5. Synthesis of Catechol Intermediate 34
a) Sodium p-toluenesulfinate hydrate, CuI, DMF, 1108, 14 h; 58%. b) HBr, Bu4NBr, AcOH, 1408, 20
G
h; 45%. c) SOCl2, MeOH, D, 12 h; 75%. d) 1. (COCl)2, 4,4’-dimethoxybenzophenone, 608, 30 min; 2.
60, 1608, 40 min; 77%. e) LiOH, THF/H2O 1:1, reflux, 4 h, 99%.
intermediate 65 were subsequently unmasked in a two-step protocol calling for initial
reaction with BBr3, followed by acid-catalyzed deprotection of the remaining methyl
ether with HBr/AcOH (! 66, 41%). Additional protecting-group transformations fur-
i
nished Pr-containing building block 36 in 58% overall yield (via 67 and 68).
Similarly, the synthesis of the CF3-substituted catechol building block 28 started
from 4-(trifluoromethyl)benzene-1,2-diol, obtained from 4-(trifluoromethyl)phenol
according to a modified literature protocol [16] (Scheme 7). Regioselective bromina-
tion (! 70, 74%), followed by Bn-protection of the OH groups (! 71, 87%), allowed
for installation of the methyl ester functionality by Br/Li exchange and interception of
the lithium arylate with methyl chloroformate (! 72, 52%). Removal of the Bn groups
by hydrogenolysis, followed by the usual installation of the desired protective group
pattern, gave access to the carboxylic acid intermediate 28 (via 73 and 74; 57% overall
yield).
For completion of the synthesis, catechol-carboxylic acids 21–38 were converted to
the corresponding N-hydroxysuccinimide esters and coupled by a one-pot procedure
with allylic amine 20 to give amides 75–92 (Scheme 8; 40–81% overall yield). Inhibi-
tors 2–19 were finally unmasked by careful treatment with acid (CF3COOH(TFA)/
H2O, 1:1) in yields ranging from 48to 99%, and purified by reversed-phase HPLC.
Low deprotection yields could, in some cases, be dramatically improved by use of
bis(4-methoxyphenyl)methyldioxy rather than unfunctionalized diphenylmethyldioxy
moiety as the catechol-protecting-group, which ensured rapid deprotection using
shorter reaction times and milder conditions, thus avoiding substrate decomposition
by depurination side-reactions (e.g., deprotection yields for CN-functionalized diphe-
nylmethyldioxy-protected 81 and the corresponding bis(4-methoxyphenyl)methyl-
dioxy-protected derivative 93 (not shown) were 42 and 99%, resp.).
2.2. Biological Activity. Biological activities (IC50 values; Table 2) of the newly syn-
thesized bisubstrate inhibitors towards COMT were determined with pre-incubation

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Scheme 6. Synthesis of Catechol Building Block 36
a) MePPh3
A
1. BuLi, THF, 08, 2.5 h; 2. ClCO2CH3, 208, 12 h; 51%. d) 1. BBr3, CH2Cl2, À788, 30 min; then 208, 1
h; 2. HBr, AcOH, 1208, 5 h; 41%. e) SOCl2, MeOH, D, 12 h; 8 3%.f) Ph2CCl2, 1608, 40 min; 74%. g)
LiOH, THF/H2O 1:1, D, 4 h; 95%.
using a radiochemical assay described, in full detail, in [17]. To assess the electronic
effects of the newly introduced substituents in position 5 of the catechol, pKa values
were measured and are given in Table 2 for the most acidic catechol OH group
along with the Hammett constants sp [18] for the respective substituents. In addition,
kinetic studies were carried out to determine the inhibition mechanism of ligands
2–19 with respect to the cofactor binding site. Initial velocities, obtained without
pre-incubation by varying the cofactor concentration for a series of different inhibitor
concentrations, were globally fitted to Eqns. 1, 2, and 3, describing the cases of compet-
itive, mixed competitive, and uncompetitive inhibition, respectively, to obtain kinetic
parameters (Ki values, Table 2).
v=V[S]/(Km
v=V[S]/(Km(1+[I]/Kic)+[S](1+[I]/Kiu))
v=V[S]/(Km +[S](1+[I]/Kiu))
A
(1)
(2)
(3)
AHCTREUNG
In the Eqns., competitive and uncompetitive inhibition constants are given by Kic
and Kiu, respectively, whereas [S] and [I] denote cofactor and inhibitor concentrations,
respectively. V is the maximal and v the initial velocity of the enzymatic reaction. In all
cases, best fit was obtained by using the competitive inhibition model (Eqn. 1), as exem-

Helvetica Chimica Acta – Vol. 89 (2006)
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Scheme 7. Synthesis of Catechol Building Block 28
a) Br2, CCl4, 208, 1 h; 74%. b) BnBr, K2CO3, acetone, D, 4 h; 87%. c) 1. BuLi, THF, À908, 15 min; 2.
ClCO2CH3, À908 ! 208, 1 h; 52%. d) H2, Pd/C, MeOH, 208, 16 h; 99%. e) 1. (COCl)2, 4,4’-
dimethoxybenzophenone, 608, 30 min; 2. 73, 1608, 40 min; 63%. f) LiOH, THF/H2O 1:1, D, 4 h; 91%.
A
plified graphically for inhibitor 2 by intersection of the lines for different inhibitor con-
centrations on the 1/v axis of the respective Lineweaver–Burk plots (Fig. 2).
We were delighted to find that, in the majority of cases, replacement of the NO2 sub-
stituent leads to potent bisubstrate inhibitors with inhibitory activities towards COMT
in the low (double-digit) nanomolar range. This data not only provides an impressive
validation of the bisubstrate inhibition approach, but also establishes the absence of lin-
ear free-energy relationships (LFERs) between the free enthalpy of inhibition
(ÀDGinh) and pKa values or Hammett parameters. This finding stands in sharp contrast
to the interdependence of biological activities and catechol pKa values in the case of
inhibitors blocking only the (catechol) substrate binding site [5a]. On the contrary,
numerous examples of bisubstrate inhibitors in the series 2–19, exhibiting high pKa val-
ues of the catechol OH group and, at the same time, having remarkably high inhibitory
activities, demonstrate the efficiency of favorable apolar interactions with the hydro-
phobic cleft at the enzyme surface (e.g., biaryl-functionalized inhibitors 2 and 3 with
pKa values 6.87 and 7.06, IC50 values of 21 and 23 nM, and Ki value of 55 nM, resp.).
These lipophilic interactions clearly compensate for the fall in binding free enthalpy
as a consequence of increased pKa values of the catechol OH groups observed in the
absence of suitable lipophilic residues R (e.g., 19, R=H, pKa =7.37, IC50 =2600 nM,
Ki =1644 nM). As a result, aromatic groups connected to position 5 of the catechol in
a biaryl-type fashion offer an optimal balance of electron-withdrawing ability and
hydrophobic contact area, and represent preferred replacements of the NO2 group.
On the other hand, binding affinity deteriorates when polar residues such as the

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Scheme 8. Synthesis of the Bisubstrate Inhibitors 2–19
a) 1. Catechol carboxylic acid, N-[3-(dimethylamino)propyl]-N’-ethylcarbodiimide (EDC)·HCl, N-
hydroxysuccinimide, CH2Cl2, 208, 1 h; 2. 20, Et3N, CH2Cl2, 208, 16 h; 40–81%. b) TFA/H2O 1:1, 08,
G
20–60 min, 42–99%. R2 =H or MeO. For an explicit description of the catechol substituents R1, see
Table 1.
N,N-dimethylcarbamoyl group of 18 are placed into the hydrophobic environment
(IC50 =2000 nM, Ki =511 nM).
Furthermore, good biological activities can also by achieved by a combination of
acceptor capacity and hydrophobic character of the catechol substituent (e.g., inhibitors
9–11). Not surprisingly, substitution of the catechol with small but strong s acceptors
also leads to potent bisubstrate inhibitors (e.g., 8).
3. Conclusions. – A new series of bisubstrate inhibitors of COMT featuring a variety
of replacements of the NO2 group as a catechol substituent have been synthesized by a
highly convergent approach. Potent inhibition could, for the first time, be achieved
despite the lack of NO2 substituent on the catechol moiety by exploitation of favorable
apolar interactions with a hydrophobic cleft near the enzyme surface, impressively val-
idating the bisubstrate inhibition approach. Further optimization of the pharmacoki-
netic properties of the new inhibitors, e.g., by modifications of the ribose and the nucle-
obase moieties are underway, and could in the future lead to the development of new
therapeutic entities for the treatment of CNS disorders. In addition, efforts to further
validate the proposed binding mode by X-ray crystal-structure analysis of enzyme–
inhibitor complexes are ongoing.

Helvetica Chimica Acta – Vol. 89 (2006)
1867
Table 2. In vitro Biological Activities (IC50 [nM] (uncertainties Æ5%), Ki, and DGinh values (310 K) [kJ
molÀ1]), Hammett Substituent Constants sp [18] of Residues R, pKa Values, and Calculated Partitioning
Coefficients (c logP) of Inhibitors 1–19. Ki Data refer to the inhibition of the SAM binding site. Parti-
tioning coefficients were calculated using the corresponding software from ACDLabs.
Compound
sp
IC50 [nM]
Ki [nM]
ÀDGinh
pKa
c logP
[kJ molÀ1
]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
0.789
0.06
À0.03
0.23
–
00.23
0.29
0.66
0.54
0.80
–
0.23
–
0.05
–
À0.09
À0.15
0.36
0
28
Æ2
44.8Æ0.2
43.1Æ0.2
43.1Æ0.1
43.1Æ0.1
42.9Æ0.2
42.1Æ0.2
43.8Æ0.2
41.0Æ0.3
42.5Æ0.4
43.2Æ0.3
42.4Æ0.2
40.2Æ0.3
841.9Æ0.2
40.5Æ0.3
41.7Æ0.1
39.6Æ0.1
37.6Æ0.1
37.3Æ0.2
34.3Æ0.2
4.42
6.87
7.06
6.89
6.15
6.54
6.184.14
5.182.14
6.22
5.74
6.95
6.65
5.46
6.34
5.07
7.56
7.63
2.05
2.70
3.23
1.38
3.12
2.70
21
23
23
27
288
29
29
35
39
42
44
8
97
213
608211
1370
2000
2600
55Æ5
55Æ3
55Æ2
60Æ5
Æ5
41Æ3
124Æ3
69Æ11
52Æ7
71Æ6
169Æ21
Æ6
3.78
2.22
1.82
2.58
3.80
0.73
2.31
3.51
2.40
0.31
1.06
3
8
151Æ17
96Æ3
Æ4
546Æ9
511Æ36
6.25
7.37
1644Æ144
Fig. 2. Exemplary Lineweaver–Burk plot of reciprocal enzymatic activity vs. reciprocal concentration
of the cofactor (SAM) for varying concentrations of inhibitor 2 at saturating benzene-1,2-diol concen-
trations. DPM=decays per min.

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Experimental Part
General. Solvents and reagents were purchased reagent-grade and used without further purification.
Solvents for extractions and chromatography were of technical grade and were distilled prior to usage.
All reactions were carried out under an Ar atmosphere unless otherwise stated. THF was distilled
from sodium benzophenone ketyl, and CH2Cl2 from CaH2. Anh. Me2SO, DMF, and pyridine, stored
G
over molecular sieves, were purchased from Fluka. All products were dried under high vacuum (10À2
Torr) before anal. characterization. The preparation of the following compounds has been reported in
the literature: 38 [19], 41 [20], 57 [14], 62 [21], 69 [22], N-methoxy-N-methylcyclohexanecarboxamide
[23]. The synthesis of intermediates 20 [9a,b] and 54 [9d] has been described previously. TLC: alumi-
num-backed sheets coated with SiO2 60 F254 from Macherey-Nagel. Column chromatography (CC):
Fluka SiO2 60 (230–400 mesh, 0.040–0.063 mm). Anal. reversed-phase (RP) HPLC: Merck LiChros-
pherꢁ 100 C-18 column (250”4 mm, 5 mm, 100 Š), eluted with a linear gradient (5–55%) of MeCN in
H2O containing 0.1% TFA during 20 min, with a flow rate of 1 cm3 minÀ1, and UV detection at 254
nm. Prep. RP-HPLC: Merck LiChrosorbꢁ C-18 column (250”25 mm, 7 mm), eluted with a linear gradi-
ent of MeCN in H2O containing 0.1% TFA, with a flow rate of 10 cm3 minÀ1, and UV detection at 254 nm.
M.p.: Büchi B-540 apparatus; uncorrected. Optical rotations: Perkin-Elmer 241 polarimeter at l=589
nm. IR Spectra: Perkin-Elmer 1600-FT-IR spectrometer or a Perkin-Elmer Spectrum BX II. 1H- and
13C-NMR spectra: Varian Gemini 300, Varian Mercury 300, or Bruker AMX-500 spectrometers; chemical
shifts (d) are reported in ppm downfield of Me4Si, using the residual signal of the solvent as an internal
N
reference; coupling constants (J) are given in Hz. MALDI Mass spectra: IonSpec Ultima instrument with
2,5-dihydroxybenzoic acid or 2,4,5-trihydroxyacetophenone/diammonium citrate 2 :1 as a matrix. Ele-
mental analyses were performed by the Mikrolabor at the Laboratorium für Organische Chemie,
ETH Zürich. The nomenclature was generated using the computer program ACD-Name (ACD/Labs).
General Procedure 1 (GP 1) for the Synthesis of Methyl 2,3-Dihydroxybenzoate Derivatives from the
Corresponding 2,3-Dihydroxybenzoic Acids. To a soln. of the 2,3-dihydroxybenzoic acid derivative (1
equiv.) in MeOH, SOCl2 (3 equiv.) was slowly added, and the mixture was heated to reflux for 12–16
h. After evaporation of the solvent under reduced pressure, the resulting grayish solid was redissolved
in AcOEt and washed twice with sat. aq. K2CO3 soln., and sat. aq. NaCl soln., before drying (MgSO4),
and evaporated in vacuo. Drying under high vacuum yielded the product as a grayish solid.
General Procedure 2 (GP 2) for the Protection of Catechols as Diarylmethylketals. GP 2.1. Protection
as Diphenylmethylketal. A suspension of the corresponding methyl 2,3-dihydroxybenzoate derivative (1
equiv.) in dichloro(diphenyl)methane (1.5 equiv.) was stirred at 1608 for 40 min.
Workup Method A. After cooling to ca. 508, MeOH (30 ml) was added to the viscous brown oil, lead-
ing to the formation of a precipitate. The precipitate was filtered, washed with MeOH (3”20 ml), and
dried under high vacuum to yield the desired compound as a colorless solid.
Workup Method B. After cooling to 208, AcOEt was added to the viscous mixture, and the soln. was
washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated under reduced pressure. The crude prod-
uct was purified by CC (SiO2; hexane/Et2O 10 :1) to yield the desired compound as a colorless solid.
A
GP 2.2. Protection as Bis(4-methoxyphenyl)methylketal. 4,4’-Dimethoxybenzophenone (1.5 equiv.)
and oxalyl chloride (8equiv.) were stirred at 60 8 for 30 min, then the temp. was raised to 1108 to remove
the excess oxalyl chloride, and the corresponding methyl 2,3-dihydroxybenzoate derivative (1 equiv.) was
added to the mixture. The dark red soln. was stirred at 1608 for 40 min. After cooling, AcOEt was added
to the viscous mixture, and the soln. was washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated
under reduced pressure. The crude product was purified by CC (SiO2; hexane/Et2
AcOEt 20 :1).
A
General Procedure 3 (GP 3) for the Hydrolysis of Catechol-carboxylates to the Corresponding Car-
boxylic Acids. A soln. of LiOH·H2O (3 equiv.) in H2O (5 ml) was added to a soln. of the methyl cate-
chol-carboxylate derivative (1 equiv.) in THF (5 ml), and the biphasic mixture was heated to reflux for
4 h. After cooling to 208, the mixture was acidified by addition of 10% aq. AcOH soln. (4 ml) or sat.
aq. NH4Cl soln. (10 ml), and partitioned between H2O (50 ml) and AcOEt (50 ml). The aq. phase was
extracted twice with AcOEt (20 ml). The combined org. fractions were washed twice with sat. aq.
NaCl soln., dried (MgSO4), and evaporated in vacuo to yield the desired compound as a colorless solid.

Helvetica Chimica Acta – Vol. 89 (2006)
1869
General Procedure 4 (GP 4) for the Synthesis of Functionalized Catechol-carboxylic Acids Starting
from 6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (25). Deprotonation Method A. To a sus-
pension of 25 (1 equiv.) in MeOH (3 ml), MeOLi (2 equiv.) was added, and the now clear soln. was stirred
20 min at 208. Volatiles were removed in vacuo, and the resulting white foam was dried overnight under
high vacuum (ca. 10À6 Torr). The residue was redissolved in dry THF (10 ml) and cooled to À788.
Deprotonation Method B. To a soln. of 25 (1 equiv.) in dry THF (8ml), LiH (2 equiv.) was added. The
mixture was stirred 15 min at 208, and then cooled to À788.
Br/Li Exchange and Quenching with Electrophile. t-BuLi (2.5 equiv.) was added dropwise to the soln.
via a syringe, and the resulting dark yellow mixture was stirred 30 min at À788. The desired electrophile
was added, and stirring was continued for 30 min at À788. The cooling bath was removed, and the mix-
ture was stirred another 2 h at 208, followed by acidification with 10% aq. AcOH soln. and extraction
with AcOEt (2”30 ml). The org. fractions were combined, dried (MgSO4), and evaporated in vacuo.
The residue was purified using CC (SiO2; hexane/AcOEt/AcOH) to yield the desired compound as a yel-
lowish to colorless solid.
General Procedure 5 (GP 5) for the Synthesis of (Diarylmethyldioxy)-catechol-carboxylates via
Suzuki Reaction. Method A. To a soln. of 39 (1 equiv.) and [Pd(PPh3)4] (0.05 equiv.) in toluene (10 ml),
a soln. of the desired arylboronic acid (4 equiv.) in EtOH (1.5 ml), and a soln. of K2CO3 (6 equiv.) in
H2O (1 ml) were added. This mixture was heated to reflux for 4 h. After cooling to 208, the mixture
was partitioned between AcOEt and H2O. The org. phase was washed twice with sat. aq. NaCl soln.,
dried (MgSO4), and evaporated in vacuo. The residue was purified by CC (SiO2; hexane/AcOEt 20 :1
! 5 :1) to afford the desired compound as a colorless solid.
Method B. To a soln. of 39 (1 equiv.) in dry toluene (20 ml), [Pd(PPh3)4] (0.05 equiv.), bis(pinacola-
to)diboron (1.3 equiv.), and AcOK (1.5 equiv.) were added, and the mixture was heated to reflux for 4 h.
After cooling to 208, the mixture was filtered over Celite. [Pd(PPh3)4] (0.05 equiv.), the desired aryl or
benzyl bromide (1.2 equiv.), and a soln. of K2CO3 (5 equiv.) in H2O (3 ml) were added to the yellowish
soln., and the mixture was heated to reflux for 16 h. After cooling to 208, the mixture was partitioned
between H2O and AcOEt, and the org. phase was washed twice with sat. aq. NaCl soln. (20 ml), dried
(MgSO4), and evaporated under reduced pressure. The residue was purified by CC (SiO2; hexane/
AcOEt 20 :1 ! 9 :1) to yield the desired compound as a colorless solid.
General Procedure 6 (GP 6) for the Amide Coupling of Catechol-carboxylic Acid Building Blocks
with Primary Amine 20. To a soln. of the corresponding carboxylic acid building block (1 equiv.) in
CH2Cl2 (5 ml), EDC·HCl (1.5 equiv.) and N-hydroxysuccinimide (1.3 equiv.) were added, and the mix-
ture was stirred 1 h at 208. After the addition of amine 20 (0.7–1 equiv.) and Et3N (0.1 ml), stirring
G
was continued for 16 h at 208. The mixture was partitioned between CH2Cl2 and H2O, and the org.
phase was washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated in vacuo. The residue was
purified by CC (SiO2; CH2Cl2/MeOH 20 :1) to yield the desired compound as a colorless foam.
General Procedure 7 (GP 7) for the Acid-Catalyzed Deprotection of Acetonide and Diarylmethylketal
Protecting Groups. The protected precursor was treated with a mixture of TFA/H2O 1:1 (3 ml) at 08 for
20–60 min. Volatiles were removed under high vacuum at ambient temp. The residue was redissolved in
Me2SO (2–3 ml) and purified by prep. RP-HPLC. The combined product fractions were evaporated to
E
dryness by lyophilization.
Methyl 6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (39). Compound 41 (3 g, 12.87 mmol)
[20] was reacted with dichloro(diphenyl)methane (3.7 ml, 4.58g, 19.31 mmol) according to GP 2.1,
Workup Method A, to afford 39 (4 g, 76%). Colorless solid. M.p. 146–1488. IR (KBr): 3079w, 2950w,
1
1718s, 1467s, 1355s, 1238s, 1204s, 1043s, 1013s, 944m, 8 67m, 78 0s. H-NMR (300 MHz, CDCl3): 3.94 (s,
3 H); 7.14 (d, J=1.9, 1 H); 7.38–7.41 (m, 6 H); 7.55–7.59 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 52.4;
112.6; 113.7; 115.6; 119.1; 125.0; 126.2; 128.3; 129.4; 139.0; 147.5; 149.1; 163.7. HR-MALDI-MS:
411.0220 ([M+H]+, C21
N
N
6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (25). Compound 39 (0.5 g, 1.216 mmol)
and LiOH·H2O (204 mg, 4.86 mmol) were reacted according to GP 3 to afford 25 (437 mg, 91%). Color-
less solid. M.p. 2158. IR (KBr): 3063m, 2873m (br.), 2538m, 1695s, 1598w, 1468s, 1406m, 1350m, 1287s,
1
1234s, 1202s, 1045s, 1023s, 949m, 8 58m, 78 4m, 698s. H-NMR (300 MHz, CDCl3): 7.19 (d, J=2.1, 1 H);

1870
Helvetica Chimica Acta – Vol. 89 (2006)
7.40–7.42 (m, 6 H); 7.58–7.62 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 112.7; 112.8; 116.4; 119.5; 125.4;
126.3; 128.4; 129.5; 138.9; 148.3; 149.3; 167.9. HR-MALDI-MS: 397.0078 ([M+H]+, C20
N
N
calc. 397.0075). Anal. calc. for C20H13BrO4 (396.00): C 60.47, H 3.30; found C 60.40, H 3.35.
Methyl 5-Chloro-2,3-dihydroxybenzoate (43). Compound 42 (290 mg, 1.54 mmol) and SOCl2 (550
mg, 4.61 mmol) were reacted according to GP 1 to yield 43 (250 mg, 80%). Grayish solid. M.p.
108–1108. IR (KBr): 3453s, 3096m, 2960m, 1700s, 1673s, 1471s, 1437s, 1316s, 1233s, 1202s, 1152s,
1
1013m, 932m, 8 63m, 78 8m, 723m. H-NMR (300 MHz, CDCl3): 3.96 (s, 3 H); 5.73 (br. s, 1 H); 7.10 (d,
J=2.1, 1 H); 7.35 (d, J=2.1); 10.84 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 52.8; 112.7; 119.7; 120.0;
124.1; 145.7; 147.6; 169.7. HR-EI-MS: 201.9774 (M+, C8
N
N
Methyl 6-Chloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (44). Compound 43 (330 mg, 1.63
mmol) and dichloro(diphenyl)methane (470 mg, 1.96 mmol) were reacted according to GP 2.1, Workup
Method B, to afford 44 (310 mg, 52%). Colorless solid. M.p. 151–1528. IR (KBr): 3086w, 2947w, 1719s,
1595w, 1468s, 1445m, 1360m, 1277m, 1245s, 1202s, 1166m, 1042m, 1014m, 905w, 8 66w, 8 06m, 78 1m,
762m, 696m. 1H-NMR (300 MHz, CDCl3): 3.94 (s, 3 H); 7.00 (d, J=2.1, 1 H); 7.38–7.40 (m, 6 H);
7.56–7.59 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 52.6; 111.1; 113.3; 119.4; 122.3; 126.3; 126.6; 128.6;
129.7; 139.4; 147.4; 149.3; 164.2. HR-MALDI-MS: 367.0731 ([M+H]+, C21
Anal. calc. for C21H15ClO4 (366.07): C 68.77, H 4.12; found C 68.64, H 4.29.
N
N
6-Chloro-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (31). Compound 44 (150 mg, 0.408mmol)
and LiOH·H2O (52 mg, 1.23 mmol) were reacted according to GP 3 to yield 31 (117 mg, 82%). Colorless
solid. M.p. 206–2078. IR (KBr): 3071m, 2868m, 2616w, 1704s, 1599w, 1469s, 1450m, 1407w, 1350w, 1284m,
1
1267m, 1238s, 1200s, 1044m, 1022m, 949w, 908w, 8 59w, 799m, 761m, 698m, 642w. H-NMR (300 MHz,
CDCl3): 7.05 (d, J=2.1, 1 H); 7.39–7.42 (m, 6 H); 7.46 (d, J=2.1, 1 H); 7.58–7.61 (m, 4 H). 13C-NMR
(75 MHz, CDCl3): 112.3; 114.1; 119.9; 122.6; 126.5; 126.6; 128.7; 129.8; 139.2; 148.1; 149.5; 168.5. HR-
MALDI-MS: 353.0576 ([M+H]+, C20
N
G
AHCTREUNG
reacted according to GP 4, Deprotonation Method A. The crude product was purified by CC (SiO2; hex-
ane/AcOEt/AcOH 77:20 :3) to afford 29 (79 mg, 38%). Yellowish solid. M.p. 1878. IR (KBr): 2925m,
2555m, 1692s, 1635m, 1482s, 1254s, 1213s, 1131s, 1048m, 1013m, 98 7m, 945m, 8 02m, 760s, 699s. 1H-
NMR (300 MHz, CDCl3): 7.40–7.44 (m, 6 H); 7.59–7.62 (m, 4 H); 7.74 (d, J=1.2, 1 H); 8.35 (m, 1 H).
13C-NMR (75 MHz, CDCl3): 111.7; 112.4; 116.5 (q, J=289); 121.0; 124.0; 126.2; 128.5; 128.9; 129.8;
138.3; 149.6; 154.3; 167.7; 178.1 (q, J=35.2). 19F-NMR (282 MHz, CDCl3): À70.7 (s). HR-MALDI-
MS: 415.0784 ([M+H]+, C22
3.16; found C 63.81, H 3.29.
A
G
N
6-(Cyclohexylcarbonyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (32). Compound 25 (1.26
g, 3.16 mmol), MeOLi (240 mg, 6.32 mmol) and N-methoxy-N-methylcyclohexanecarboxamide (650
mg, 3.8mmol) as the electrophile were reacted according to GP 4, Deprotonation Method A. The
crude product was purified by CC (SiO2; hexane/Et2O/AcOH 5 :1:0.1), and subsequent recrystallization
G
from CH2Cl2/hexane afforded 32 (338mg, 25%). Yellowish solid. M.p. 212–214 8. IR (KBr): 3062w,
2932m, 2854m, 1693s, 1628w, 1448s, 1250s, 1205s, 1155m, 1042m, 1020m, 98 8m, 948m, 8 75w, 752m,
1
695s. H-NMR (300 MHz, CDCl3): 1.26–1.52 (m, 6 H); 1.72–1.86 (m, 4 H); 3.24 (m, 1 H); 7.38–7.45
(m, 6 H); 7.59–7.65 (m, 4 H); 7.70 (d, J=1.7, 1 H); 8.16 (d, J=1.7, 1 H). 13C-NMR (75 MHz, CDCl3):
25.9; 26.0; 29.7; 45.4; 110.9; 112.1; 119.8; 125.4; 126.3; 128.4; 129.6; 130.7; 138.8; 149.3; 152.4; 168.8;
201.2. HR-MALDI-MS: 429.1693 ([M+H]+, C27
N
N
6-[Hydroxy(pyridine-4-yl)methyl]-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (45). Compound
25 (1 g, 2.52 mmol), MeOLi (192 mg, 5.04 mmol), and pyridine-4-carbaldehyde (0.48ml, 5.03 mmol) as
the electrophile were reacted according to GP 4, Deprotonation Method A. The crude product was puri-
fied by CC (SiO2; CH2Cl2/MeOH 92 :8 ! 80 :20) to yield 45 (350 mg, 33%). Yellowish solid. M.p.
213–2178 (dec.). IR (KBr): 3381s (br.), 1565s, 1473m, 1410s, 1257s, 1205s, 1047s, 1026m, 948w, 8 06w,
1
777m, 698m, 642m. H-NMR (300 MHz, (CD3)2
G
(d, J=5.7, 2 H); 7.40–7.42 (m, 7 H); 7.50–7.54 (m, 4 H); 8.46 (d, J=5.7, 1 H). 13C-NMR (75 MHz,
(CD3)2SO): 62.6; 108.2; 116.1; 120.9; 121.4; 125.7; 128.2; 129.1; 137.3; 139.5; 139.6; 145.3; 147.0; 149.2;
153.6; 189.8. HR-MALDI-MS: 426.1332 ([M+H]+, C26 NO5þ ; calc. 426.1341).
H20
AHCTREUNG

Helvetica Chimica Acta – Vol. 89 (2006)
1871
2,2-Diphenyl-6-[(pyridine-4-yl)carbonyl]-1,3-benzodioxole-4-carboxylic Acid (30). To a soln. of 45
(128mg, 0.324 mmol) in Me 2CO/Me2SO 3 :1 (12 ml), IBX (273 mg, 0.973 mmol) was added, and the mix-
A
ACHTREUNG
ture was stirred for 3 h at 508. The mixture was partitioned between H2O and AcOEt, and the org. phase
washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated under reduced pressure to yield 30 (130
mg, 95%). Yellowish solid. M.p. 256–2578. IR (KBr): 3447w (br.), 3062w, 2426w, 1709m, 1669m, 1624m,
1
1475m, 1440s, 1408w, 1323w, 1270s, 1211s, 1048s, 1017m, 910w, 8 01w, 759m, 698m, 642m. H-NMR (300
MHz, (CD3)2
NMR (75 MHz, (CD3)2
148.4; 149.8; 151.1; 163.9; 192.1. HR-MALDI-MS: 425.1254 ([M+2 H]+, C26
G
6-[(Dimethylamino)carbonyl]-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (37). Compound 25
(200 mg, 0.486 mmol), LiH (10 mg, 0.97 mmol), and N,N-dimethylcarbamoyl chloride (0.18ml, 1.94
mmol) as the electrophile were reacted according to GP 4, Deprotonation Method B. The crude product
was purified by CC (SiO2; hexane/AcOEt/AcOH 67:30 :3) to yield 37 (40 mg, 21%). Colorless solid.
M.p. 207–2088. IR (KBr): 3417w, 2935w, 1718s, 1635m, 1607s, 1448s, 1415m, 1247s, 1207s, 1075w,
1
1041s, 1023s, 949m, 8 8 m1 , 78 8m, 765m, 701s, 643m. H-NMR (300 MHz, CDCl3): 3.06 (br. s, 6 H); 7.20
(d, J=1.5, 1 H); 7.37–7.41 (m, 6 H); 7.56 (d, J=1.5, 1 H); 7.58–7.62 (m, 4 H). 13C-NMR (75 MHz,
CDCl3): 35.8; 40.0; 111.2; 112.4; 119.3; 122.7; 126.4; 128.4; 129.4; 129.5; 139.1; 148.8; 149.8; 168.5;
170.1. HR-MALDI-MS: 390.1340 ([M+H]+, C23
N
N
Methyl 6-(4-Fluorophenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (46). Compound 39 (100
mg, 0.243 mmol), [Pd(PPh3)4] (15 mg, 0.012 mmol), (4-fluorophenyl)boronic acid (135 mg, 0.972
mmol), and K2CO3 (202 g, 1.46 mmol) were reacted according to GP 5, Method A, to afford 46 (80
mg, 78%). Colorless solid. M.p. 125–1278. IR (KBr): 3061m, 2950m, 1723s, 1634w, 1603m, 1517m,
1
1472s, 1364m, 1257s, 1215s, 1053s, 947m, 8 33s, 78 0m, 698s, 640m. H-NMR (300 MHz, CDCl3): 3.97 (s,
3 H); 7.10 (tt, J=8.7, 2.0, 2 H); 7.20 (d, J=2.0, 1 H); 7.39–7.42 (m, 6 H); 7.45–7.50 (m, 2 H); 7.59 (d,
J=2.0, 1 H); 7.62–7.65 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 52.2; 111.1; 112.7; 115.6 (d, J=21.2);
118.4; 121.1; 126.3; 128.2; 128.3; 129.2; 134.0; 136.0; 139.4; 147.4; 148.8; 162.2 (d, J=244.7); 164.8. 19F-
NMR (282 MHz, CDCl3): À115.9 (tt, J=9.6, 5.4). HR-MALDI-MS: 426.1258( M+, C27
N
G
426.1267).
6-(4-Fluorophenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (21). Compound 46 (250 mg,
0.586 mmol) and LiOH·H2O (74 mg, 1.76 mmol) were reacted according to GP 3 to yield 21 (214 mg,
89%). Colorless solid. M.p. 215–2178. IR (KBr): 3032m, 2625w, 1687s, 1635w, 1604m, 1519m, 1473s,
1
1422m, 1355w, 1281s, 1219s, 1179m, 1055s, 1022s, 948m, 918w, 8 32s, 78 4m, 756m, 699s, 641m. H-NMR
(300 MHz, CDCl3): 7.10 (t, J=8.7, 2 H); 7.26 (d, J=1.0, 1 H); 7.39–7.43 (m, 6 H); 7.46–7.51 (m, 2 H);
7.63–7.66 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 111.7; 112.0; 115.7 (d, J=21.2); 118.9; 121.6; 126.3;
128.3; 128.4; 129.4; 134.3; 135.9 (d, J=3.1); 139.3; 148.1; 149.0; 162.3 (d, J=245); 169.0. 19F-NMR
(282 MHz, CDCl3): À115.7 (tt, J=8.5, 5.4). HR-MALDI-MS: 435.1000 ([M+Na]+, C27
N
G
calc. 435.1009).
Methyl 6-(4-Methylphenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (47). Compound 39 (500
mg, 1.215 mmol), [Pd(PPh3)4] (70 mg, 0.06 mmol), (4-methylphenyl)boronic acid (330 mg, 2.43 mmol),
and K2CO3 (1 g, 7.29 mmol) were reacted according to GP 5, Method A, to yield 46 (403 mg, 79%). Col-
orless solid. M.p. 159–1608. IR (KBr): 3034w, 2941w, 1719s, 1470s, 1450s, 1429m, 1363w, 1255s, 1209s,
1
1161m, 1053s, 1028s, 944w, 8 17m, 775m, 702s, 640m. H-NMR (300 MHz, CDCl3): 2.38( s, 3 H); 3.97 (s,
3 H); 7.22 (d, J=7.8, 2 H); 7.26 (d, J=1.8, 1 H); 7.38–7.44 (m, 8H); 7.62–7.66 ( m, 5 H). 13C-NMR
(75 MHz, CDCl3): 21.2; 52.2; 111.1; 112.7; 118.2; 121.0; 126.3; 126.6; 128.2; 129.2; 129.4; 135.0; 136.9;
137.0; 139.6; 147.3; 148.7; 164.9. HR-MALDI-MS: 445.1406 ([M+Na]+, C28
N
N
6-(4-Methylphenyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (22). Compound 46 (280 mg,
0.662 mmol) and LiOH·H2O (84 mg, 2 mmol) were reacted according to GP 3 to afford 22 (251 mg,
93%). Colorless solid. M.p. 223–2248. IR (KBr): 3030m, 2624m, 1684s, 1634m, 1602w, 1473s, 1421m,
1355w, 1282s, 1213s, 1055s, 1023s, 947m, 918w, 8 71w, 8 14m, 78 4m, 758m, 699s, 640m. 1H-NMR (300
MHz, CDCl3): 2.39 (s, 3 H); 7.23 (d, J=7.8, 2 H); 7.31 (d, J=1.8, 1 H); 7.39–7.45 (m, 8H); 7.64–7.67
(m, 4 H); 7.71 (d, J=1.8). 13C-NMR (75 MHz, CDCl3): 21.1; 111.8; 112.0; 118.7; 121.5; 126.4; 126.7;
128.4; 129.4; 129.5; 135.3; 136.9; 137.2; 139.5; 148.0; 149.0; 169.4. HR-MALDI-MS: 431.1259
([M+Na]+, C27
N
N

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Helvetica Chimica Acta – Vol. 89 (2006)
Methyl 6-Cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (55). To a soln. of 39 (800 mg, 1.95
mmol) in benzene/DMF 3 :1 (20 ml), [Pd(PPh3)4] (225 mg, 0.195 mmol), KCN (127 mg, 1.95 mmol),
and 18-crown-6 (415 mg, 1.56 mmol) were added, and the mixture was stirred for 16 h at 1008. The mix-
ture was partitioned between AcOEt (50 ml) and H2O (50 ml), and the aq. phase was extracted with
AcOEt (2”20 ml). The combined org. phases were washed with H2O and sat. aq. NaCl soln., dried
(MgSO4), and evaporated under reduced pressure. CC (SiO2; hexane/AcOEt 20 :1 ! 9 :1) afforded 55
(530 mg, 76%). Colorless solid. M.p. 1418. IR (KBr): 3051w, 2951w, 2228m, 1713s, 1470s, 1375m, 1264s,
1225s, 1045s, 917m, 78 6s. 1H-NMR (300 MHz, CDCl3): 3.97 (s, 3 H); 7.20 (d, J=1.9, 1 H); 7.39–7.43
(m, 6 H); 7.55–7.58( m, 4 H); 7.82 (d, J=1.9, 1 H). 13C-NMR (75 MHz, CDCl3): 52.7; 104.8; 113.4;
113.9; 118.0; 120.4; 126.2; 128.4; 129.2; 129.7; 138.4; 148.9; 151.5; 163.1. HR-MALDI-MS: 358.1071
([M+H]+, C22
N
N
6-Cyano-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (27). A soln. of LiOH·H2O (21 mg, 0.5
mmol) in H2O (3 ml) was added to a soln. of 55 (60 mg, 0.168mmol) in MeOH/CH 2Cl2 (6 :1, 3.5 ml),
and the mixture was vigorously stirred for 16 h at 208. Sat. aq. NH4Cl soln. (10 ml) was added, and the
mixture was partitioned between H2O (40 ml) and AcOEt (40 ml). The aq. phase was extracted with
AcOEt (3”20 ml), and the combined org. phases were washed with sat. aq. NaCl soln., dried
(MgSO4), and evaporated in vacuo to afford 27 (53 mg, 92%). Colorless solid. M.p. 2218. IR (KBr):
1
2925m, 2229m, 1696s, 1449s, 1267s, 1213s, 1048s, 949m, 922m, 756m, 694s, 641m, 617w. H-NMR (300
MHz, CDCl3): 7.25 (d, J=1.7, 1 H); 7.41 (m, 6 H); 7.58( m, 4 H); 7.87 (d, J=1.7, 1 H). 13C-NMR (75
MHz, CDCl3): 105.0; 112.6; 114.4; 117.8; 120.7; 126.1; 128.5; 129.6; 129.8; 138.2; 149.0; 152.1; 167.1.
HR-MALDI-MS: 344.0910 ([M+H]+, C21
N
N
Methyl 6-Cyano-2,2-bis(4-methoxyphenyl)-1,3-benzodioxole-4-carboxylate (56). A soln. of 54 (600
mg, 1.27 mmol), [Pd(PPh3)4] (150 mg, 0.127 mmol), KCN (170 mg, 2.55 mmol), and 18-crown-6 (530
mg, 2.0 mmol) in toluene/DMF (3 :1, 20 ml) was stirred at 1008 for 16 h. After cooling to 208, the mixture
was partitioned between H2O (50 ml) and AcOEt (50 ml), and the aq. phase was extracted with AcOEt
(2”50 ml). The pooled org. phases were washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated
in vacuo. CC (SiO2; hexane/AcOEt 20 :1 ! 9 :1) afforded 56 (265 mg, 48%). Colorless solid. M.p.
159–1608. IR (KBr): 3414w, 2946w, 2836w, 2222m, 1719s, 1611m, 1581w, 1513m, 1464s, 1417w, 1375w,
1309w, 1282m, 1254s, 1207m, 1171s, 1032m, 1004m, 953w, 939w, 8 36m, 8 17m, 78 2m, 617w. 1H-NMR
(300 MHz, CDCl3): 3.81 (s, 6 H); 3.95 (s, 3 H); 6.90 (d, J=8.9, 4 H); 7.17 (d, J=1.7, 1 H); 7.45 (d,
J=8.9, 4 H); 7.80 (d, J=1.7, 1 H). 13C-NMR (75 MHz, CDCl3): 52.5; 55.3; 104.6; 113.3; 113.7; 113.8;
118.1; 120.9; 128.0; 129.1; 130.6; 149.1; 151.8; 160.7; 163.3. HR-MALDI-MS: 418.1290 ([M+H]+,
C
N
G
(60 mg, 1.43 mmol) in H2O (5 ml) was added to a soln. of 56 (200 mg, 0.479 mmol) in MeOH/CH2Cl2
6 :1 (7 ml), and the mixture was vigorously stirred for 16 h at 208. Sat. aq. NH4Cl soln. (15 ml) was
added, and the mixture was partitioned between H2O (40 ml) and AcOEt (40 ml). The aq. phase was
extracted with AcOEt (3”20 ml), and the combined org. phases were washed with sat. aq. NaCl soln.,
dried (MgSO4), and evaporated in vacuo to afford 53 (179 mg, 93%). Colorless solid. M.p. 100–1028.
IR (KBr): 3446w (br.), 2934w, 2837w, 2228m, 1685w, 1610s, 1513m, 1466s, 1414m, 1308m, 1254s,
1210m, 1175s, 1032m, 1004m, 931w, 8 32m, 617w. 1H-NMR (300 MHz, (CD3)2
SO): 3.74 (br. s, 6 H);
A
6.97 (br. s, 4 H); 7.38( m, 5 H); 7.54 (br. s, 1 H). 13C-NMR (75 MHz, CDCl3): 55.3; 103.2; 113.8; 118.6;
119.0; 127.9; 129.7; 130.0; 130.5; 131.9; 148.1; 150.4; 160.2; 162.5. HR-MALDI-MS: 404.1134
([M+H]+, C23
N
N
Methyl 6-[(E)-3-(Dimethylamino)-3-oxoprop-1-enyl]-2,2-diphenyl-1,3-benzodioxole-4-carboxylate
(52). A soln. of 39 (130 mg, 0.32 mmol), N,N-dimethylacrylamide (47 mg, 0.47 mmol), P(OPh)3 (980
mg, 3.16 mmol), Bu4NBr (20 mg, 0.06 mmol), Na2CO3 (40 mg, 0.38mmol), and Pd(OAc) 2 (10 mg, 0.03
A
mmol) in DMA (10 ml) was stirred at 1408 for 72 h. After cooling to 208, the mixture was partitioned
between AcOEt (50 ml) and H2O (50 ml). The org. phase was washed with sat. aq. NaCl soln. (2”30
ml), dried (MgSO4), and evaporated in vacuo. CC (SiO2; hexane/AcOEt 5 :1 ! 3 :2) afforded 52 (60
mg, 44%). Colorless, viscous oil. IR (KBr): 3059w, 2927w, 1721s, 1652s, 1607m, 1481m, 1447s, 1396m,
1
1300m, 1256s, 1203s, 1046m, 1017m, 970w, 779w, 699m, 641w. H-NMR (300 MHz, CDCl3): 3.11 (br. s,
6 H); 3.96 (s, 3 H); 6.75 (d, J=15.6, 1 H); 7.20 (d, J=1.8, 1 H); 7.36–7.41 (m, 6 H); 7.55–7.61 (m, 6

Helvetica Chimica Acta – Vol. 89 (2006)
1873
H). 13C-NMR (75 MHz, CDCl3): 36.2; 37.7; 52.5; 110.5; 113.0; 116.8; 119.1; 124.1; 126.6; 128.6; 129.6;
129.7; 139.6; 141.5; 149.2; 149.5; 164.9; 166.7. HR-MALDI-MS: 452.1473 ([M+Na]+, C26 NNaO5þ ;
H23
calc. 452.1474).
A
ACHTREUNG
6-[(E)-3-(Dimethylamino)-3-oxoprop-1-enyl]-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (33).
Compound 52 (170 mg, 0.4 mmol) and LiOH·H2O (50 mg, 1.19 mmol) were reacted according to GP 3
to afford 33 (126 mg, 77%). Colorless solid. M.p. 230–2318. IR (KBr): 3431w, 3058w, 1710s, 1653m,
1
1596m, 1467m, 1445m, 1404w, 1249s, 1212m, 1176m, 1050m, 1027w, 975w, 8 43w, 78 4w, 697w, 641w. H-
NMR (300 MHz, CDCl3): 3.07 (s, 3 H); 3.16 (s, 3 H); 6.75 (d, J=15.3, 1 H); 7.24 (d, J=1.5, 1 H);
7.35–7.40 (m, 6 H); 7.59–7.62 (m, 5 H); 7.67 (d, J=1.5, 1 H). 13C-NMR (75 MHz, CDCl3): 36.1; 37.5;
110.6; 112.3; 116.4; 119.2; 124.6; 126.3; 128.4; 129.4; 129.5; 139.2; 141.5; 149.1; 149.8; 166.8; 167.8.
HR-MALDI-MS: 416.1498([ M+H]+, C25
N
N
Methyl 6-[(4-Methylphenyl)methyl]-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (51). Compound
39 (200 mg, 1.486 mmol), [Pd(PPh3)4] (57 mg, 0.049 mmol), bis(pinacolato)diboron (160 mg, 0.632
mmol), and AcOK (72 mg, 0.73 mmol), then [Pd(PPh3)4] (57 mg, 0.049 mmol), 1-(bromomethyl)-4-meth-
ylbenzene (117 mg, 0.63 mmol), and K2CO3 (336 mg, 2.43 mmol) were reacted according to GP 5,
Method B, to yield 51 (197 mg, 80%). Colorless, very viscous oil. IR (neat): 3030w, 2950w, 1722s,
1636w, 1603w, 1477s, 1449s, 1381w, 1251s, 1202s, 1047s, 1019m, 948w, 918w, 8 29w, 78 2m, 763m, 699m,
1
642m. H-NMR (300 MHz, CDCl3): 2.32 (s, 3 H); 3.85 (s, 2 H); 3.93 (s, 3 H); 6.83 (d, J=1.8, 1 H); 7.06
(d, J=8.6, 2 H); 7.10 (d, J=8.6, 1 H); 7.29 (d, J=1.8, 1 H); 7.35–7.38 (m, 6 H); 7.57–7.60 (m, 4 H).
13C-NMR (75 MHz, CDCl3): 21.0; 41.1; 52.0; 112.2; 113.1; 117.9; 122.3; 126.3; 128.2; 128.7; 129.1;
129.2; 134.9; 135.8; 137.5; 139.8; 146.6; 148.5; 165.2. HR-MALDI-MS: 459.1573 ([ M+Na]+,
C
N
G
(300 mg, 0.69 mmol) and LiOH·H2O (87 mg, 2.06 mmol) were reacted according to GP 3 to afford 35
(287 mg, 99%). Colorless solid. M.p. 211–2138. IR (KBr): 3434w (br.), 2904w, 2571w, 1685m, 1638w,
1604w, 1479m, 1464m, 1304m, 1252m, 1209s, 1050m, 1027m, 947w, 921w, 8 28w, 78 4m, 750w, 797m,
1
641w. H-NMR (300 MHz, CDCl3): 2.32 (s, 3 H); 3.86 (s, 2 H); 6.88 (d, J=1.2, 1 H); 7.07 (d, J=8.4, 2
H); 7.11 (d, J=8.4, 2 H); 7.34–7.40 (m, 7 H); 7.58–7.62 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 21.0;
41.1; 111.3; 113.9; 118.4; 122.7; 126.4; 128.3; 128.7; 129.3; 135.2; 135.9; 137.4; 139.6; 147.3; 148.6;
169.7. HR-MALDI-MS: 445.1415 ([M+Na]+, C28
N
N
Methyl 2,2-Diphenyl-6-(1,3-thiazol-2-yl)-1,3-benzodioxole-4-carboxylate (50). Compound 39 (250
mg, 0.608mmol), [Pd(PPh 3)4] (70 mg, 0.06 mmol), bis(pinacolato)diboron (200 mg, 0.79 mmol), and
AcOK (90 mg, 0.912 mmol), then [Pd(PPh3)4] (70 mg, 0.06 mmol), 2-bromothiazole (110 mg, 0.67
mmol), and K2CO3 (420 mg, 3.04 mmol) were reacted according to GP 5, Method B, to afford 50 (166
mg, 66%). Colorless solid. M.p. 154–1558. IR (KBr): 3054w, 2947w, 1712s, 1627w, 1497w, 1468s, 1447s,
1359m, 1321w, 1286m, 1254s, 1212s, 1047s, 1017s, 944w, 929w, 8 8w3, 8 01m, 78 1m, 760m, 699s, 641m.
1H-NMR (300 MHz, CDCl3): 3.97 (s, 3 H); 7.28( d, J=3.2, 1 H); 7.37–7.42 (m, 6 H); 7.60–7.63 (m, 4
H); 7.71 (d, J=2.3, 1 H); 7.81 (d, J=3.2, 1 H); 8.01 (d, J=2.3, 1 H). 13C-NMR (75 MHz, CDCl3): 52.5;
110.4; 113.1; 118.9; 119.4; 122.2; 126.6; 127.8; 128.6; 129.7; 139.5; 143.5; 149.4; 149.9; 164.6; 167.4.
HR-MALDI-MS: 416.0947 ([M+H]+, C24
A
G
N
2,2-Diphenyl-6-(1,3-thiazol-2-yl)-1,3-benzodioxole-4-carboxylic Acid (24). Compound 50 (300 mg,
0.722 mmol) and LiOH·H2O (91 mg, 2.17 mmol) were reacted according to GP 3 to afford 24 (290 mg,
96%). Colorless solid. M.p. 226–2278. IR (KBr): 3122w, 2924w, 1702m, 1629w, 1477s, 1446s, 1319w,
1
1266s, 1235m, 1213s, 1133s, 1048m, 1018m, 948w, 909w, 8 51w, 792m, 762w, 720w, 699m, 641w. H-NMR
(300 MHz, (CD3)2
H); 7.89 (d, J=3.0, 1 H); 7.92 (d, J=1.8, 1 H). 13C-NMR (75 MHz, (CD3)2
120.4; 121.3; 125.9; 127.3; 128.7; 129.7; 138.7; 143.7; 148.4; 148.5; 164.4; 165.7. HR-MALDI-MS:
402.0794 ([M+H]+, C23 S+; calc. 402.0800).
H16NO4
ACHTREUNG
AHCTREUNG
A
N
ACHTREUNG
Methyl 6-(1,3-Benzothiazol-2-yl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (49). Compound 39
(600 mg, 1.459 mmol), [Pd(PPh3)4] (85 mg, 0.073 mmol), bis(pinacolato)diboron (480 mg, 1.9 mmol),
and AcOK (216 mg, 2.2 mmol), then [Pd(PPh3)4] (85 mg, 0.073 mmol), 2-bromo-1,3-benzothiazole (375
mg, 1.75 mmol), and K2CO3 (1 g, 7.3 mmol) were reacted according to GP 5, Method B, to afford 49
(271 mg, 40%). Colorless solid. M.p. 184–1858. IR (KBr): 3055w, 2950w, 1718s, 1635w, 1502w, 1446s,

1874
Helvetica Chimica Acta – Vol. 89 (2006)
1368m, 1297m, 1239s, 1212s, 1163m, 1047s, 1015s, 945m, 921m, 8 74m, 795m, 776s, 759s, 723w, 701s, 640m.
1H-NMR (300 MHz, CDCl3): 4.00 (s, 3 H); 7.38–7.51 (m, 8H); 7.62–7.64 ( m, 4 H); 7.86 (d, J=1.7, 1 H);
7.88 (d, J=9.3, 1 H); 8.04 (d, J=9.3, 1 H); 8.13 (d, J=1.7, 1 H). 13C-NMR (75 MHz, CDCl3): 52.4; 110.6;
112.8; 119.3; 121.5; 122.9; 123.2; 125.1; 126.3; 127.5; 128.3; 129.4; 134.8; 139.1; 149.1; 150.2; 153.7; 164.1;
166.5. HR-MALDI-MS: 466.1113 ([M+H]+, C28
A
G
N
(465.10): C 72.24, H 4.11, N 3.01; found C 72.15, H 4.03, N 3.19.
6-(1,3-Benzothiazol-2-yl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (26). Compound 49 (210
mg, 0.451 mmol) and LiOH·H2O (57 mg, 1.35 mmol) were reacted according to GP 3 to afford 26 (201
mg, 99%). Colorless solid. M.p. 2278. IR (KBr): 3437w, 2965w, 2610w, 1738m, 1688s, 1634w, 1460s,
1427m, 1360w, 1256s, 1237s, 1211s, 1047s, 1048m, 1015m, 999m, 928w, 8 78w, 78 8m, 760m, 726w, 699m,
1
641w. H-NMR (300 MHz, CDCl3): 7.36–7.44 (m, 7 H); 7.46–7.53 (m, 1 H); 7.53–7.67 (m, 4 H); 7.88
(d, J=1.8, 1 H); 7.89 (d, J=8.7, 1 H); 8.15 (d, J=8.7, 1 H); 8.28 (d, J=1.8, 1 H). 13C-NMR (75 MHz,
CDCl3): 111.4; 112.2; 119.7; 121.5; 123.1; 123.7; 125.2; 126.3; 126.4; 127.5; 128.3; 129.5; 134.6; 138.9;
149.3; 150.9; 153.6; 166.6; 167.8. HR-MALDI-MS: 452.0955 ([M+H]+, C27
A
G
N
Methyl 2,2-Diphenyl-6-(pyridin-4-yl)-1,3-benzodioxole-4-carboxylate (48). Compound 39 (400 mg,
0.973 mmol), [Pd(PPh3)4] (100 mg, 0.087 mmol), bis(pinacolato)diboron (320 mg, 1.26 mmol), and
AcOK (150 mg, 1.5 mmol), then [Pd(PPh3)4] (112 mg, 0.097 mmol), 2-bromopyridine hydrochloride
(265 mg, 1.36 mmol), and K2CO3 (680 mg, 4.9 mmol) were reacted according to GP 5, Method B, to
yield 48 (264 mg, 67%). Colorless solid. M.p. 151–1528. IR (KBr): 3030w, 2954w, 1718s, 1635w, 1594m,
1475s, 1439s, 1418m, 1325m, 1291m, 1269s, 1225s, 1180m, 1054s, 1038m, 1018m, 947w, 927w, 8 8w6,
815m, 78 2m, 753w, 703m, 693m, 641m. 1H-NMR (300 MHz, CDCl3): 3.98( s, 3 H); 7.31 (d, J=1.8, 1
H); 7.39–7.41 (m, 6 H); 7.48( dd, J=4.7, 1.8, 1 H); 7.61–7.64 (m, 4 H); 7.75 (d, J=1.7, 1 H); 8.63 (dd,
J=4.7, 1.8, 1 H). 13C-NMR (75 MHz, CDCl3): 52.6; 110.9; 113.4; 119.4; 121.6; 122.3; 126.6; 128.6;
129.8; 131.7; 139.5; 148.0; 149.4; 149.7; 149.8; 164.9. HR-MALDI-MS: 410.1383 ([ M+H]+, C26
N
N
calc. 410.1392).
2,2-Diphenyl-6-(pyridin-4-yl)-1,3-benzodioxole-4-carboxylic Acid (23). Compound 48 (250 mg, 0.61
mmol) and LiOH·H2O (80 mg, 1.84 mmol) were reacted according to GP 3 to afford 23 (220 mg,
92%). Grayish solid. M.p. 2668 (dec.). IR (KBr): 3446w (br.), 3061w, 2447w (br.), 1696m, 1632w,
1603m, 1469s, 1440m, 1373w, 1326w, 1273s, 1213s, 1182m, 1054s, 1015m, 949w, 921w, 906w, 8 32m, 78 9w,
777w, 765m, 701m, 640w. 1H-NMR (300 MHz, (CD3)2
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
Methyl 2,3-Dimethoxy-5-[(4-methylphenyl)sulfonyl]benzoate (58). To a soln. of 57 (2.25 g, 7.0 mmol)
in DMF (20 ml), sodium p-toluenesulfinate hydrate (2.21 g, 11.26 mmol) and CuI (2.22 g, 11.6 mmol)
were added, and the light green soln. was stirred at 1108 for 14 h. The mixture was partitioned between
H2O (80 ml) and AcOEt (50 ml), and the aq. phase was extracted with AcOEt (2”40 ml). The combined
org. phases were washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated under reduced pressure.
CC (SiO2; hexane/AcOEt 8:2 ! 3 :2) afforded 58 (1.41 g, 58%). Colorless solid. M.p. 1148. IR (KBr):
3081w, 2945w, 1731s, 1594w, 1482m, 1426w, 1317s, 1273s, 1146s, 1104m, 994w, 8 72w, 8 11w, 713w, 665m,
1
585m, 535w. H-NMR (300 MHz, CDCl3): 2.40 (s, 3 H); 3.90 (s, 3 H); 3.92 (s, 3 H); 3.92 (s, 3 H); 7.31
(d, J=8.1, 2 H); 7.54 (d, J=2.1, 1 H); 7.82 (d, J=8.1, 2 H); 7.87 (d, J=2.1, 1 H). 13C-NMR (75 MHz,
CDCl3): 21.7; 52.6; 56.5; 61.7; 113.4; 122.0; 126.4; 127.5; 129.9; 136.8; 138.2; 144.2; 152.7; 153.8; 164.9.
HR-MALDI-MS: 373.0714 ([M+Na]+, C17
A
G
N
AHCTREUNG
was stirred at 1408 for 20 h. H2O (20 ml) was added, and the mixture was extracted with AcOEt
(3”30 ml). The combined org. phases were washed with sat. aq. NaCl soln., dried (MgSO4), and evapo-
rated in vacuo. CC (SiO2, hexane/AcOEt/AcOH 3 :2 :0.2 ! 1:3 :0.2) afforded 59 (560 mg, 45%).
Orange solid. M.p. 223–2258 (dec.). IR (KBr): 3165m (br.), 1692m, 1597w, 1467m, 1403w, 1282s,
1
1214w, 1141s, 1094m, 967w, 8 93w, 799w, 743w, 709m, 665m. H-NMR (300 MHz, (CD3)2
A

Helvetica Chimica Acta – Vol. 89 (2006)
1875
H); 4.42 (br. s, 1 H); 7.28( d, J=2.1, 1 H); 7.39 (d, J=8.1, 2 H); 7.75 (m, 3 H); 9.86 (br. s, 1 H). 13C-NMR
(75 MHz, (CD3)2SO): 21.0; 114.7; 115.6; 120.0; 126.8; 128.7; 130.0; 138.9; 143.6; 147.1; 156.4; 170.5. HR-
ACHTREUNG
MALDI-MS: 331.0246 ([M+Na]+, C14 S+; calc. 331.0252).
A
N
ACHTREUNG
Methyl 2,3-Dihydroxy-5-[(4-methylphenyl)sulfonyl]benzoate (60). Compound 59 (410 mg, 1.33
mmol) and SOCl2 (790 mg, 6.65 mmol) were reacted according to GP 1 to afford 60 (321 mg, 75%). Col-
orless solid. M.p. 168–1708 (dec.). IR (KBr): 3362m (br.), 2956w, 1695s, 1596m, 1494m, 1447m, 1284s,
1
1243s, 1146s, 1094s, 1018m, 937w, 8 8 m3, 8 10m, 736w, 700w, 666s. H-NMR (300 MHz, CDCl3): 2.39 (s,
3 H); 4.00 (s, 3 H); 5.91 (br. s, 1 H); 7.29 (d, J=7.8, 2 H); 7.55 (d, J=1.2, 1 H); 7.83 (d, J=7.8, 2 H);
8.05 (d, J=1.2, 1 H); 11.43 (br. s, 1 H). 13C-NMR (75 MHz, CDCl3): 21.7; 53.1; 112.2; 117.8; 120.9;
127.4; 129.8; 132.8; 138.5; 144.1; 145.6; 152.5; 169.6. HR-MALDI-MS: 345.0402 ([ M+Na]+, C15
A
G
N
calc. 345.0409).
Methyl 2,2-Bis(4-methoxyphenyl)-6-[(4-methylphenyl)sulfonyl]-1,3-benzodioxole-4-carboxylate (61).
Compound 60 (200 mg, 0.62 mmol), 4,4’-dimethoxybenzophenone (225 mg, 0.93 mmol), and oxalyl chlo-
ride (944 mg, 7.44 mmol) were reacted according to GP 2.2. CC (SiO2; hexane/AcOEt 20 :1 ! 9 :1)
afforded 61 (260 mg, 77%). Colorless solid. M.p. 79–828. IR (KBr): 2951w, 2832w, 1727m, 1610m,
1512m, 1464s, 1320m, 1285m, 1248s, 1210m, 1175s, 1150s, 1090m, 1042m, 1004w, 8 8w5, 8 32w, 739w,
1
663w, 616w. H-NMR (300 MHz, CDCl3): 2.39 (s, 3 H); 3.80 (s, 6 H); 3.93 (s, 3 H); 6.88 (dt, J=8.7, 2.5,
4 H); 7.29 (d, J=8.1, 2 H); 7.43 (m, 5 H); 7.81 (d, J=8.7, 2 H); 8.09 (d, J=1.8, 1 H). 13C-NMR (75
MHz, CDCl3): 21.7; 52.5; 55.4; 110.1; 112.5; 113.6; 120.9; 124.0; 127.5; 127.9; 129.9; 130.7; 134.9;
138.4; 144.1; 149.2; 151.9; 160.4; 163.4. HR-MALDI-MS: 547.1428 ([M+H]+, C30
A
G
N
547.1427). Anal. calc. for C30H26O8S (546.13): C 65.65, H 4.87; found C 65.92, H 4.79.
2,2-Bis(4-methoxyphenyl)-6-[(4-methylphenyl)sulfonyl]-1,3-benzodioxole-4-carboxylic Acid (34).
Compound 61 (205 mg, 0.375 mmol) and LiOH·H2O (79 mg, 1.88 mmol) were reacted according to
GP 3 to afford 34 (197 mg, 99%). Colorless solid. M.p. 109–1108. IR (KBr): 3423w (br.), 2961w,
1
2837w, 1649w, 1611m, 1514m, 1443m, 1313s, 1254s, 1175s, 1119m, 1030s, 931w, 903w, 8 32m, 675w. H-
NMR (300 MHz, CD
(d, J=8.7, 4 H); 7.43 (d, J=1.8, 1 H); 7.74 (d, J=8.1, 2 H); 8.03 (d, J=1.8, 1 H). 13C-NMR (75 MHz,
CD3OD): 21.5; 55.8; 110.1; 114.0; 114.5; 125.4; 128.1; 128.4; 129.1; 130.8; 131.0; 132.0; 133.2; 135.9;
139.1; 145.7; 150.5; 162.0. HR-MALDI-MS: 533.1274 ([M+H]+, C29 S+; calc. 533.1270).
H25O8
3OD): 2.32 (s, 3 H); 3.73 (s, 6 H); 6.85 (d, J=8.7, 4 H); 7.27 (d, J=8.1, 2 H); 7.38
AHCTREUNG
A
N
ACHTREUNG
2-Methoxy-1-{[(methoxy)methyl]oxy}-4-(1-methylethenyl)benzene (63). A suspension of methyl(tri-
phenyl)phosphonium bromide (1.1 g, 3.09 mmol) in dry THF (5 ml) was cooled to À788 and slowly
treated with BuLi (1.6M in hexane, 1.94 ml). To this yellow suspension, a soln. of 62 (500 mg, 2.38
mmol) in dry THF (5 ml) was added, and the mixture was stirred at 208 for 12 h. The suspension was fil-
tered, and the solvent was evaporated in vacuo. CC (SiO2; hexane/AcOEt 6 :1) afforded 63 (424 mg,
86%). Colorless oil. IR (neat): 3085w, 2952m, 2827w, 1627w, 1602w, 1580m, 1513s, 1463m, 1413m,
1300m, 1248s, 1224m, 1157s, 1139s, 1077s, 997s, 922m, 8 8m5, 8 55m, 8 17w, 765w. 1H-NMR (300 MHz,
CDCl3): 2.14 (s, 3 H); 3.52 (s, 3 H); 3.91 (s, 3 H); 5.03 (d, J=1.5, 1 H); 5.23 (s, 2 H); 5.29 (d, J=1.5, 1
H); 6.99 (dd, J=8.4, 2.1, 1 H); 7.02 (dd, J=6.9, 2.1, 1 H); 7.11 (d, J=8.4, 1 H). 13C-NMR (75 MHz,
CDCl3): 21.9; 55.8; 56.2; 95.4; 109.2; 111.4; 115.9; 118.1; 135.9; 142.9; 146.0; 149.3. HR-EI-MS:
208.1097 (M+, C12
N
N
2-Methoxy-1-{[(methoxy)methyl]oxy}-4-(1-methylethyl)benzene (64). To a soln. of 63 (3.5 g, 16.81
mmol) in MeOH (20 ml), Pd/C (10%, 350 mg) was added, and the mixture was stirred 16 h under an
H2 atmosphere. The mixture was filtered over Celite, evaporated in vacuo, and briefly dried at ca. 10
Torr to yield 64 (3.31 g, 94%). Colorless oil. IR (neat): 2959s, 2827w, 1592w, 1516s, 1464s, 1419m,
1
1297w, 1266s, 1228s, 1198m, 1156s, 1079s, 1037w, 1004s, 923m, 8 52w, 8 15w, 763w, 653w. H-NMR (300
MHz, CDCl3): 1.24 (d, J=7.0, 6 H); 2.86 (sept., J=7.0, 1 H); 3.52 (s, 3 H); 3.88 (s, 3 H); 5.20 (s, 2 H);
6.75 (dd, J=8.2, 2.2, 1 H); 6.77 (dd, J=3.5, 2.2, 1 H); 7.07 (d, J=8.2, 1 H). 13C-NMR (75 MHz,
CDCl3): 24.1; 33.8; 55.8; 56.1; 95.6; 110.3; 116.5; 118.2; 143.5; 144.4; 149.5. HR-EI-MS: 210.1246 ( M+,
C
N
G
9.51 mmol) in dry THF (35 ml) cooled to 08, BuLi (1.6M in hexane, 9 ml) was added dropwise, and the
mixture was stirred for 2.5 h at 08. This soln. was then slowly added to a soln. of methyl chloroformate
(9 g, 95.1 mmol) in dry THF (10 ml) cooled to 08. The mixture was stirred 12 h at 208 and then partitioned

1876
Helvetica Chimica Acta – Vol. 89 (2006)
between sat. aq. KHCO3 soln. (60 ml) and AcOEt (60 ml). The org. phase was washed with sat. aq. NaCl
soln. (2”40 ml), dried (MgSO4), and evaporated in vacuo. CC (SiO2; hexane/AcOEt 9 :1 ! 6 :1)
afforded 65 (1.3 g, 51%). Colorless oil. IR (neat): 2960m, 2841w, 1769m, 1729s, 1586w, 1487m, 1464m,
1
1439m, 1339m, 1263s, 1207s, 1157m, 1063s, 961s, 8 60w, 797w, 656w. H-NMR (300 MHz, CDCl3): 1.24
(d, J=6.9, 6 H); 2.88 (sept., J=6.9, 1 H); 3.57 (s, 3 H); 3.86 (s, 3 H); 3.90 (s, 3 H); 5.10 (s, 2 H); 6.91
(d, J=2.1, 1 H); 7.18( d, J=2.1, 1 H). 13C-NMR (75 MHz, CDCl3): 24.0; 34.0; 52.2; 56.2; 75.4; 99.4;
114.4; 119.8; 126.0; 143.3; 144.9; 152.8; 166.8. HR-EI-MS: 268.1300 (M+, C14
N
N
2,3-Dihydroxy-5-(1-methylethyl)benzoic Acid (66). To a soln. of 65 (900 mg, 3.35 mmol) in dry
CH2Cl2 (5 ml) cooled to À808, BBr3 (1M in CH2Cl2, 3.4 ml) was added dropwise, and the mixture was stir-
red 30 min at À788, then 1 h at 208. The reaction was the quenched by addition of H2O (10 ml), and the
resulting mixture was extracted with CH2Cl2 (2”30 ml). The combined org. phases were dried (MgSO4)
and evaporated in vacuo. The residue was redissolved in AcOH (1 ml), and HBr (33% in AcOH, 2.5 ml)
was added. The mixture was stirred at 1208 for 5 h, then H2O (10 ml) was slowly added, and the mixture
was extracted with AcOEt (2”40 ml). The combined org. phases were washed with sat. aq. NaCl soln.,
dried (MgSO4), and evaporated in vacuo to yield 66 (270 mg, 41%). Brownish solid. M.p. 151–1528. IR
(KBr): 3311m, 2958s, 1675s, 1613w, 1483s, 1384w, 1276s, 1161s, 98 6w, 8 72w, 796w, 778w, 728w, 703w. 1H-
NMR (300 MHz, CDCl3): 1.22 (d, J=7.1, 6 H); 2.84 (sept., J=7.1, 1 H); 5.64 (br. s, 1 H); 7.09 (d, J=2.4, 1
H); 7.30 (d, J=2.4, 1 H); 10.29 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 23.9; 33.5; 110.8; 118.7; 119.7; 140.5;
144.8; 147.4; 174.8. HR-EI-MS: 196.0720 ( M+, C10
N
N
Methyl 2,3-Dihydroxy-5-(1-methylethyl)benzoate (67). Compound 66 (140 mg, 0.71 mmol) and
SOCl2 (430 mg, 3.6 mmol) were reacted according to GP 1 to afford 67 (125 mg, 83%). Colorless solid.
M.p. 66–678. IR (KBr): 3425s, 2955m, 1688s, 1485s, 1438s, 1338s, 1276s, 1231m, 1159m, 1112w, 1018m,
1
964w, 8 93w, 78 5m, 693w, 641w. H-NMR (300 MHz, CDCl3): 1.21 (d, J=6.9, 6 H); 2.82 (sept., J=6.9, 1
H); 3.95 (s, 3 H); 5.61 (s, 1 H); 7.02 (d, J=2.0, 1 H); 7.21 (d, J=2.0, 1 H); 10.69 (s, 1 H). 13C-NMR (75
MHz, CDCl3): 23.9; 33.5; 52.3; 111.8; 117.7; 118.4; 140.1; 144.7; 146.9; 170.8. HR-EI-MS: 210.0892
(M+, C11
N
N
Methyl 6-(1-Methylethyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (68). Compound 67 (85 mg,
0.4 mmol) and Ph2CCl2 (125 mg, 0.53 mmol) were reacted according to GP 2.1, Workup Method B, to
afford 68 (112 mg, 74%). Colorless solid. M.p. 108–1108. IR (KBr): 2959w, 1714s, 1478s, 1447s, 1385w,
1285m, 1045m, 1017m, 915w, 8 68w, 8 07m, 78 2m, 701s, 641m. 1H-NMR (300 MHz, CDCl3): 1.21 (d,
J=6.8, 6 H); 2.85 (sept., J=6.8, 1 H); 3.94 (s, 3 H); 6.92 (d, J=1.9, 1 H); 7.26 (d, J=1.9, 1 H);
7.35–7.41 (m, 6 H); 7.60–7.65 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 24.0; 33.9; 52.0; 111.0; 112.1;
117.7; 119.9; 126.4; 128.2; 129.2; 140.0; 142.5; 146.3; 148.3; 165.4. HR-MALDI-MS: 397.1414
([M+Na]+, C24
N
N
6-(1-Methylethyl)-2,2-diphenyl-1,3-benzodioxole-4-carboxylic Acid (36). Compound 68 (100 mg,
0.267 mmol) and LiOH·H2O (45 mg, 1.07 mmol) were reacted according to GP 3 to afford 36 (91 mg,
95%). Colorless solid. M.p. 155–1568. IR (KBr): 2958m, 2630w, 1683s, 1478s, 1450s, 1254s, 1207s,
1
1044m, 1023m, 947w, 8 64w, 760w, 697m, 641w. H-NMR (300 MHz, CDCl3): 1.21 (d, J=6.9, 6 H); 2.86
(sept., J=6.9, 1 H); 6.97 (d, J=1.8, 1 H); 7.31 (d, J=1.8, 1 H); 7.35–7.42 (m, 6 H); 7.61–7.64 (m, 4
H). 13C-NMR (75 MHz, CDCl3): 24.0; 33.8; 111.2; 111.9; 118.2; 120.3; 126.4; 128.3; 129.3; 139.8; 142.7;
146.9; 148.4; 169.6. HR-MALDI-MS: 383.1250 ([M+Na]+, C23
N
N
3-Bromo-5-(trifluoromethyl)benzene-1,2-diol (70). To a soln. of 69 (870 mg, 4.8 mmol) in CCl4 (20
ml), Br2 (770 mg, 4.8mmol) was added, and the mixture was stirred at 20 8 for 1 h. The solvent was
removed in vacuo, and the residue was purified by CC (SiO2; hexane/AcOEt 4 :1 ! 3 :2) to yield 70
(910 mg, 74%). Yellowish oil. IR (neat): 3048w (br.), 1599w, 1502w, 1433w, 1312s, 1234m, 1168m,
1
1115s, 934m, 8 66w, 8 38w, 767w, 726w, 670m. H-NMR (300 MHz, CDCl3): 5.68(br. s, 1 H); 5.81 (br. s,
1 H); 7.14 (dd, J=2.3, 0.6, 1 H); 7.32 (dd, J=2.3, 0.6, 1 H). 13C-NMR (75 MHz, CD3
OD): 110.2; 111.6
A
(q, J=3.4); 121.4 (q, J=4.2); 123.1 (q, J=33.0); 125.0 (q, J=270); 147.4; 147.7. 19F-NMR (282 MHz,
CDCl3): À61.6 (s). HR-EI-MS: 255.9348( M+, C7
C
G
G

Helvetica Chimica Acta – Vol. 89 (2006)
1877
org. phases were washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated in vacuo. CC (SiO2;
hexane/AcOEt 10 :1) afforded 71 (750 mg, 87%). Colorless solid. M.p. 79–808. IR (KBr): 3032w,
2935w, 2884w, 1576w, 1499w, 1485w, 1455w, 1424m, 1382w, 1335s, 1290m, 1230m, 1164s, 1120s, 1011m,
1
957m, 919w, 8 59w, 751m, 698m. H-NMR (300 MHz, CDCl3): 5.09 (s, 2 H); 5.15 (s, 2 H); 5.97 (s, 1 H);
7.18( d, J=1.5, 1 H); 7.32–7.47 (m, 11 H). 13C-NMR (75 MHz, CDCl3): 71.5; 75.0; 110.3 (q, J=3.9);
118.4; 122.5 (q, J=3.9); 123.1 (q, J=271); 127.0 (q, J=33.6); 127.6; 128.2; 128.3; 128.4; 128.5; 128.6;
135.5; 136.3; 148.4; 152.8. 19F-NMR (282 MHz, CDCl3): À62.6 (s). HR-MALDI-MS: 459.0169
([M+Na]+, C21
found C 57.45, H 3.82.
A
G
N
Methyl 2,3-Bis(phenylmethoxy)-5-(trifluoromethyl)benzoate (72). To a soln. of 71 (750 mg, 1.76
mmol) in dry THF (10 ml) cooled to À908, BuLi (1.6M in hexane, 3.3 ml, 5.28mmol) was slowly
added, and the yellow soln. was stirred at À908 for 15 min. Methyl chloroformate (1.66 g, 17.6 mmol)
was added, and the mixture was allowed to warm to 208 and stirred at this temp. for 1 h. H2O (10 ml)
was added, and the mixture was extracted with AcOEt (2”30 ml). The combined org. phases were
washed with sat. aq. NaCl soln., dried (MgSO4), and evaporated in vacuo. CC (SiO2; hexane/AcOEt
10 :1) afforded 72 (383 mg, 52%). Colorless solid. M.p. 78–798. IR (KBr): 3033w, 2950w, 1733s, 1610w,
1486w, 1430m, 1363s, 1299m, 1250s, 1199m, 1151m, 1121s, 1045s, 956w, 935w, 909w, 8 67w, 750w, 698m.
1H-NMR (300 MHz, CDCl3): 3.87 (s, 3 H); 5.14 (s, 2 H); 5.17 (s, 2 H); 7.30–7.45 (m, 11 H); 7.65 (dd,
J=1.8, 1.2, 1 H). 13C-NMR (75 MHz, CDCl3): 52.5; 71.6; 75.8; 113.9 (q, J=3.3); 118.0; 119.9 (q,
J=3.3); 123.4 (q, J=270); 126.0 (q, J=33.6); 127.0; 127.6; 128.1; 128.3; 128.4; 128.5; 128.6; 135.5;
136.6; 150.7; 153.0; 165.4. 19F-NMR (282 MHz, CDCl3): À62.7 (s). HR-MALDI-MS: 439.1132
([M+Na]+, C23
C 66.16, H 4.78.
A
G
N
Methyl 2,3-Dihydroxy-5-(trifluoromethyl)benzoate (73). To a soln. of 72 (280 mg, 0.67 mmol) in
MeOH (10 ml), Pd/C (10%, 30 mg) was added, and the mixture was stirred 16 h under an H2 atmosphere.
The mixture was then filtered over Celite and evaporated in vacuo to yield 73 (148mg, 99%). Grayish
solid. M.p. 94–958. IR (KBr): 3462m, 3132w, 2961w, 1676m, 1494m, 1447m, 1338s, 1245s, 1199m, 1120s,
1
1014w, 936w, 8 8w7, 793m, 679m. H-NMR (300 MHz, CD3
G
H). 13C-NMR (75 MHz, CD3
148.6; 154.6; 170.9. 19F-NMR (282 MHz, CD3
calc. 236.0296).
ACHTREUNG
G
Methyl 2,2-Bis(4-methoxyphenyl)-6-(trifluoromethyl)-1,3-benzodioxole-4-carboxylate (74). 4,4’-
Dimethoxybenzophenone (213 mg, 0.88 mmol), oxalyl chloride (900 mg, 7.1 mmol), and 73 (130 mg,
0.59 mmol) were reacted according to GP 2.2. CC (SiO2; hexane/Et2O 10 :1) afforded 74 (170 mg,
G
63%). Colorless, very viscous oil. IR (neat): 3003w, 2956w, 2839w, 1727s, 1642w, 1612s, 1585w, 1514s,
1
1486m, 1445s, 1324s, 1268s, 1234s, 1175s, 1123m, 1042s, 1005m, 935w, 8 32m, 78 3w, 674w. H-NMR (300
MHz, CDCl3): 3.81 (s, 6 H); 3.95 (s, 3 H); 6.90 (dd, J=6.7, 2.3, 4 H); 7.18( d, J=1.5, 1 H); 7.47 (dd,
J=6.7, 2.3, 4 H); 7.74 (d, J=1.5, 1 H). 13C-NMR (75 MHz, CDCl3): 52.4; 55.4; 108.6 (q, J=3.1); 112.3;
113.7; 120.2; 120.8( q, J=4.3); 123.5 (q, J=270); 123.6 (q, J=33.4); 128.0; 131.0; 148.9; 150.7; 160.4;
163.8. 19F-NMR (282 MHz, CDCl3): À61.8( s). HR-MALDI-MS: 461.1202 ([M+H]+, C24
A
G
A
calc. 461.1212). Anal. calc. for C24H19O6F3 (460.11): C 62.61, H 4.16; found C 62.52, H 4.26.
2,2-Bis(4-methoxyphenyl)-6-(trifluoromethyl)-1,3-benzodioxole-4-carboxylic Acid (28). Compound
74 (60 mg, 0.13 mmol) and LiOH·H2O (28mg, 0.65 mmol) were reacted according to GP 3 to afford
28 (53 mg, 91%). Colorless solid. M.p. 114–1168. IR (KBr): 3441w (br.), 2936w, 2837w, 1687w, 1611s,
1513s, 1442m, 1364m, 1312s, 1253s, 1175s, 1121m, 1031s, 1005m, 952w, 931w, 8 31m, 676w. 1H-NMR
(300 MHz, CDCl3): 3.79 (s, 6 H); 6.94 (dd, J=6.9, 2.1, 4 H); 7.30 (d, J=1.5, 1 H); 7.46 (dd, J=6.9, 2.1,
4 H); 7.70 (d, J=1.5, 1 H). 19F-NMR (282 MHz, CDCl3): À63.7 (s). HR-MALDI-MS: 447.1059
([M+H]+, C23
A
G
N
9-[(E)-5,6,7-Trideoxy-7-({[6-(4-fluorophenyl)-2,2-diphenyl-1,3-benzodioxol-4-yl]carbonyl}amino)-2,3-
N
O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (75). Compound 21 (130 mg,
0.315 mmol), EDC·HCl (91 mg, 0.473 mmol), N-hydroxysuccinimide (48mg, 0.409 mmol), 20 (90 mg,
0.271 mmol), and Et
C

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Helvetica Chimica Acta – Vol. 89 (2006)
3175w, 2987w, 1636s, 1598m, 1517m, 1469s, 1373w, 1274m, 1213s, 1158w, 1082m, 1052m, 1016w, 8 67w,
1
834w, 777w, 699m. H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3 H); 4.08( m, 2 H); 4.71 (m, 1
H); 4.95 (dd, J=6.6, 3.6, 1 H); 5.44 (dd, J=6.6, 2.3, 1 H); 5.87 (m, 2 H); 5.93 (br. s, 2 H); 6.09 (d,
J=2.3, 1 H); 7.10 (tt, J=8.7, 2.1, 2 H); 7.12 (t, J=5.6, 1 H); 7.22 (d, J=1.8, 1 H); 7.37–7.41 (m, 6 H);
7.47–7.56 (m, 6 H); 7.77 (d, J=1.8); 7.87 (s, 1 H); 8.19 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 25.5;
27.3; 40.9; 84.1; 84.5; 87.1; 90.3; 110.6; 114.7; 115.3; 115.6 (d, J=21.2); 118.8; 120.1; 121.0; 126.4;
128.2; 128.4; 128.5; 129.7; 130.7; 135.0; 136.1; 138.7; 139.9; 144.1; 147.8; 149.2; 152.0; 154.8; 162.3 (d,
J=244.7); 163.1. 19F-NMR (282 MHz, CDCl3): À115.9 (tt, J=8.5, 5.4). HR-MALDI-MS: 749.2501
([M+Na]+, C41
A
G
N
9-[(E)-5,6,7-Trideoxy-2,3-O-(1-methylethylidene)-7-({[6-(4-methylphenyl)-2,2-diphenyl-1,3-benzo-
dioxol-4-yl]carbonyl}amino)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (76). Compound 22 (164
mg, 0.4 mmol), EDC·HCl (115 mg, 0.6 mmol), N-hydroxysuccinimide (60 mg, 0.52 mmol), 20 (90 mg,
0.271 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2; CH2Cl2/MeOH
N
19 :1) afforded 76 (111 mg, 57%). Colorless foam. [a]2D0 =+1.7 (c=0.95, CHCl3). IR (KBr): 3423m,
3176m, 2986w, 1638s, 1597s, 1531m, 1469s, 1434m, 1373w, 1329w, 1276s, 1207s, 1156w, 1081m, 1052s,
1016m, 970w, 8 67m, 8 18m, 777m, 699m, 641m. 1H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3
H); 2.37 (s, 3 H); 4.09 (m, 2 H); 4.71 (m, 1 H); 4.94 (dd, J=6.5, 3.6, 1 H); 5.42 (dd, J=6.5, 2.6, 1 H);
5.86 (m, 2 H); 6.06 (br. s, 2 H); 6.09 (d, J=2.6, 1 H); 7.17 (t, J=5.6, 1 H); 7.21 (d, J=8.3, 2 H); 7.26
(d, J=1.8, 1 H); 7.36–7.42 (m, 6 H); 7.46 (d, J=8.3, 2 H); 7.51–7.56 (m, 4 H); 7.82 (d, J=1.8, 1 H);
7.88 (s, 1 H); 8.19 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 25.2; 25.5; 27.2; 40.8; 84.1; 84.4; 87.1; 90.3;
110.5; 114.7; 115.2; 118.6; 120.0; 120.8; 126.4; 126.6; 128.0; 128.3; 129.4; 129.6; 130.8; 135.9; 136.0;
137.0; 138.8; 140.0; 143.8; 147.7; 149.1; 151.5; 154.6; 163.2. HR-MALDI-MS: 745.2750 ([M+Na]+,
C
A
G
N
69.61, H 5.56, N 11.93.
9-[(E)-5,6,7-Trideoxy-7-({[2,2-diphenyl-6-(pyridine-4-yl)-1,3-benzodioxol-4-yl]carbonyl}amino)-2,3-
O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (77). Compound 23 (160 mg,
0.405 mmol), EDC·HCl (117 mg, 0.608mmol), N-hydroxysuccinimide (61 mg, 0.527 mmol,), 20 (100
mg, 0.3 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted in CH 2Cl2/DMF (1:1, 5 ml) according to
E
GP 6. CC (SiO2; CH2Cl2/MeOH 19 :1) afforded 77 (95 mg, 45%). Yellowish foam. [a]2D0 =+2.5
(c=0.4, CHCl3). IR (neat): 3321w (br.), 2963m, 1696m, 1645m, 1597m, 1530w, 1468s, 1435w, 1374w,
1
1261s, 1213s, 1053s, 8 67w, 799m, 699m, 642w. H-NMR (300 MHz, CDCl3): 1.37 (s, 3 H); 1.61 (s, 3 H);
4.08( m, 2 H); 4.70 (m, 1 H); 4.96 (dd, J=6.3, 3.9, 1 H); 5.45 (dd, J=6.3, 2.3, 1 H); 5.86 (m, 2 H); 5.98
(br. s, 2 H); 6.08( d, J=2.3, 1 H); 7.16 (t, J=5.7, 1 H); 7.31 (d, J=1.7, 1 H); 7.36–7.42 (m, 6 H);
7.47–7.55 (m, 6 H); 7.86 (s, 1 H); 7.92 (d, J=1.7, 1 H); 8.18 (s, 1 H); 8.61 (d, J=6.3, 2 H). 13C-NMR
(75 MHz, CDCl3): 25.6; 27.4; 41.1; 84.3; 84.7; 87.4; 90.5; 110.4; 114.9; 116.0; 119.7; 120.4; 121.6; 122.0;
126.2; 126.7; 128.8; 130.2; 130.8; 132.8; 138.8; 140.1; 145.9; 147.6; 148.6; 149.6; 150.2; 153.0; 155.6;
163.1. HR-MALDI-MS: 732.2549 ([M+Na]+, C40
A
G
N
9-[(E)-5,6,7-Trideoxy-7-({[2,2-diphenyl-6-(1,3-thiazole-2-yl)-1,3-benzodioxol-4-yl]carbonyl}amino)-
2,3-O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (78). Compound 24 (170
mg, 0.38mmol), EDC·HCl (110 mg, 0.565 mmol), N-hydroxysuccinimide (57 mg, 0.49 mmol), 20 (100
mg, 0.3 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2; CH2Cl2/
E
MeOH 19 :1) afforded 78 (158mg, 73%). Colorless foam. [ a]2D0 =+3.5 (c=0.63, CHCl3). IR (KBr):
3424m, 3199w, 2987w, 1639s, 1598m, 1532m, 1471m, 1440m, 1374w, 1329w, 1263m, 1212s, 1156w,
1
1081m, 1050m, 1015m, 8 67w, 779w, 700m, 643w. H-NMR (300 MHz, CDCl3): 1.39 (s, 3 H); 1.62 (s, 3
H); 4.08( m, 2 H); 4.76 (m, 1 H); 4.93 (dd, J=6.2, 3.0, 1 H); 5.42 (dd, J=6.2, 2.0, 1 H,); 5.82 (m, 2 H);
6.10 (d, J=2.0, 1 H); 6.63 (br. s, 2 H); 7.12 (t, J=5.7, 1 H); 7.30 (d, J=3.5, 1 H); 7.37–7.43 (m, 6 H);
7.50–7.54 (m, 4 H); 7.73 (d, J=1.7, 1 H); 7.81 (d, J=3.5, 1 H); 7.92 (s, 1 H); 8.14 (d, J=1.7, 1 H); 8.20
(s, 1 H). 13C-NMR (75 MHz, CDCl3): 25.4; 27.1; 40.9; 84.3; 84.4; 87.3; 90.7; 109.7; 114.6; 115.4; 119.0;
119.3; 119.9; 121.9; 126.4; 127.9; 128.4; 128.6; 129.8; 130.8; 138.4; 140.5; 143.3; 145.9; 148.0; 148.9;
149.5; 153.8; 162.6; 167.2. HR-MALDI-MS: 738.2095 ([ M+Na]+, C38
A
N7
G
N
Anal. calc. for C42H38N6O6 (722.29): C 63.76, H 4.65, N 13.70; found C 63.55, H 4.70, N 13.68.
9-[(E)-7-{[(6-Bromo-2,2-diphenyl-1,3-benzodioxol-4-yl)carbonyl]amino}-5,6,7-trideoxy-2,3-O-(1-
methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (79). Compound 25 (200 mg, 0.503

Helvetica Chimica Acta – Vol. 89 (2006)
1879
mmol), EDC·HCl (145 mg, 0.755 mmol), N-hydroxysuccinimide (76 mg, 0.654 mmol), 20 (120 mg, 0.361
mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 7. CC (SiO2; CH2Cl2/MeOH 19 :1)
AHCTREUNG
afforded 79 (166 mg, 65%). Colorless foam. [a]2D0 =+9.3 (c=0.6, CHCl3). IR (KBr): 3424m, 3170w (br.),
2985w, 1636s, 1594s, 1531m, 1495s, 1423w, 1373w, 1236s, 1207s, 1156w, 1082s, 1016m, 8 67w, 778w, 698m.
1H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3 H); 4.04 (m, 2 H); 4.69 (m, 1 H); 4.95 (dd, J=6.3,
3.6, 1 H); 5.45 (dd, J=6.3, 2.3, 1 H); 5.84 (m, 2 H); 5.96 (br. s, 2 H); 6.09 (d, J=2.3, 1 H); 7.05 (t,
J=5.6, 1 H); 7.15 (d, J=2.0, 1 H); 7.35–7.40 (m, 6 H); 7.44–7.50 (m, 4 H); 7.72 (d, J=2.0, 1 H); 7.87
(s, 1 H); 8.20 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 25.5; 27.3; 40.9; 84.1; 84.5; 87.1; 90.3; 114.0; 114.7;
115.2; 116.3; 119.5; 120.1; 125.0; 126.3; 128.4; 129.8; 130.5; 138.3; 140.1; 144.1; 148.1; 149.2; 151.7;
154.7; 162.0. HR-MALDI-MS: 711.1553 ([M+H]+, C35
A
G
N
C35H31BrN6O6 (710.15): C 59.08, H 4.39, N 11.81; found C 59.06, H 4.54, N 11.62.
9-[(E)-7-({[6-(1,3-Benzothiazol-2-yl)-2,2-diphenyl-1,3-benzodioxol-4-yl]carbonyl}amino)-5,6,7-tri-
deoxy-2,3-O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (80). Compound 26
(170 mg, 0.38mmol), EDC·HCl (110 mg, 0.565 mmol), N-hydroxysuccinimide (57 mg, 0.49 mmol), 20
(100 mg, 0.3 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2; CH2Cl2/
E
MeOH 19 :1) afforded 80 (151 mg, 66%). Colorless foam. [a]2D0 =À1.7 (c=0.9, CHCl3). IR (KBr):
3424m, 2982w, 1635s, 1596m, 1533m, 1463m, 1436s, 1373w, 1259m, 1208s, 1155w, 1081m, 1048m,
1011m, 8 67w, 759w, 699w, 641w. 1H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3 H); 4.07 (m, 2
H); 4.72 (m, 1 H); 4.95 (dd, J=6.3, 3.6, 1 H); 5.44 (dd, J=6.3, 2.3, 1 H); 5.85 (m, 2 H); 6.09 (d, J=2.3,
1 H); 6.17 (br. s, 2 H); 7.13 (t, J=5.7, 1 H); 7.34–7.49 (m, 8H); 7.49–7.55 ( m, 4 H); 7.87 (s, 1 H); 7.88
(d, J=7.8, 1 H); 7.91 (d, J=1.9, 1 H); 7.81 (d, J=7.8, 1 H); 8.20 (s, 1 H); 8.22 (d, J=1.9, 1 H). 13C-
NMR (75 MHz, CDCl3): 25.4; 27.2; 40.9; 84.1; 84.4; 87.2; 90.3; 110.1; 114.6; 115.4; 119.5; 120.0; 121.5;
122.9; 123.2; 125.1; 126.2; 126.4; 128.3; 128.4; 128.6; 129.8; 130.5; 135.0; 138.3; 140.0; 146.7; 148.1;
149.1; 151.5; 153.7; 154.7; 162.4; 166.7. HR-MALDI-MS: 788.2266 ([M+Na]+, C42
788.2267).
A
N7
G
N
9-[(E)-7-{[(6-Cyano-2,2-diphenyl-1,3-benzodioxol-4-yl)carbonyl]amino}-5,6,7-trideoxy-2,3-O-(1-
methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (81). Compound 27 (80 mg, 0.23
mmol), EDC·HCl (73 mg, 0.38mmol), 20 (50 mg, 0.15 mmol), and Et3N (0.05 ml, 0.34 mmol) were
U
reacted according to GP 6. CC (SiO2; CH2Cl2/MeOH 19 :1) afforded 81 (201 mg, 68%). Colorless
foam. [a]2D0 =+12.5 (c=0.4, CHCl3). IR (KBr): 3428s, 3171w, 2986w, 2227w, 1635s, 1597m, 1528m,
1
1466s, 1374m, 1262s, 1209s, 1082m, 1017m, 8 67w, 762w, 699m, 641w. H-NMR (300 MHz, CDCl3): 1.38
(s, 3 H); 1.62 (s, 3 H); 4.05 (m, 2 H); 4.70 (m, 1 H); 4.96 (dd, J=6.3, 3.9, 1 H); 5.46 (dd, J=6.3, 2.0, 1
H); 5.79 (br. s, 2 H); 5.83 (m, 2 H); 6.08( d, J=2.0, 1 H); 7.00 (t, J=5.7, 1 H); 7.22 (d, J=1.7, 1 H);
7.38–7.49 (m, 10 H); 7.86 (s, 1 H); 7.99 (d, J=1.7, 1 H); 8.19 (s, 1 H). 13C-NMR (75 MHz, CDCl3):
25.5; 27.3; 41.0; 84.1; 84.5; 87.2; 90.3; 105.9; 113.7; 114.7; 116.1; 118.0; 120.2; 120.7; 126.3; 128.6; 128.8;
129.1; 130.1; 130.2; 137.6; 140.0; 147.8; 148.0; 149.2; 152.3; 155.0; 161.2. HR-MALDI-MS: 658.2403
([M+H]+, C36
A
G
N
9-[(E)-7-({[2,2-Bis(4-methoxyphenyl)-6-cyano-1,3-benzodioxol-4-yl]carbonyl}amino)-5,6,7-tri-
deoxy-2,3-O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (93). Compound 53
(100 mg, 0.248mmol), EDC·HCl (71 mg, 0.372 mmol), N-hydroxysuccinimide (37 mg, 0.322 mmol), 20
(83 mg, 0.248 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2;
G
CH2Cl2/MeOH 19 :1) afforded 93 (122 mg, 69%). Colorless foam. [a]2D0 =+11.2 (c=1.0, CHCl3). IR
(KBr): 3424m, 3176w, 2934w, 2226w, 1635s, 1610s, 1514s, 1465s, 1440m, 1373m, 1254s, 1209s, 1174s,
1
1082m, 1025m, 1004w, 8 67w, 8 32m, 649w. H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3 H); 3.81
(s, 6 H); 4.03 (m, 2 H); 4.68( dd, J=5.7, 3.6, 1 H); 4.96 (dd, J=6.3, 3.6, 1 H); 5.47 (dd, J=6.3, 2.1, 1
H); 5.72 (br. s, 2 H); 5.81 (m, 2 H); 6.08( d, J=2.1, 1 H); 6.90 (dd, J=9.0, 1.5, 4 H); 7.01 (t, J=5.7, 1
H); 7.18( d, J=1.5, 1 H); 7.37 (m, 4 H); 7.85 (s, 1 H); 7.97 (d, J=1.5, 1 H); 8.20 (s, 1 H). 13C-NMR (75
MHz, CDCl3): 25.3; 27.1; 40.9; 55.4; 84.1; 84.5; 87.2; 90.3; 105.7; 113.6; 113.7; 114.6; 116.0; 118.2;
120.2; 121.4; 128.2; 128.8; 129.0; 129.8; 130.1; 139.9; 148.1; 148.3; 149.4; 152.9; 155.3; 161.0; 161.5.
HR-MALDI-MS: 718.2631 ([M+H]+, C38
A
N7
A
9-[(E)-7-({[2,2-Bis(4-methoxyphenyl)-6-(trifluoromethyl)-1,3-benzodioxol-4-yl]carbonyl}amino)-
ACHTREUNG

1880
20 (70 mg, 0.2 mmol), and Et3
Helvetica Chimica Acta – Vol. 89 (2006)
AHCTREUNG
MeOH 19 :1) afforded 82 (119 mg, 77%). Colorless foam. [a]2D0 =+10.4 (c=1.5, CHCl3). IR (KBr):
3426m, 3178w, 2935w, 2837w, 1640s, 1607s, 1514m, 1443w, 1375w, 1317s, 1254s, 1210m, 1175s, 1121m,
1
1025m, 1004w, 8 67w, 732m. H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3 H); 3.81 (s, 6 H); 4.04
(m, 2 H); 4.68( m, 1 H); 4.95 (dd, J=6.6, 3.6, 1 H); 5.45 (dd, J=6.6, 2.1, 1 H); 5.81 (m, 4 H); 6.08( d,
J=2.1, 1 H); 6.88–6.92 (m, 4 H); 7.09 (t, J=5.7, 1 H); 7.19 (d, J=2.1, 1 H); 7.36–7.42 (m, 4 H); 7.85
(s, 1 H); 7.91 (d, J=2.1, 1 H); 8.22 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 25.4; 27.2; 40.9; 55.4; 84.1;
84.5; 87.1; 90.2; 108.3; 113.7; 114.6; 115.1; 120.1; 120.6; 120.7; 123.54 (q, J=270); 124.6 (q, J=33.5);
128.1; 128.5; 130.1; 130.3; 139.8; 147.2; 147.9; 149.2; 152.3; 155.1; 160.7; 162.0. 19F-NMR (282 MHz,
CDCl3): À61.7 (s). HR-MALDI-MS: 759.2535 ([M+H]+, C38
C
F3
G
G
ACHTREUNG
mg, 0.361 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2; CH2Cl2/
N
MeOH 19 :1) afforded 83 (174 mg, 66%). Colorless foam. [a]2D0 =+9.6 (c=0.55, CHCl3). IR (KBr):
3426m, 3199m, 2986w, 2227w, 1644s, 1599m, 1534m, 1476m, 1442m, 1378w, 1253s, 1207s, 1151m,
1
1082m, 1017w, 8 66w, 761w, 699m, 642w. H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3 H); 4.07
(m, 2 H); 4.68( m, 1 H); 4.97 (dd, J=6.3, 3.6, 1 H); 5.47 (dd, J=6.3, 2.1, 1 H); 5.85 (m, 4 H); 6.08( d,
J=2.1, 1 H); 7.03 (t, J=5.7, 1 H); 7.38–7.45 (m, 6 H); 7.47–7.52 (m, 4 H); 7.69 (d, J=1.7, 1 H); 7.86
(s, 1 H); 8.21 (s, 1 H); 8.43 (d, J=1.7, 1 H). 13C-NMR (75 MHz, CDCl3): 25.5; 27.3; 41.1; 84.1; 84.5;
87.1; 90.2; 111.5; 114.7; 115.5; 116.6 (q, J=281.0); 120.1; 120.9; 124.8; 126.3; 128.2; 128.6; 128.8; 130.2;
137.6; 137.7; 139.9; 148.4; 149.2; 150.2; 152.3; 155.0; 161.6; 178.5 (q, J=35.5). 19F-NMR (282 MHz,
CDCl3): À71.24 (s). HR-MALDI-MS: 729.2291 ([M+H]+, C37
C
F3
G
G
ACHTREUNG
(72 mg, 0.215 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2;
G
CH2Cl2/MeOH 19 :1) afforded 84 (98mg, 62%). Colorless foam. [ a]2D0 =+9.4 (c=0.2, CHCl3). IR
(KBr): 3427m, 1661s, 1596m, 1528m, 1472m, 1435m, 1374w, 1266s, 1208s, 1019w, 8 67w, 78 0w, 759w,
1
700w, 647w. H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3 H); 4.07 (m, 2 H); 4.72 (m, 1 H); 4.93
(dd, J=6.3, 3.6, 1 H); 5.40 (dd, J=6.3, 2.0, 1 H); 5.83 (m, 2 H); 6.10 (d, J=2.0, 1 H); 6.55 (br. s, 2 H);
7.10 (t, J=5.4, 1 H); 7.39–7.45 (m, 6 H); 7.51–7.55 (m, 6 H); 7.65 (d, J=1.8, 1 H); 7.92 (s, 1 H); 8.03
(d, J=1.8); 8.29 (s, 1 H); 8.79 (dd, J=4.5, 1.8, 2 H). 13C-NMR (75 MHz, CDCl3): 25.5; 27.2; 41.0; 84.2;
84.4; 87.2; 90.4; 111.8; 114.6; 114.7; 120.0; 120.4; 122.6; 126.3; 128.0; 128.6; 130.1; 130.3; 130.8; 137.9;
138.0; 140.2; 144.3; 148.4; 148.9; 149.1; 150.3; 151.0; 154.4; 162.1; 193.0. HR-MALDI-MS: 738.2677
([M+H]+, C41
A
G
N
9-[(E)-7-{[(6-Chloro-2,2-diphenyl-1,3-benzodioxol-4-yl)carbonyl]amino}-5,6,7-trideoxy-2,3-O-(1-
methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (85). Compound 31 (90 mg, 0.255
mmol), EDC·HCl (75 mg, 0.383 mmol), N-hydroxysuccinimide (40 mg, 0.332 mmol), 20 (85 mg, 0.255
mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2; CH2Cl2/MeOH
U
19 :1) afforded 85 (123 mg, 73%). Colorless foam. [a]2D0 =+10.6 (c=1.7, CHCl3). IR (KBr): 3424m,
3176m, 2986m, 1638s, 1595s, 1530m, 1462s, 1374m, 1329m, 1240s, 1208s, 1156w, 1083m, 1047m, 1017m,
1
971w, 8 67w, 778w, 698m. H-NMR (300 MHz, CDCl3): 1.37 (s, 3 H); 1.61 (s, 3 H); 4.04 (m, 2 H); 4.69
(m, 1 H); 4.94 (dd, J=6.3, 3.6, 1 H); 5.44 (dd, J=6.3, 2.1, 1 H); 5.83 (m, 2 H); 6.05 (br. s, 2 H); 6.08
(d, J=2.1, 1 H); 7.00 (d, J=2.1, 1 H); 7.06 (t, J=5.7, 1 H); 7.35–7.40 (m, 6 H); 7.44–7.50 (m, 4 H);
7.56 (d, J=2.1, 1 H); 7.87 (s, 1 H); 8.19 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 25.6; 27.4; 41.0; 84.4;
84.7; 87.4; 90.5; 112.8; 115.0; 116.1; 119.8; 120.2; 122.3; 126.6; 127.6; 128.6; 128.8; 130.2; 130.8; 138.7;
140.4; 143.9; 148.3; 149.5; 152.2; 155.1; 162.5. HR-MALDI-MS: 667.2065 ([M+H]+, C35
A
G
N
calc. 667.2072).
9-[(E)-7-({[6-(Cyclohexylcarbonyl)-2,2-diphenyl-1,3-benzodioxol-4-yl]carbonyl}amino)-5,6,7-tri-
deoxy-2,3-O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (86). Compound 32
(197 mg, 0.46 mmol), EDC·HCl (133 mg, 0.69 mmol), N-hydroxysuccinimide (70 mg, 0.6 mmol), 20
(130 mg, 0.391 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2;
N

Helvetica Chimica Acta – Vol. 89 (2006)
1881
CH2Cl2/MeOH 19 :1) afforded 86 (145 mg, 50%). Colorless foam. [a]2D0 =+7.4 (c=0.45, CHCl3). IR
(KBr): 3428m (br.), 2931m, 2853w, 1667s, 1636s, 1596m, 1529m, 1473m, 1433m, 1376w, 1252s, 1209s,
1
1154w, 1082m, 1049m, 1018w, 8 67w, 777w, 699w. H-NMR (300 MHz, CDCl3): 1.24–1.52 (m, 9 H); 1.62
(s, 3 H); 1.70–1.86 (m, 4 H); 3.70 (m, 1 H); 4.07 (m, 2 H); 4.70 (m, 1 H); 4.96 (dd, J=6.5, 3.9, 1 H);
5.45 (dd, J=6.5, 2.1, 1 H); 5.86 (m, 2 H); 5.92 (br. s, 2 H); 6.09 (d, J=2.1, 1 H); 7.11 (t, J=5.4, 1 H);
7.36–7.41 (m, 6 H); 7.48–7.52 (m, 4 H); 7.65 (d, J=1.5, 1 H); 7.87 (s, 1 H); 8.22 (s, 1 H); 8.24 (d,
J=1.5, 1 H). 13C-NMR (75 MHz, CDCl3): 25.4; 25.8; 26.0; 27.2; 29.6; 40.9; 45.3; 84.1; 84.4; 87.1; 90.2;
110.9; 114.4; 114.7; 119.7; 120.1; 124.6; 126.3; 128.4; 129.8; 130.4; 131.5; 138.1; 138.2; 139.9; 148.0;
148.1; 149.2; 152.0; 154.8; 162.5; 201.8. HR-MALDI-MS: 743.3195 ([M+H]+, C42
A
G
N
743.3193). Anal. calc. for C42H42N6O5 (710.32): C 67.91, H 5.70, N 11.31; found C 67.77, H 5.85, N 11.05.
9-{(E)-5,6,7-Trideoxy-7-[({6-[(E)-3-(dimethylamino)-3-oxoprop-1-enyl]-2,2-diphenyl-1,3-benzo-
dioxol-4-yl}carbonyl)amino]-2,3-O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl}-9H-purin-6-
amine (87). Compound 33 (90 mg, 0.22 mmol), EDC·HCl (63 mg, 0.33 mmol), N-hydroxysuccinimide (33
mg, 0.28mmol), 20 (72 mg, 0.22 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6.
N
CC (SiO2; CH2Cl2/MeOH 19 :1) afforded 87 (63 mg, 40%). Colorless foam. [a]2D0 =+3.9 (c=0.1,
CHCl3). IR (KBr): 3424m, 2931w, 1653s, 1598s, 1528m, 1474m, 1437m, 1374w, 1259m, 1207m, 1154w,
1
1081m, 1049m, 1019m, 973w, 8 67w, 776w, 699w, 642w. H-NMR (300 MHz, CDCl3): 1.37 (s, 3 H); 1.61
(s, 3 H); 3.05 (s, 3 H); 3.14 (s, 3 H); 4.05 (m, 2 H); 4.69 (m, 1 H); 4.96 (dd, J=6.6, 3.9, 1 H); 5.46 (dd,
J=6.6, 2.1, 1 H); 5.70 (br. s, 2 H); 5.84 (m, 2 H); 6.08( d, J=2.1, 1 H); 6.82 (d, J=15.5, 1 H); 7.07 (t,
J=6.0, 1 H); 7.17 (d, J=1.7, 1 H); 7.35–7.42 (m, 6 H); 7.47–7.52 (m, 4 H); 7.60 (d, J=15.5, 1 H); 7.80
(d, J=1.7, 1 H); 7.84 (s, 1 H); 8.19 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 25.4; 27.1; 35.9; 37.4; 40.7;
84.1; 84.5; 87.2; 90.3; 110.6; 114.6; 115.4; 117.0; 119.2; 120.2; 122.8; 126.4; 128.5; 129.8; 130.3; 130.5;
138.5; 138.6; 139.8; 141.2; 145.6; 147.9; 149.4; 153.0; 155.3; 162.9; 166.5. HR-MALDI-MS: 730.2993
([M+H]+, C40
A
N7
A
9-{(E)-7-[({2,2-Bis(4-methoxyphenyl)-6-[(4-methylphenyl)sulfonyl]-1,3-benzodioxol-4-yl}carbonyl)-
ACHTREUNG
mmol), 20 (100 mg, 0.31 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC
E
(SiO2; CH2Cl2/MeOH 19 :1) afforded 88 (146 mg, 62%). Colorless foam. [a]2D0 =+6.9 (c=1.53,
CHCl3). IR (KBr): 3424m, 2930w, 1640s, 1638s, 1607s, 1514s, 1458s, 1374w, 1315m, 1249s, 1209m, 1175s,
1
1184s, 1090s, 1004m, 8 33m, 664m, 616w. H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.61 (s, 3 H); 2.38
(s, 3 H); 3.80 (s, 6 H); 4.01 (m, 2 H); 4.69 (m, 1 H); 4.94 (dd, J=6.5, 3.6, 1 H); 5.45 (dd, J=6.5, 2.1, 1
H); 5.77 (m, 2 H); 5.83 (br. s, 2 H); 6.09 (d, J=2.1, 1 H); 6.88 (dt, J=8.7, 1.8, 4 H); 6.99 (t, J=5.7, 1
H); 7.27 (d, J=7.8, 2 H); 7.31–7.38 (m, 4 H); 7.48( d, J=1.8, 1 H); 7.83 (d, J=7.8, 2 H); 7.84 (s, 1 H);
8.21 (s, 1 H); 8.22 (d, J=1.8, 1 H). 13C-NMR (75 MHz, CDCl3): 21.7; 25.4; 27.2; 40.9; 55.4; 84.2; 84.5;
87.2; 90.3; 109.8; 113.7; 114.5; 115.4; 120.1; 121.2; 124.0; 127.7; 128.1; 128.5; 129.8; 130.2; 136.1; 138.2;
139.8; 144.1; 148.1; 148.3; 149.2; 152.4; 155.0; 160.7; 161.6. HR-MALDI-MS: 847.2747 ([M+H]+,
C
A
N6
G
N
62.16, H 5.21, N 9.81.
9-{(E)-5,6,7-Trideoxy-2,3-O-(1-methylethylidene)-7-[({6-[(4-methylphenyl)methyl]-2,2-diphenyl-1,3-
benzodioxol-4-yl}carbonyl)amino]-b-D-ribo-hept-5-enofuranosyl}-9H-purin-6-amine (89). Compound 35
(165 mg, 0.39 mmol), EDC·HCl (115 mg, 0.59 mmol), N-hydroxysuccinimide (57 mg, 0.49 mmol), 20 (100
mg, 0.3 mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2; CH2Cl2/MeOH
G
19 :1) afforded 89 (172 mg, 78%). Colorless foam. [a]2D0 =+2.4 (c=0.4, CHCl3). IR (KBr): 3426m, 3176w,
2986w, 1636s, 1597s, 1529m, 1474s, 1440m, 1374w, 1328w, 1254s, 1207s, 1156w, 1082m, 1049m, 1020m,
1
868w, 776w, 699m, 642w. H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.62 (s, 3 H); 2.29 (s, 3 H); 3.87 (s,
2 H); 4.05 (m, 2 H); 4.71 (m, 1 H); 4.91 (dd, J=6.4, 3.6, 1 H); 5.38( dd, J=6.4, 2.4, 1 H); 5.83 (m, 2
H); 6.09 (d, J=2.4, 1 H); 6.40 (br. s, 2 H); 6.83 (d, J=1.8, 1 H); 7.07 (s, 4 H); 7.14 (t, J=5.7, 1 H);
7.33–7.38( m, 6 H); 7.45–7.49 (m, 5 H); 7.91 (s, 1 H); 8.16 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 21.1;
25.4; 27.2; 40.7; 41.3; 84.2; 84.4; 87.1; 90.4; 112.5; 114.7; 114.8; 118.2; 119.9; 122.1; 126.3; 127.7; 128.3;
128.6; 129.1; 129.5; 131.0; 135.7; 136.0; 137.5; 138.9; 140.5; 143.0; 147.3; 148.9; 149.8; 153.8; 163.4.
HR-MALDI-MS: 759.2909 ([M+Na]+, C43
(736.30): C 70.09, H 5.47, N 11.41; found C 69.89, H 5.60, N 11.33.
A
G
N

1882
Helvetica Chimica Acta – Vol. 89 (2006)
9-[(E)-5,6,7-Trideoxy-7-({[6-(1-methylethyl)-2,2-diphenyl-1,3-benzodioxol-4-yl]carbonyl}amino)-2,3-
O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl]-9H-purin-6-amine (90). Compound 36 (80 mg,
0.22 mmol), EDC·HCl (64 mg, 0.33 mmol), N-hydroxysuccinimide (34 mg, 0.29 mmol), 20 (81 mg, 0.24
mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2; CH2Cl2/MeOH
G
19 :1) afforded 90 (89 mg, 59%). Colorless foam. [a]2D0 =+5.0 (c=0.3, CHCl3). IR (KBr): 3424m,
3179w, 2960w, 1645s, 1598s, 1530m, 1475s, 1449m, 1330w, 1255s, 1208s, 1156w, 1081m, 1047m, 1018m,
1
949w, 8 67w, 779w, 699w, 642w. H-NMR (300 MHz, CDCl3): 1.21 (d, J=6.9, 6 H); 1.37 (s, 3 H); 1.62 (s,
3 H); 2.88 (sept., J=6.9, 1 H); 4.05 (m, 2 H); 4.68( m, 1 H); 4.93 (dd, J=6.6, 3.9, 1 H); 5.44 (dd,
J=6.6, 2.4, 1 H); 5.79 (br. s, 2 H); 5.86 (m, 2 H); 6.08( d, J=2.4, 1 H); 6.92 (d, J=1.5, 1 H); 7.14 (t,
J=5.4, 1 H); 7.35–7.39 (m, 6 H); 7.43 (d, J=1.5, 1 H); 7.48–7.53 (m, 4 H); 7.86 (s, 1 H); 8.23 (s, 1 H).
13C-NMR (75 MHz, CDCl3): 24.1; 25.5; 27.2; 34.1; 40.7; 84.0; 84.4; 87.0; 90.1; 110.3; 114.7; 118.0;
119.7; 120.1; 126.3; 128.0; 128.3; 128.4; 129.5; 130.8; 139.1; 139.8; 142.7; 143.4; 147.1; 149.3; 152.5;
155.0; 163.5. HR-MALDI-MS: 675.2947 ([M+H]+, C38
A
G
N
9-{(E)-5,6,7-Trideoxy-7-[({6-[(dimethylamino)carbonyl]-2,2-diphenyl-1,3-benzodioxol-4-yl}carbo-
nyl)amino]-2,3-O-(1-methylethylidene)-b-D-ribo-hept-5-enofuranosyl}-9H-purin-6-amine (91). Com-
pound 37 (120 mg, 0.31 mmol), EDC·HCl (90 mg, 0.46 mmol), N-hydroxysuccinimide (46 mg, 0.4
mmol), 20 (93 mg, 0.28mmol), and Et 3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC
G
(SiO2; CH2Cl2/MeOH 19 :1) afforded 91 (160 mg, 81%). Colorless foam. [a]2D0 =+7.6 (c=0.5, CHCl3).
IR (KBr): 3425m, 3193w, 2932w, 1639s, 1528m, 1471m, 1449m, 1396w, 1329w, 1263m, 1208s, 1157w,
1
1082m, 1048m, 1018m, 8 67w, 78 1w, 700m, 643w. H-NMR (300 MHz, CDCl3): 1.38( s, 3 H); 1.61 (s, 3
H); 3.02 (br. s, 3 H); 3.07 (br. s, 3 H); 4.05 (m, 2 H); 4.74 (dd, J=7.2, 3.3, 1 H); 4.91 (dd, J=6.5, 3.3, 1
H); 5.43 (dd, J=6.5, 2.0, 1 H); 5.79 (m, 2 H); 6.08( d, J=2.0, 1 H); 6.18(br. s, 2 H); 7.08( t, J=5.7, 1
H); 7.16 (d, J=1.8, 1 H); 7.35–7.42 (m, 6 H); 7.46–7.51 (m, 4 H); 7.69 (d, J=1.8, 1 H); 7.82 (s, 1 H);
8.17 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 25.3; 27.0; 35.5; 39.8; 40.6; 84.4; 84.6; 87.5; 90.7; 111.2;
114.5; 114.6; 119.3; 120.1; 122.2; 126.4; 128.0; 128.5; 129.8; 130.3; 130.8; 138.5; 139.9; 145.6; 147.5;
149.1; 151.6; 154.8; 162.7; 170.3. HR-MALDI-MS: 704.2834 ([ M+H]+, C38
9-((E)-5,6,7-Trideoxy-7-{[(2,2-diphenyl-1,3-benzodioxol-4-yl)carbonyl]amino}-2,3-O-(1-
methylethylidene)-b-D-ribo-hept-5-enofuranosyl)-9H-purin-6-amine (92). Compound 38 (50 mg, 0.157
mmol), EDC·HCl (47 mg, 0.240 mmol), N-hydroxysuccinimide (24 mg, 0.210 mmol), 20 (50 mg, 0.150
A
N7
A
AHCTREUNG
mmol), and Et3N (0.1 ml, 0.68mmol) were reacted according to GP 6. CC (SiO2; CH2Cl2/MeOH
N
19 :1) afforded 92 (69 mg, 73%). Colorless foam. [a]2D0 =À14.3 (c=1.0, CH3OH). IR (KBr): 3424m,
1
3175m, 2987w, 1651s, 1532s, 1455s, 1373m, 1246s, 1082s, 8 67m, 748m. H-NMR (300 MHz, CDCl3): 1.37
(s, 3 H); 1.62 (s, 3 H); 4.05 (m, 2 H); 4.69 (m, 1 H); 4.95 (dd, J=6.5, 3.7, 1 H); 5.46 (dd, J=6.5, 2.2, 1
H); 5.61 (br. s, 2 H); 5.86 (m, 2 H); 6.08( d, J=2.2, 1 H); 6.95 (t, J=8.1, 1 H); 7.02 (dd, J=8.1, 1.2, 1
H); 7.14 (t, J=5.6, 1 H); 7.37 (m, 6 H), 7.51 (m, 4 H); 7.58( dd, J=8.7, 1.2, 1 H); 7.84 (s, 1 H); 8.20 (s,
1 H). 13C-NMR (75 MHz, CDCl3): 25.5; 27.2; 40.7; 84.0; 84.5; 87.1; 90.2; 111.8; 114.6; 115.5; 118.1;
120.1; 122.0; 122.4; 126.3; 128.2; 128.3; 129.5; 130.6; 138.8; 139.6; 144.5; 147.0; 149.3; 153.0; 155.3;
163.2. HR-MALDI-MS: 633.2442 ([M+H]+, C35
A
G
N
9-((E)-5,6,7-Trideoxy-7-{[(4’-fluoro-4,5-dihydroxy-1,1’-biphenyl-3-yl)carbonyl]amino}-b-D-ribo-
hept-5-enofuranosyl)-9H-purin-6-amine (2). Deprotection of 75 (70 mg, 96 mmol) according to GP 7
afforded
(CH3)2SO). IR (KBr): 3407s (br.), 1700s, 1641m, 1542w, 1479w, 1314w, 1204s, 1137m, 1050w, 8 35w,
801w, 725w. 1H-NMR (500 MHz, CD3
OD): 4.07 (m, 2 H); 4.24 (t, J=5.3, 1 H); 4.52 (t, J=5.3, 1 H);
2
(28mg, 56%). Colorless solid. tR 17.8min. M.p. 144–147 8. [a]2D0 =+2.5 (c=0.16,
AHCTREUNG
AHCTREUNG
4.73 (t, J=4.8, 1 H); 5.96 (br. d, J=3.3, 2 H); 6.05 (d, J=4.8, 1 H); 7.13 (t, J=8.8, 2 H); 7.20 (d,
J=2.0, 1 H); 7.51 (d, J=2.0, 1 H); 7.58( dd, J=8.8, 5.4, 2 H); 8.23 (s, 1 H); 8.37 (s, 1 H). 13C-NMR
(125 MHz, CD3
130.3; 131.0; 132.3; 138.1; 143.0; 147.8; 149.0; 152.6; 149.8; 163.6 (d, J=242.5); 171.2. HR-MALDI-
MS: 523.1731 ([M+H]+, C25 O6þ ; calc. 523.1741).
H24FN6
OD): 41.7; 75.2; 75.6; 86.1; 90.5; 116.4 (d, J=21.3); 117.0; 117.1; 118.2; 129.3; 129.4;
A
N
ACHTREUNG
9-((E)-5,6,7-Trideoxy-7-{[(4,5-dihydroxy-4’-methyl-1,1’-biphenyl-3-yl)carbonyl]amino}-b-D-ribo-
hept-5-enofuranosyl)-9H-purin-6-amine (3). Deprotection of 76 (70 mg, 97 mmol) according to GP 7
afforded 3 (28mg, 56%). Colorless solid. tR 18.3 min. [a]2D0 =+7.4 (c=0.3, (CH3)2
ACHTREUNG
AHCTREUNG

Helvetica Chimica Acta – Vol. 89 (2006)
1883
5.83–5.90 (m, 2 H); 5.91 (d, J=5.1, 1 H); 7.20 (d, J=1.9, 1 H); 7.22 (d, J=8.0, 1 H); 7.51 (d, J=8.0, 1 H);
7.63 (d, J=1.9, 1 H); 8.12 (br. s, 1 H); 8.23 (s, 1 H); 8.47 (s, 1 H); 9.16 (t, J=5.5, 1 H); 12.79 (br. s, 1 H).
13C-NMR (125 MHz, (CD3)2
ACHTREUNG
A
N
ACHTREUNG
9-[(E)-5,6,7-Trideoxy-7-({[2,3-dihydroxy-5-(pyridin-4-yl)phenyl]carbonyl}amino)-b-D-ribo-hept-5-
enofuranosyl]-9H-purin-6-amine (4). Deprotection of 77 (35 mg, 49 mmol) according to GP 7 afforded 4
(15 mg, 61%). Yellowish solid. tR 10.6 min. [a]2D0 =À1.9 (c=0.1, (CH3)2
ACHTREUNG
1633m, 1474w, 1431m, 1321m, 1202s, 1134m, 8 32w, 723w. 1H-NMR (500 MHz, (CD3)2
ACHTREUNG
4.11 (t, J=4.8, 1 H); 4.37 (m, 1 H); 4.67 (t, J=5.1, 1 H); 5.82–5.94 (m, 2 H); 5.91 (d, J=5.1, 1 H); 7.52 (d,
J=1.8, 1 H); 7.85 (br. s, 1 H); 8.01 (d, J=1.8, 1 H); 8.08 (d, J=5.2, 1 H); 8.17 (s, 1 H); 8.42 (s, 1 H); 8.79
(d, J=5.2, 1 H); 9.23 (t, J=5.5, 1 H); 9.69 (br. s, 1 H); 13.35 (br. s, 1 H). 13C-NMR (125 MHz, (CD3)2
ACHTREUNG
A
N
ACHTREUNG
9-[(E)-5,6,7-Trideoxy-7-({[2,3-dihydroxy-5-(1,3-thiazol-2-yl)phenyl]carbonyl}amino)-b-D-ribo-hept-
5-enofuranosyl]-9H-purin-6-amine (5). Deprotection of 78 (80 mg, 112 mmol) according to GP 7 afforded
5 (43 mg, 75%). Colorless solid. tR 13.1 min. [a]2D0 =À10.3 (c=0.1, (CH3)2
C
1
(500 MHz, (CD3)2SO): 3.97 (m, 2 H); 4.10 (t, J=4.9, 1 H); 4.37 (dd, J=5.0, 4.9, 1 H); 4.63 (t, J=5.0, 1
G
H); 5.82–5.91 (m, 2 H); 5.92 (d, J=5.0, 1 H); 7.53 (d, J=1.7, 1 H); 7.68( d, J=3.3, 1 H); 7.83 (d,
J=3.3, 1 H); 7.92 (d, J=1.7, 1 H); 8.52 (s, 1 H); 8.56 (br. s, 1 H); 9.27 (t, J=5.7, 1 H); 9.71 (s, 1 H);
12.98(br. s, 1 H). 13C-NMR (125 MHz, (CD3)2
ACHTREUNG
A
G
A
ACHTREUNG
9-((E)-7-{[(5-Bromo-2,3-dihydroxyphenyl)carbonyl]amino}-5,6,7-trideoxy-b-D-ribo-hept-5-enofura-
nosyl)-9H-purin-6-amine (6). Deprotection of 79 (50 mg, 70 mmol) according to GP 7 afforded 6 (18mg,
52%). Colorless solid. tR 13.4 min. [a]2D0 =À6.7 (c=0.13, (CH3)2
ACHTREUNG
1
1637m, 1467w, 1426w, 1325w, 1203s, 1135m, 1050w. H-NMR (500 MHz, CD3
ACHTREUNG
(t, J=5.0, 1 H); 4.52 (m, 1 H); 4.72 (t, J=4.8, 1 H); 5.92–5.94 (m, 2 H); 6.06 (d, J=4.8, 1 H); 7.05 (d,
J=2.3, 1 H); 7.43 (d, J=2.3, 1 H); 8.27 (s, 1 H); 8.39 (s, 1 H). 13C-NMR (125 MHz, CD3
OD): 41.6;
75.2; 75.6; 86.1; 90.6; 111.2; 118.2; 120.7; 121.3; 122.3; 130.3; 130.9; 143.4; 147.8; 148.8; 149.6; 150.2;
153.5; 169.9. HR-MALDI-MS: 507.0628([ M+H]+, C19 O6þ ; calc. 507.0627).
H20BrN6
9-[(E)-7-({[5-(1,3-Benzothiazol-2-yl)-2,3-dihydroxyphenyl]carbonyl}amino)-5,6,7-trideoxy-b-D-ribo-
hept-5-enofuranosyl]-9H-purin-6-amine (7). Deprotection of 80 (83 mg, 108 mmol) according to GP 7
afforded 7 (38mg, 64%). Colorless solid. tR 17.7 min. [a]2D0 =+4.0 (c=0.8, (CD3)2
SO). IR (KBr): 3377s
AHCTREUNG
A
N
ACHTREUNG
ACHTREUNG
AHCTREUNG
1
(br.), 1685s, 1645m, 1544w, 1436m, 1303m, 1202s, 1137m, 8 34w, 8 00w, 759w, 724w. H-NMR (500 MHz,
(CD3)2SO): 4.01 (m, 2 H); 4.13 (t, J=4.9, 1 H); 4.39 (dd, J=6.7, 4.9, 1 H); 4.66 (t, J=5.0, 1 H);
AHCTREUNG
5.80–5.96 (m, 2 H); 5.93 (d, J=5.0, 1 H); 7.43 (t, J=8.0, 1 H); 7.53 (t, J=8.0, 1 H); 7.68 (d, J=2.0, 1
H); 8.00 (d, J=8.0, 1 H); 8.09 (d, J=2.0, 1 H); 8.12 (d, J=8.0, 1 H); 8.27 (s, 1 H); 9.37 (t, J=5.3, 1 H);
9.86 (s, 1 H); 13.19 (br. s, 1 H). 13C-NMR (125 MHz, (CD3)2
ACHTREUNG
A
G
A
ACHTREUNG
9-((E)-7-{[(5-Cyano-2,3-dihydroxyphenyl)carbonyl]amino}-5,6,7-trideoxy-b-D-ribo-hept-5-enofura-
nosyl)-9H-purin-6-amine (8). Deprotection of 93 (51 mg, 70 mmol) according to GP 7 afforded 8 (32 mg,
99%). Colorless solid. tR 9.0 min. [a]2D0 =À3.0 (c=0.23, Me2
N
1
4.24 (t, J=4.9, 1 H); 4.51 (t, J=4.9, 1 H); 4.73 (t, J=4.6, 1 H); 5.94 (m, 2 H); 6.04 (d, J=4.6, 1 H);
7.17 (d, J=1.8, 1 H); 7.70 (d, J=1.8, 1 H); 8.23 (s, 1 H); 8.33 (s, 1 H). 13C-NMR (125 MHz, (CD3
ACHTREUNG
A
N
ACHTREUNG
9-[(E)-5,6,7-Trideoxy-7-({[2,3-dihydroxy-5-(trifluoromethyl)phenyl]carbonyl}amino)-b-D-ribo-hept-
5-enofuranosyl]-9H-purin-6-amine (9). Deprotection of 82 (75 mg, 100 mmol) according to GP 7 afforded
9 (49 mg, 99%). Colorless solid. tR 14.7 min. [a]2D0 =À9.2 (c=0.1, (CD3)2
A

1884
Helvetica Chimica Acta – Vol. 89 (2006)
1649m, 1607m, 1545w, 1398w, 1327m, 1194m, 1124m, 1049w, 8 01w, 725w. 1H-NMR (500 MHz, CD3
A
4.06 (m, 2 H); 4.24 (t, J=5.1, 1 H); 4.52 (m, 1 H); 4.71 (t, J=4.8, 1 H); 5.95 (m, 2 H); 6.06 (d, J=4.8, 1 H);
7.15 (d, J=1.2, 1 H); 7.64 (d, J=1.2, 1 H); 8.29 (s, 1 H); 8.39 (s, 1 H). 13C-NMR (125 MHz, CD3
OD): 41.8;
75.3; 75.6; 86.1; 90.6; 115.5 (q, J=2.5); 116.4 (q, J=5.0); 116.9; 120.8; 121.9 (q, J=32.5); 125.7 (q,
AHCTREUNG
J=269); 130.5; 130.9; 143.4; 147.8; 148.3; 150.3; 153.3; 153.6; 170.1. 19F-NMR (282 MHz, CD3
OD):
A
À61.6 (s). HR-MALDI-MS: 497.1401 ([M+H]+, C20
C
G
G
A
afforded 10 (40 mg, 56%). Colorless solid. tR 11.1 min. [a]2D0 =+3.3 (c=0.27, Me2
ACHTREUNG
AHCTREUNG
AHCTREUNG
A
G
A
ACHTREUNG
9-{(E)-5,6,7-Trideoxy-7-[({2,3-dihydroxy-5-[(pyridin-4-yl)carbonyl]phenyl}carbonyl)amino]-b-D-ribo-
hept-5-enofuranosyl}-9H-purin-6-amine (11). Deprotection of 84 (50 mg, 68 mmol) according to GP 7
afforded 11 (18mg, 50%). Yellowish solid. tR 10.9 min. [a]2D0 =+2.9 (c=0.14, (CH3)2
ACHTREUNG
AHCTREUNG
3.94 (d, J=3.7, 2 H); 4.13 (t, J=5.3, 1 H); 4.39 (t, J=5.3, 1 H); 4.64 (t, J=4.8, 1 H); 5.82 (m, 2 H); 5.93 (d,
J=4.8, 1 H); 7.37 (d, J=2.1, 1 H); 7.57 (dd, J=4.6, 1.6, 2 H); 7.71 (d, J=2.1, 1 H); 8.12 (s, 1 H); 8.22 (s, 1
H); 8.65 (dd, J=4.6, 1.6, 2 H). 13C-NMR (125 MHz, CD3
ACHTREUNG
A
N
ACHTREUNG
9-((E)-7-{[(5-Chloro-2,3-dihydroxyphenyl)carbonyl]amino}-5,6,7-trideoxy-b-D-ribo-hept-5-enofura-
nosyl)-9H-purin-6-amine (12). Deprotection of 85 (70 mg, 105 mmol) according to GP 7 afforded 12 (35
mg, 73%). Colorless solid. tR 13.1 min. [a]2D0 =À5.2 (c=0.1, (CH3)2
C
(CD3)2
H); 5.91 (d, J=5.1, 1 H); 6.92 (d, J=2.5, 1 H); 7.41 (d, J=2.5, 1 H); 8.12 (br. s, 1 H); 8.23 (s, 1 H);
8.46 (s, 1 H); 9.02 (t, J=5.4, 1 H); 12.62 (br. s, 1 H). 13C-NMR (125 MHz, (CD3)2
SO): 40.1; 73.0; 73.9;
84.3; 87.8; 115.7; 116.5; 118.3; 119.1; 121.7; 129.3; 129.4; 141.1; 147.6; 148.8; 148.9; 149.3; 153.4; 168.3.
HR-MALDI-MS: 463.1133 ([M+H]+, C19 O6þ ; calc. 463.1132).
H20ClN6
SO): 3.93 (m, 2 H); 4.09 (t, J=4.9, 1 H); 4.35 (m, 1 H); 4.64 (t, J=5.1, 1 H); 5.78–5.89 ( m, 2
AHCTREUNG
A
N
ACHTREUNG
9-[(E)-7-({[5-(Cyclohexylcarbonyl)-2,3-dihydroxyphenyl]carbonyl}amino)-5,6,7-trideoxy-b-D-ribo-
5-enofuranosyl]-9H-purin-6-amine (13). Deprotection of 86 (60 mg, 81 mmol) according to GP 7 afforded
13 (25 mg, 59%). Colorless solid. tR 14.5 min. [a]2D0 =À3.5 (c=0.12, (CH3)2
C
(500 MHz, CD
H); 4.25 (t, J=5.0, 1 H); 4.52 (t, J=5.0, 1 H); 4.74 (t, J=4.7, 1 H); 5.96 (m, 2 H); 6.04 (d, J=4.7, 1 H);
7.53 (d, J=2.0, 1 H); 8.02 (d, J=2.0, 1 H); 8.23 (s, 1 H); 8.34 (s, 1 H). 13C-NMR (125 MHz, CD3
OD):
26.8; 27.1; 30.8; 41.7; 46.0; 75.1; 75.6; 86.0; 90.5; 116.4; 118.5; 120.7; 128.6; 130.5; 130.9; 142.8; 147.8;
149.7; 150.3; 154.7; 154.9; 170.7; 204.6. HR-MALDI-MS: 539.2244 ([M+H]+, C26 O7þ ; calc.
H31N6
539.2254).
3OD): 1.23–1.50 (m, 5 H); 1.72–1.83 (m, 5 H); 3.35 (t, J=1.6, 1 H); 4.08( d, J=3.3, 2
AHCTREUNG
A
N
ACHTREUNG
9-{(E)-5,6,7-Trideoxy-7-[({5-[(E)-3-(dimethylamino)-3-oxoprop-1-enyl]-2,3-dihydroxyphenyl}carbo-
nyl)amino]-b-D-ribo-hept-5-enofuranosyl}-9H-purin-6-amine (14). Deprotection of 87 (35 mg, 48 mmol)
according to GP 7 afforded 14 (12 mg, 48%). Colorless solid. tR 9.7 min. [a]2D0 =À14.2 (c=0.1, Me2
N
800w, 723w, 642w. 1H-NMR (500 MHz, CD3
OD): 3.05 (s, 3 H); 3.22 (s, 3 H); 4.07 (m, 2 H); 4.24 (t, J=5.0,
G
1 H); 4.53 (m, 1 H); 4.74 (t, J=4.8, 1 H); 5.95 (m, 2 H); 6.06 (d, J=4.8, 1 H); 6.96 (d, J=15.4, 1 H); 7.25
(d, J=1.8, 1 H); 7.46 (d, J=15.4, 1 H); 7.53 (d, J=1.8, 1 H); 8.26 (s, 1 H); 8.40 (s, 1 H). 13C-NMR (125
MHz, CD3
131.0; 143.5; 143.6; 147.5; 148.0; 150.2; 152.4; 153.3; 169.3; 171.0. HR-MALDI-MS: 548.1859
([M+Na]+, C24 NaOþ7 ; calc. 548.1864).
H27N7
OD): 36.3; 37.9; 41.7; 75.3; 75.8; 86.2; 90.7; 116.5; 116.6; 117.9; 199.9; 120.8; 127.5; 130.4;
A
N
ACHTREUNG

Helvetica Chimica Acta – Vol. 89 (2006)
1885
9-{(E)-5,6,7-Trideoxy-7-[({2,3-dihydroxy-5-[(4-methylphenyl)sulfonyl]phenyl}carbonyl)amino]-b-D-
ribo-hept-5-enofuranosyl}-9H-purin-6-amine (15). Deprotection of 88 (90 mg, 106 mmol) according to GP 7
afforded 15 (61 mg, 98%). Colorless solid. tR 13.9 min. [a]2D0 =+6.6 (c=0.26, Me2
ACHTREUNG
1
723w, 666m. H-NMR (500 MHz, CD3OD): 2.37 (s, 3 H); 4.05 (m, 2 H); 4.23 (t, J=4.9, 1 H); 4.51 (t,
A
J=4.9, 1 H); 4.72 (t, J=4.8, 1 H); 5.94 (m, 2 H); 6.05 (d, J=4.8, 1 H); 7.33 (d, J=8.2, 2 H); 7.35 (d,
J=2.2, 1 H); 7.78( d, J=8.2, 2 H); 7.95 (d, J=2.2, 1 H); 8.25 (s, 1 H); 8.38 (s, 1 H). 13C-NMR (125
MHz, CD
133.0; 140.5; 143.5; 145.7; 147.7; 148.6; 150.2; 153.5; 154.7; 169.8. HR-MALDI-MS: 583.1600
([M+H]+, C26 S+; calc. 583.1611).
H27N6O6
3OD): 21.51; 41.8; 75.3; 75.6; 86.1; 90.7; 117.0; 117.2; 119.5; 120.8; 128.5; 130.5; 130.8; 131.1;
A
G
A
ACHTREUNG
9-{(E)-5,6,7-Trideoxy-7-[({2,3-dihydroxy-5-[(4-methylphenyl)methyl]phenyl}carbonyl)amino]-b-D-
ribo-hept-5-enofuranosyl}-9H-purin-6-amine (16). Deprotection of 89 (90 mg, 117 mmol) according to
GP 7 afforded 16 (62 mg, 97%). Colorless solid. tR 15.8min. M.p. 119–120 8. [a]2D0 =À3.4 (c=0.1, Me2-
SO). IR (KBr): 3384s (br.), 1700s, 1640m, 1596m, 1534w, 1513w, 1484w, 1437m, 1324m, 1290w, 1205s,
1
1133m, 1048w, 972w, 8 36w, 799w, 725w. H-NMR (500 MHz, CD3OD): 2.25 (s, 3 H); 3.79 (s, 2 H); 4.03
A
(m, 2 H); 4.22 (t, J=5.0, 1 H); 4.51 (m, 1 H); 4.73 (t, J=4.9, 1 H); 5.93 (m, 2 H); 6.05 (d, J=4.9, 1 H);
6.76 (d, J=2.1, 1 H); 7.04 (s, 4 H); 7.14 (d, J=2.1, 1 H); 8.17 (s, 1 H); 8.39 (s, 1 H). 13C-NMR (75
MHz, CD
131.2; 133.6; 136.7; 139.7; 143.5; 147.3; 147.6; 148.5; 150.2; 153.4; 171.3. HR-MALDI-MS: 555.1957
([M+Na]+, C27 NaOþ6 ; calc. 555.1968).
H28N6
3OD): 21.1; 41.6; 41.9; 75.3; 75.7; 86.2; 90.7; 116.5; 118.8; 120.6; 120.8; 129.7; 130.1; 130.2;
A
N
ACHTREUNG
9-[(E)-5,6,7-Trideoxy-7-({[2,3-dihydroxy-5-(1-methylethyl)phenyl]carbonyl}amino)-b-D-ribo-hept-5-
enofuranosyl]-9H-purin-6-amine (17). Deprotection of 90 (50 mg, 74 mmol) according to GP 7 afforded
17 (29 mg, 85%). Colorless solid. tR 12.2 min. [a]2D0 =+22.7 (c=0.1, Me2
ACHTREUNG
AHCTREUNG
AHCTREUNG
A
N
ACHTREUNG
9-{(E)-5,6,7-Trideoxy-7-[({5-[(dimethylamino)carbonyl]-2,3-dihydroxyphenyl}carbonyl)amino]-b-D-
ribo-hept-5-enofuranosyl}-9H-purin-6-amine (18). Deprotection of 91 (90 mg, 128 mmol) according to
GP 7 afforded 18 (54 mg, 86%). Colorless solid. tR 7.3 min. [a]2D0 =À5.4 (c=0.11, Me2
G
1
972w, 8 38w, 8 01w, 725w. H-NMR (500 MHz, CD3
1 H); 4.42 (t, J=4.9, 1 H); 4.66 (t, J=4.8, 1 H); 5.83 (m, 2 H); 5.96 (d, J=4.8, 1 H); 6.92 (d, J=2.0, 1
H); 7.29 (d, J=2.0, 1 H); 8.15 (s, 1 H); 8.31 (s, 1 H). 13C-NMR (125 MHz, CD3
OD): 34.4; 38.8; 40.1;
73.7; 74.2; 84.8; 89.3; 115.1; 116.7; 116.8; 119.3; 126.0; 128.7; 129.4; 142.4; 145.4; 146.1; 148.6; 150.3;
151.5; 169.0; 171.8. HR-MALDI-MS: 500.1894 ([M+H]+, C22 O7þ ; calc. 500.1894).
H26N7
A
AHCTREUNG
A
N
ACHTREUNG
9-((E)-5,6,7-Trideoxy-7-{[(2,3-dihydroxyphenyl)carbonyl]amino}-b-D-ribo-hept-5-enofuranosyl)-
9H-purin-6-amine (19). Deprotection of 92 (120 mg, 190 mmol) according to GP 7 afforded 19 (60 mg,
74%). Colorless solid. tR 10.9 min. [a]2D0 =À6.1 (c=0.2, Me2
ACHTREUNG
1460w, 1420w, 1340w, 1278m, 1129w, 1050w. 1H-NMR (500 MHz, (CD3)2
ACHTREUNG
J=4.8, 1 H); 4.37 (m, 1 H); 4.65 (t, J=5.1, 1 H); 5.82–5.93 (m, 2 H); 5.93 (d, J=5.1, 1 H); 6.69 (t,
J=7.9, 1 H); 6.92 (dd, J=7.9, 1.1, 1 H); 7.31 (dd, J=7.9, 1.1, 1 H); 8.23 (s, 1 H); 8.49 (s, 1 H); 8.97 (t,
J=5.4, 1 H); 12.64 (br. s, 1 H). 13C-NMR (125 MHz, (CD3)2
ACHTREUNG
A
N
ACHTREUNG
We thank F. Hoffmann-La Roche AG, Basel, for generous support of this work. We are grateful to
Dr. B. Wagner and Dr. M. Kansy for the measurement of pKa values.