A new class of inhibitors for the metalloprotease neprilysin based on a central imidazole scaffold

Article abstract of DOI:10.1002/hlca.200590050

Neprilysin (NEP; neutral endopeptidase EC 3.4.24.11) is a Zn ^II-dependent, membrane-bound endopeptidase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and it is involved in the metabolism of a number of smaller

Full text of DOI:10.1002/hlca.200590050

Helvetica Chimica Acta ± Vol. 88 (2005)
707
A New Class of Inhibitors for the Metalloprotease Neprilysin Based on a
Central Imidazole Scaffold
by Stefan Sahli, Bernhard Stump, Tobias Welti, W. Bernd Schweizer, and François Diederich*
Laboratorium für Organische Chemie der Eidgenössischen Technischen Hochschule, ETH-Hönggerberg, HCI,
8093 Zürich (e-mail: diederich@org.chem.ethz.ch)
and
Denise Blum-Kaelin, Johannes D. Aebi, and Hans-Joachim Böhm
Pharma Research Basel, Discovery Chemistry, F. Hoffmann-La Roche Ltd., 4070 Basel
Neprilysin (NEP; neutral endopeptidase EC 3.4.24.11) is a ZnII-dependent, membrane-bound endopepti-
dase. NEP is widely distributed in the organs, particularly in the kidneys and lungs, and it is involved in the
metabolism of a number of smaller regulatory peptides. Inhibition of NEP has been proposed as a potential
target for analgesic and antihypertensive therapies. In this study, new nonpeptidic inhibitors of neprilysin ((Æ)-1,
(Æ)-43, (Æ)-45, and (Æ)-46; Table) were designed, based on the X-ray crystal structure of NEP complexed to
phosphoramidon (Fig. 1). They feature an imidazole ring as the central scaffold, acting as a peptide bond isoster
to undergo H-bonding with the side chains of Asn542 and Arg717 (Fig. 2). The scaffold is decorated with a thiol
group to ligate to the ZnII ion and two aromatic residues to bind into the hydrophobic S1' and S2' pockets. The
synthesis of the new inhibitors was approached by two routes (Schemes 1 ± 4 and 5 ± 8), with the second one
involving a double directed ortho-metallation of the imidazole platform and a Stille cross-coupling, providing
the desired target molecules as hydrochloride salts. In a fluorescence assay, inhibitors (Æ)-1, (Æ)-43, (Æ)-45, and
(Æ)-46 all exhibit IC50 values in the single-digit micromolar activity range (2 ± 4 mm, Table), which validates the
binding mode postulated by modeling. Useful guidelines for a next lead optimization cycle were obtained in
several control runs.
1. Introduction. ± Neprilysin (EC 3.4.24.11) is a mammalian, ZnII-dependent,
membrane-bound endopeptidase (type-II integral membrane protein), related to other
mammalian metalloproteases such as the endothelin-converting enzymes (ECE-1 and
ECE-2), KELL, and PEX [1][2]. It is involved in the metabolism of a number of
regulatory peptides of the nervous, cardiovascular, inflammatory, and immune systems.
The enzyme was extracted for the first time in 1974 from rabbit kidney brush border
[3]. It is found in various tissues, but most abundantly in the kidney [4]. Besides the
wide distribution, it also has broad substrate specificity. The first substrates discovered
were the pentapeptidic endorphins Leu- and Met-enkephalin and substance P [5][6].
Among numerous other substrates [4][7], the cardiovascular peptide ANP (atrial
natriuretic peptide) is the most familiar [8]. Furthermore, NEP plays an important role
in various cancers. The downregulation of NEP in the lung by cigarette smoke may be
causally related to the development of small-cell carcinomas [9][10]. Recently, it has
been reported that NEP degrades both amyloid b-peptides 1-40 and 1-42, which play a
pivotal role in Alzheimerꢀs disease [11][12].
Since NEP cleaves ANP and enkephalins, it is a potential drug target. ANP reduces
blood pressure by sodium excretion in the kidneys [8]. Selective NEP inhibitors are,
ꢁ 2005 Verlag Helvetica Chimica Acta AG, Zürich

708
Helvetica Chimica Acta ± Vol. 88 (2005)
therefore, possible anti-hypertensive agents, either alone or in combination with
selective ACE (angiotensin-converting enzyme) inhibitors or as dual NEP/ACE
inhibitors, so called vasopeptidase inhibitors [13 ± 16]. Enkephalins act as endogenous
painkillers in the central nervous system by binding to m- and d-opiate receptors [17].
Blocking NEP by a selective inhibitor leads to enhanced enkephalin concentrations in
vitro and to antinociceptic activity in mice [18]. This suggests that selective inhibitors of
neprilysin can act as new analgesic therapeutics [4].
When the structure of the extracellular domain (residues 52 ± 749) of human NEP
complexed with the metalloprotease inhibitor phosphoramidon was solved by X-ray
crystallography at 2.1-Š resolution (PDB: 1DMT) [19] (for some current structures,
see [20]), we became interested in the development of novel nonpeptidic inhibitors of
neprilysin by X-ray structure-based de novo design. This strategy has been successfully
pursued in a variety of medicinal-chemistry projects in the Diederich group [21 ± 23]. In
addition to the therapeutic and basic pharmacological interest of the target, we were
motivated to contribute to an enhanced understanding of the structural and molecular-
recognition requirements for selective metalloprotease inhibition. As the intriguing
ultimate target of this research program, we envision blocking NEP selectively and with
high affinity without binding to the ZnII ion.
Here, we report the synthesis and in vitro evaluation of the first generation of
nonpeptidic neprilysin inhibitors based on a central imidazole scaffold. This scaffold is
elegantly decorated using double directed-ortho-metallation strategies [24]. The first-
generation ligands, which still contain a ZnII-binding thiol ligand, show IC50 values in
the low micromolar activity range (for a preliminary communication of parts of this
work, see [25]; IC50: concentration of inhibitor at which 50% Vmax is observed). Their
proposed binding mode is fully validated by the X-ray crystal-structure data reported in
the following paper in this issue [26].
2. Results and Discussion. ± 2.1. Design of the Lead Structure. The basis for the
design of new inhibitors was the crystal structure of neprilysin complexed with
phosphoramidon [19] (Fig. 1). We used the molecular modeling package MOLOC [27]
to analyze the active site and to design our lead structure 1 featuring a 2,5-disubstituted
1H-imidazole as central scaffold (Fig. 2). Important features included in the design of 1
are: i) The central 1H-imidazole platform of the active, (1'S,1''R)-configured
enantiomer should act as a peptide-bond isoster and anchor at the active site by
forming H-bonds to Asn542 and Arg717. Both residues had been shown in site-directed
mutagenesis studies to be important for substrate and ligand binding [28][29]. ii) An
ethylsulfanyl residue departs from C(2) of the 1H-imidazole platform to coordinate to
the ZnII ion, ligated to the side chains of Glu646, His583, and His587 of the protein. iii)
The two hydrophobic pockets S1' and S2' at the active site should be filled in an
energetically beneficial way [30][31] by Ph rings attached by short linkers to the central
scaffold. The S1' pocket, defined by Phe106, Ile558, Phe563, Met579, Val580, Val692,
and Trp693, is deep and can accommodate substituents as large as biphenyls [20][32].
The S2' pocket, defined by the residues Arg102, Phe106, Arg110, Val541, and Trp693, is
shallower and less specific than the S1' pocket [33]. iv) We also hoped to gain
additional affinity by engaging the NH2 moiety of Asn542 in a H-bond with a MeO
substituent at the (R)-configured C(1'') in 1.

Helvetica Chimica Acta ± Vol. 88 (2005)
709
Fig. 1. Analysis of the active site as revealed in the crystal structure of NEP complexed with phosphoramidon
[19]. Active site residues and catalytically active ZnII ion are shown whereas phosphoramidon is removed.
Important aspects for the design of the lead structure are highlighted in pink. Color code: grey: C-atom
skeleton, red: O-atoms, blue: N-atoms, yellow: S-atoms, red sphere: ZnII ion.
2.2. Synthetic Approach towards Lead Structure (Æ)-1 via C1-Homologation. This
synthetic route started from N-protected 1H-imidazole 2 obtained by protection of 1H-
imidazole with the N,N-dimethylsulfamoyl group, which is ortho-directing and can be
easily introduced and removed [34] (Scheme 1). Metallation of 2 with BuLi occurred
selectively at C(2), and the following conversion with DMF afforded the 2-formylated
1H-imidazole 3 in high yield [35][36]. Benzyl-Grignard reagent, formed in situ from
BnBr and Mg, was reacted with aldehyde 3 to give the racemic secondary alcohol (Æ)-4,
which was protected as silyl ether (Æ)-5 using (t-Bu)Me2SiCl.
After selective ortho-metallation with s-BuLi at C(5) of (Æ)-5, reaction with DMF
led to 5-formylated 1H-imidazole (Æ)-6 (Scheme 1). Treatment of aldehyde (Æ)-6 with
a phenyl-Grignard reagent afforded a mixture of the diastereoisomeric pairs of
enantiomers (Æ)-7 and (Æ)-8 in low yield only. An alternative and easier access to (Æ)-7
and (Æ)-8 was provided by treatment of (Æ)-5 with s-BuLi and PhCHO. Separation of
the diastereoisomers was possible by column chromatography: (Æ)-7 and (Æ)-8 were
isolated in 37 and 28% yield, respectively, showing a slight diastereoselectivity
(diastereoisomeric ratio dr 1.3 :1) for the nucleophilic addition to PhCHO.
Methylation of the secondary OH groups of (Æ)-7 and (Æ)-8 to the methyl ethers
(Æ)-9 and (Æ)-10, respectively, was accomplished using NaH and MeI (Scheme 2).
Deprotection of the (t-Bu)Me2Si-protected OH groups of (Æ)-7, (Æ)-8, (Æ)-9, and (Æ)-

710
Helvetica Chimica Acta ± Vol. 88 (2005)
Fig. 2. Lead structure (Æ)-1 (top) and the proposed interactions of the active, (1'S,1''R)-configured enantiomer
with the active-site residues of NEP in a schematic view (middle), and a molecular model (bottom). H-Bonds and
coordinative bonds to the ZnII ion are shown as red and black dashed lines, respectively. Color code: see caption
to Fig. 1; green: C-atom skeleton of the inhibitor.

Helvetica Chimica Acta ± Vol. 88 (2005)
711
Scheme 1. Synthesis of Diastereoisomers (Æ)-7 and (Æ)-8
a) BuLi, DMF, THF, À 788 ! r.t.; 81%. b) Mg, BnBr, Et2O, THF, r.t.; 57%. c) (t-Bu)Me2SiCl, DMAP, CH2Cl2,
16 h, r.t.; 82%. d) s-BuLi, DMF, THF, À 788; 67%. e) PhMgBr, Et2O, THF, 08 ! r.t.; 11% (Æ)-7; 7% (Æ)-8.
f) s-BuLi, PhCHO, THF, À 788; 28% (Æ)-7; 37% (Æ)-8. DMAP ˆ 4-(dimethylamino)pyridine.
Scheme 2. Synthesis of 2,5-Disubstituted Imidazoles (Æ)-15 ± (Æ)-18
a) NaH, MeI, THF, 08 ! r.t., 2 h; 82% (Æ)-9; 90% (Æ)-10. b) Bu4NF, THF, r.t., 2.5 h; 76 ± 86%. c) 4% HCl in
EtOH, r.t., 3 h; 40 ± 78%.
10 with Bu4NF gave the corresponding secondary alcohols (Æ)-11, (Æ)-12, (Æ)-13, and
(Æ)-14, respectively, in good yields. Crystals suitable for X-ray analysis of compound
(Æ)-14 were obtained by recrystallization from Et2O (Fig. 3). This crystal structure led
to the configurational assignment of the above-mentioned diastereoisomers.

712
Helvetica Chimica Acta ± Vol. 88 (2005)
Fig. 3. Crystal structure of (Æ)-14. The ORTEP representation is shown with atomic-displacement-parameter
ellipsoids at 50% probability level. Arbitrary numbering.
Removal of the sulfamoyl protecting group in (Æ)-11, (Æ)-12, (Æ)-13, and (Æ)-14 in
ethanolic HCl gave the corresponding 2,5-disubstituted 1H-imidazoles (Æ)-15, (Æ)-16,
(Æ)-17, and (Æ)-18, respectively (Scheme 2).
We envisaged two possibilities for a C1-homologation at C(1'): i) generation of a
nucleophile at this position and attack at a C1-electrophile, or ii) generation of an
electrophile at C(1'), for instance, a carbonyl group and attack of a C1-nucleophile.
Following the first route, the secondary alcohol (Æ)-13 was deoxygenated according to
Barton and McCombie to give the phenethyl derivative (Æ)-19 (Scheme 3) [37]. Noyce
et al. showed that 1,2-dimethyl-1H-imidazole is not metallated in the imidazole ring,
but at the 2-Me group [38]. This finding suggested that metallation of (Æ)-19 could
occur at C(1'), since both C(2) and C(5) in the heterocyclic nucleus are substituted.
Unfortunately, application of BuLi, s-BuLi, t-BuLi, or (i-Pr)2NLi as base for
deprotonation of (Æ)-19, followed by addition of s-trioxane, did not afford any of the
desired diastereoisomers (Æ)-20 and (Æ)-21. 1H-NMR Measurements of probes
quenched with D2O indeed suggested that a regioselective deprotonation of (Æ)-19 is
quite difficult. Removal of the sulfamoyl group of (Æ)-19 afforded (Æ)-22.
Oxidation of the secondary alcohol (Æ)-13 to the corresponding ketone (Æ)-23 was
accomplished with Dess ± Martin periodinane [39]. Several nucleophilic C1-homolo-
gation procedures were subsequently explored. First, all attempts at conducting a
Darzens glycidic ester synthesis [40] using various bases and a-halo esters under a
variety of reaction conditions were unsuccessful, and none of the desired glycidic ester
(Æ)-24 was isolated (Scheme 4). A C1-homologation by Peterson olefination [41] to
provide vinyl derivative (Æ)-25 failed just as the Wittig olefination [42], whereas the
desired olefination was achieved with the Tebbe reagent [43], although in disappoint-
ingly low yield (9%; Scheme 4). The poor results of the nucleophilic C1-homologation
attempts are presumably due to the acidity of the benzylic H-atoms in a-position to the
CˆO group in (Æ)-23.
2.3. Synthesis of Lead Structure (Æ)-1 via Stille Cross-Coupling. Next, we envisaged
a more direct approach to build up the ꢂrightꢀ part of the molecule via a Stille cross-
coupling [44]. Stannylation of sulfamoyl-protected 1H-imidazole 2 at C(2) was

Helvetica Chimica Acta ± Vol. 88 (2005)
713
Scheme 3. Attempted C1-Homologation at C(1')
a) 1. NaH, CS2, MeI, THF, 08 ! r.t., 2.5 h; 2. Bu3SnH, AIBN, PhH, 5 h, D; 85% over 2 steps. b) 4% HCl in
EtOH, r.t., 3 h; 84%. c) BuLi, s-BuLi, t-BuLi, or (i-Pr)2NLi, s-trioxane. AIBN ˆ 2,2'-azobis[isobutyronitrile].
Scheme 4. Synthesis of the Olefin (Æ)-25
a) Dess ± Martin periodinane, CH2Cl2, r.t., 2.5 h; 47%. b) t-BuOK, ClCH2CO2Et, t-BuOH, r.t. or NaH,
ClCH2CO2Et, THF, À 108 ! r.t., 2 h or (i-Pr)2NLi, ClCH2CO2Et, THF, À 788 ! r.t., 40 min or (Me3Si)2NLi,
ClCH2CO2Et, THF, À 788 ! r.t., 3 h or NaH, BrCH2CO2Et, THF, À 788 ! r.t, 2 h or (Me3Si)2NLi,
BrCH2CO2Et, THF, À 788 ! r.t., 3 h. c) Tebbe reagent, THF, PhMe, À 788 !À 208, 125 min; 9%.
accomplished according to Gutierrez et al. by selective metallation, followed by
reaction with Bu3SnCl [45] (Scheme 5). The stannylated derivative 26 was then cross-
coupled with halo-olefins 27 ± 29 with [PdCl2(PPh3)2] (10 mol-%) as catalyst and a

714
Helvetica Chimica Acta ± Vol. 88 (2005)
Scheme 5. Stille Cross-Couplings and Synthesis of Key Intermediate (Æ)-36 on the Way to (Æ)-1
a) [PdCl2(PPh3)2], Ag2O, DMF, 1008, 48 h; 50%. b) [Pd(PPh3)4], Bu3SnH, AcOH, PhH, r.t., 14 h; 82%.
c) (t-Bu)Me2SiCl, DMAP, CH2Cl2, 16 h, r.t.; 79%. d) 27 or 28, [PdCl2(PPh3)2], Ag2O, DMF, 1008, 48 h; 76%
(from 27) or 39% (from 28). e) AIBN, AcSH, PhH, 1008, 4 h; 99%. f) s-BuLi, PhCHO, THF, À 788, 2 h; 31%.
stoichiometric amount of Ag2O, which seems to be important for the acceleration of the
reaction [45][46]. The couplings with 27 and 28, respectively, yielded 2-vinyl-1H-
imidazole 30. It is noteworthy that the transformation gave better yields with bromide
27 than with iodide 28. The cross-coupling with bromo aldehyde 29 gave 31 in moderate
yields.
Radical addition of AcSH to the CˆC bond of 30 using AIBN as initiator afforded
thioester (Æ)-32 in good yield. We assumed that the thioester group is not stable under
the metallation conditions, so the substituent in 5-position of the 1H-imidazole core was
introduced earlier, by ortho-metallation of 30, followed by reaction with PhCHO to
give (Æ)-33. The yield, however, was much lower than in similar reactions described
above (Scheme 1). Radical addition of AcSH to (Æ)-33 did not afford the desired
thioester (Æ)-34, presumably because of decomposition of the benzylic alcohol moiety.
Since the synthesis starting from 30 was unsatisfactory, we continued on the way to
(Æ)-1 from a,b-unsaturated aldehyde 31. We tried to reduce selectively the CˆC bond
to obtain the corresponding saturated aldehyde by Pd-catalyzed conjugate reduction
with Bu3SnH as hydride donor and AcOH as proton donor [47]. Surprisingly, addition
of 2 equiv. of Bu3SnH, 9equiv. of AcOH, and [Pd(PPh 3)4] (1 mol-%) as catalyst led to

Helvetica Chimica Acta ± Vol. 88 (2005)
715
the reduction of both CˆC and CˆO bonds to give the primary alcohol (Æ)-35
(Scheme 5), which was subsequently converted into silyl ether (Æ)-36.
ortho-Metallation of (Æ)-36 with s-BuLi, followed by addition to PhCHO afforded
a mixture of the diastereoisomeric 1,2,5-trisubstituted 1H-imidazoles (Æ)-37 and (Æ)-38
(Scheme 6). This mixture was O-methylated to give, in almost quantitative yield, a
mixture of (Æ)-39 and (Æ)-40. Cleavage of the silyl ether moieties afforded the primary
alcohols (Æ)-20 and (Æ)-21, which were separated by column chromatography. The
isolated yields of 62% ((Æ)-20) and 35% ((Æ)-21) reflect the diastereoselectivity (dr
1.8 :1) for the nucleophilic addition to PhCHO. Conversion of (Æ)-20 and (Æ)-21 to the
thioesters (Æ)-41 and (Æ)-42, respectively, was accomplished in excellent yields by a
Mitsunobu reaction [48]. The assignment of the diastereoisomers of this series was
based on the X-ray analysis of crystals of (Æ)-41 (Fig. 4). Thiol and imidazole
deprotection in one step with NaOMe in MeOH under H2 [49], followed by addition of
CF3COOH, and subsequent treatment of the crude product with methanolic HCl and
purification by reverse-phase column chromatography afforded the hydrochloride salts
of lead structure (Æ)-1 and its diastereoisomer (Æ)-43, respectively (Scheme 6).
Comparison compound (Æ)-44 was obtained by removal of the sulfamoyl group of (Æ)-
20.
2.4. Synthesis of Inhibitors (Æ)-45 and (Æ)-46. Treatment of (Æ)-36 with s-BuLi and
naphthalene-2-carbaldehyde afforded the diastereoisomers (Æ)-47 and (Æ)-48, which
Scheme 6. Synthesis of the Potential Inhibitors (Æ)-1, (Æ)-43, and (Æ)-44
a) s-BuLi, PhCHO, THF, À 788, 2 h; 85%. b) NaH, MeI, THF, 08 ! r.t., 2 h; 98%. c) Bu4NF, THF, r.t., 2.5 h;
62% (Æ)-20; 35% (Æ)-21. d) DIAD, PPh3, AcSH, THF, 08 ! r.t., 3 h; 95% (Æ)-41; 93% (Æ)-42. e) 1. NaOMe,
MeOH, r.t., 75 min then CF3COOH, r.t., 105 min; 2. 0.1% HCl in MeOH, r.t., 5 min; 41% (Æ)-1; 43% (Æ)-43
over 2 steps. f) 4% HCl in EtOH, r.t., 3 h; 82%. DIAD ˆ Diisopropyl azodicarboxylate.

716
Helvetica Chimica Acta ± Vol. 88 (2005)
Fig. 4. Crystal structure of (Æ)-41. The ORTEP representation is shown with atomic-displacement-parameter
ellipsoids at 50% probability level. Arbitrary numbering.
were separated by column chromatography (Scheme 7). Methylation provided (Æ)-49
and (Æ)-50, silyl deprotection gave (Æ)-51 and (Æ)-52, and Mitsunobu reaction yielded
(Æ)-53 and (Æ)-54, respectively. The final one-step removal of the Ac and sulfamoyl
protecting groups in (Æ)-53 and (Æ)-54 was not very successful, so the sulfamoyl group
Scheme 7. Synthesis of Inhibitor (Æ)-45
a) s-BuLi, 2-naphthalene-2-carbaldehyde, THF, À 788, 2 h; 56% (Æ)-47; 40% (Æ)-48. b) NaH, MeI, THF, 08 !
r.t., 2 h; 94% (Æ)-49; 97% (Æ)-50. c) Bu4NF, THF, r.t., 2.5 h; 80% (Æ)-51; 76% (Æ)-52. d) DIAD, PPh3, AcSH,
THF, 08 ! r.t., 3 h; 83% (Æ)-53; 87% (Æ)-54. e) 4% HCl in EtOH, r.t., 3 h; 75%. f) 1. DIAD, PPh3, AcSH, THF,
08 ! r.t., 3 h; 2. NaOMe, MeOH, r.t., 75 min; 3. 0.1% HCl in MeOH, r.t., 5 min; 21% over 3 steps.

Helvetica Chimica Acta ± Vol. 88 (2005)
717
of (Æ)-51 was cleaved to 1H-imidazole (Æ)-55. Subsequent Mitsunobu reaction with
AcSH and cleavage of the Ac group afforded the desired inhibitor (Æ)-45, which was
isolated as hydrochloride salt.
Treatment of (Æ)-36 with s-BuLi and BnBr afforded (Æ)-56, which was deprotected
to (Æ)-57 and converted to (Æ)-58 as described above (Scheme 8). The thioester moiety
was cleaved with HCl in boiling MeOH. Under these conditions, the sulfamoyl group
was also removed to yield (Æ)-46. Note that these conditions could not be used for
double deprotection of (Æ)-41, (Æ)-42, (Æ)-53, or (Æ)-54, since these compounds
decomposed. The pure hydrochloride salt (Æ)-46 was obtained by treatment with HCl
gas in CHCl3 and purification by reverse-phase column chromatography.
Scheme 8. Synthesis of Inhibitor (Æ)-46
a) s-BuLi, BnBr, THF, À 788 ! r.t., 3.5 h; 67%. b) Bu4NF, THF, r.t., 2.5 h; 81%. c) DIAD, PPh3, AcSH, THF,
08 ! r.t., 3 h; 92%. d) 1. 4% HCl in MeOH, 708, 4 h; 2. HCl (g), CHCl3, r.t. 10 min; 46% over two steps. Bn ˆ
benzyl.
2.5. Biological Activity. The in vitro activity of compounds (Æ)-15, (Æ)-16, (Æ)-17,
(Æ)-18, (Æ)-22, (Æ)-44, and the hydrochloride salts of (Æ)-1, (Æ)-43, (Æ)-45, and (Æ)-46
towards neprilysin was determined in a fluorimetric assay (Table; for a description of
the assay, see Exper. Part). In the active form of the ligands, the 1H-imidazole core is
not protonated. Gratifyingly, our designed lead structure (Æ)-1 (IC50 ˆ 2.0 mm) shows a
good binding affinity. This suggests that our proposed binding mode is correct, and that
the 1H-imidazole core acts indeed as a peptide bond isoster. The similar activity of its
diastereoisomeric analog (Æ)-43 (IC50 ˆ 1.7 mm) indicates that the predicted H-bond
between the O-atom of the MeO group in (Æ)-1 and the side-chain NÀH of Asn542 is
not effective. Indeed, the H-bond-accepting MeO group can be completely omitted
without penalty as shown by the activity of (Æ)-46 (IC50 ˆ 2.5 mm), which lacks the
MeO group and is about as active as (Æ)-1 and (Æ)-43. The IC50 value of naphthyl
derivative (Æ)-45 (IC50 ˆ 3.6 mm) is by a factor of 1.8 higher than the value measured

718
Helvetica Chimica Acta ± Vol. 88 (2005)
Table. Activities of the New Imidazole-Based Inhibitors towards Neprilysin
Inhibitor
R1
R2
R3
Active enantiomer
IC50 [mm]
(Æ)-15
OH
OH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Npc)
Ph
OH
OH
OH
OH
(1'S,1''R)
(1'S,1''S)
(1'S,1''R)
(1'S,1''S)
(1''S)
(1'S,1''R)
(1'S,1''R)
(1'S,1''S)
(1'S,1''R)
(1'S)
15a)
18a)
24a)
17a)
17a)
17a)
2.0
1.7
3.6
2.5
(Æ)-16
(Æ)-17
MeO
MeO
MeO
MeO
MeO
MeO
MeO
H
(Æ)-18
(Æ)-22
H
(Æ)-44
CH2OH
CH2SH
CH2SH
CH2SH
CH2SH
(Æ)-1b)
(Æ)-43b)
(Æ)-45b)
(Æ)-46b)
a) % Inhibition at 100 mm inhibitor concentration. b) The hydrochloride salts were used in the assay; in the
active ligand, the imidazole is not protonated. c) Np ˆ Naphthalen-2-yl.
for lead compound (Æ)-1. This result indicates that no additional binding free enthalpy
is gained upon introduction of a larger aromatic substituent in the S2' pocket and con-
firms the assumption that this pocket is less well-defined and rather promiscuous [19][33].
The substitution of the sulfanylmethyl by a hydroxymethyl group as in (Æ)-44 leads
to a dramatic loss in activity. Similarly, the hydroxy derivatives (Æ)-15, (Æ)-16, (Æ)-17,
and (Æ)-18 were all inactive as was compound (Æ)-22 lacking any vector for potential
ZnII binding. This clearly shows that, at the stage of the compounds resulting from the
first design cycle, strong ligation to the metal ion by a thiol residue is required for
biological activity.
3. Conclusions. ± This paper describes the first generation of nonpeptidic inhibitors
of the ZnII-dependent membrane-bound endopeptidase neprilysin (NEP) resulting
from X-ray-structure-based design. Their synthesis involves an elegant double directed
ortho-metallation of an 1H-imidazole scaffold introduced as peptide-bond isoster. The
first of the metallations is followed by a Stille cross-coupling, thereby providing another
example for the versatile directed ortho-metallation-cross-coupling strategy, largely
developed and recently reviewed by Anctil and Snieckus [50]. The IC50 values of the
new inhibitors (Æ)-1, (Æ)-43, (Æ)-45, and (Æ)-46, determined by a fluorescence assay,
are all in the lower micromolar range (IC50 ˆ 2 ± 4 mm). This suggests that the binding
mode predicted by modeling is basically correct: the imidazole ring acts as peptide
bond isoster, the two aromatic rings occupy the two hydrophobic S1' and S2' pockets,
and the thiol vector ligates to the ZnII ion. Control experiments show that, at this stage
of lead development, thiol ligation to the ZnII ion is absolutely required. The inactive
compounds (Æ)-15, (Æ)-16, (Æ)-17, and (Æ)-18 clearly do not bind with their OH group
in the 1'-position to the ZnII ion via the ꢂcatalyticꢀ H2O acting as a bridging molecule.
Presumably, the ligand exchange of the catalytically active H2O at the ZnII ion is too

Helvetica Chimica Acta ± Vol. 88 (2005)
719
fast to establish a stable inhibitorÀH2OÀZnII complex. Contrary to the kinetically
stable binding of ZnII to the protein, the hydrolytic function of the enzyme requires a
labile complexation of the active H2O molecule [51]. Two additional results provide
useful guidance for the next lead-optimization cycle: H-bonding to the side-chain NÀH
of Asn542 does not make a measurable contribution to the binding free enthalpy and
can be omitted (see comparison (Æ)-1, (Æ)-43, and (Æ)-46). Also, occupancy of the
wider, conformationally less-defined S2' pocket by larger aromatic side chains does not
enhance binding affinity. In summary, this project has again demonstrated the potential
of structure-based de novo design as a powerful tool for nonpeptidic lead generation,
complementing other strategies such as high-throughput screening. The activity of the
first NEP inhibitor ((Æ)-1; IC50 ˆ 2 mm) is well in the range of those of the first ligands
prepared in other de novo design programs in our laboratory (thrombin: inhibition
constant Ki ˆ 18 mm [52], catechol O-methyltransferase: IC50 ˆ 6 mm [53], tRNA
guanine transglycosylase: Ki ˆ 100 nm [54], and plasmepsin II: Ki ˆ 5 mm [55]). These
data suggest that single leads with inhibitory activities between Ki ꢀ 20 mm and 100 nm
can be generated with great confidence by structure-based design, provided the target
enzyme active site is conformationally well-defined and possesses pronounced concave/
convex surfaces, which is the case for all five targets.
We thank the ETH Research Council and F. Hoffmann-La Roche, Basel, for generous support of this work,
and Dr. C. Thilgen for help with the nomenclature.
Experimental Part
General. Solvents and reagents were of reagent-grade, purchased from commercial suppliers, and used
without further purification unless otherwise stated. The following compounds were prepared according to
literature procedures: 2 [34], 26 [45], 27 [56], 28 [57], and 29 [58]. THF was freshly distilled from sodium
benzophenone ketyl, CH2Cl2 from CaH2. Evaporation in vacuo was conducted at 30 ± 708 and 600 ± 15 mbar
pressure. All products were dried under high vacuum (10À2 Torr) before anal. characterization. Column
chromatography (CC): SiO2-60 (40 ± 63 mm) and RP-18 SiO2 (40 ± 63 mm) from Fluka, 0 ± 0.4 bar pressure. TLC:
SiO2-60 F254, Merck, visualization by UV light at 254 nm or by staining with a soln. of KMnO4 (3 g) and K2CO3
(20 g) in 5% aq. NaOH soln. (5 ml) and H2O (300 ml) or a soln. of (NH4)6 Mo7O24 ´ 6 H2O (20 g) and Ce(SO4)2
(0.4 g) in 10% aq. H2SO4 soln. (400 ml). M.p.: Büchi B-540 melting-point apparatus; uncorrected. IR [cmÀ1]:
Perkin-Elmer 1600-FT or Perkin-Elmer Spectrum BX spectrometer. NMR (1H and 13C): Varian Gemini-300 or
Bruker AMX-500; spectra were recorded at r.t. with solvent peak as reference. MS (m/z (%)): EI-MS: VG-
TRIBRID spectrometer at 70 eV; ESI-MS: Finnigan MAT TSQ 7000 spectrometer; HR-MALDI-MS: IonSpec
Ultima (2,5-dihydroxybenzoic acid (DHB) or 2-{(2E)-3-[4-(tert-butyl)phenyl)]-2-methylprop-2-enylidene}ma-
lononitrile (DTCB) matrix). Elemental analyses were performed by the Mikrolabor at the Laboratorium für
Organische Chemie, ETH-Zürich.
Biological Assay. The NEP assay was based on the method described by Carvalho et al. [59] with a minor
difference in the substrate. The fluorescent substrate (ABZ-GGdFLRRVQEDDnp) contained an additional
glutamine between the valine and the fluorescent group. Incubations (for 1 h at 378) were carried out in 96-well
microplates in triplicate at 4 to 6 concentrations ranging from 100 mm to 1 nm. IC50 Values were calculated after
logit/log transformation of the percent inhibition data with a best-fit regression model. The inhibitors were
tested for their fluorescence or quenching properties, and values were corrected accordingly. Thiorphan as
reference compound gave an IC50 value of 7.0 Æ 0.2 nm (n ˆ 6) in this assay.
General Procedure for the Silylation of a OH Group with (t-Bu)Me2SiCl (GP 1). To a soln. of the alcohol
(1 equiv.) in dry CH2Cl2 (0.04m), (t-Bu)Me2SiCl (1.5 equiv.) and DMAP (1.7 equiv.) were added, and the
mixture was stirred for 16 h at r.t. After addition of Et2O, and washing with H2O and sat. aq. NaCl soln., the aq.
phases were extracted (CH2Cl2), and the combined org. phases were dried (MgSO4) and concentrated in vacuo.
General Procedure for the Nucleophilic Addition of 5-Metallated 1H-Imidazoles to Aromatic Aldehydes
(GP 2). At À 788, s-BuLi (1.3m in cyclohexane, 1.2 equiv.) was added dropwise to a soln. of the 1,2-disubstituted

720
Helvetica Chimica Acta ± Vol. 88 (2005)
1H-imidazole (1 equiv.) in dry THF (0.06m), and the mixture was stirred for 30 min. The aldehyde (3 equiv.)
was added, followed by stirring for 3 h at À 788. The reaction was quenched by addition of 1n HCl, and the
mixture was neutralized with sat. aq. NaHCO3 soln., and extracted (CH2Cl2). The org. phases were dried
(MgSO4) and concentrated in vacuo.
General Procedure for the Deprotection of a (t-Bu)Me2Si-Protected Hydroxy Group (GP 3). To a soln of the
silyl-protected compound (1 equiv.) in dry THF (0.07m), Bu4NF (1m in THF, 2 equiv.) was added dropwise at r.t.
The mixture was stirred for 2.5 h at r.t., and the reaction was quenched by addition of H2O. After extraction
(CH2Cl2), the org. phase was dried (MgSO4) and concentrated in vacuo.
General Procedure for the Deprotection of a N-Me2NSO2-Protected 1H-Imidazole (GP 4). A soln. of the N-
protected 1H-imidazole (1 equiv.) in 4% ethanolic HCl soln. (0.1m) was stirred for 3 h at r.t. The mixture was
neutralized by addition of sat. aq. NaHCO
3
soln., extracted (CH
2
Cl
2
), and the org. phases were dried (MgSO ),
4
and the solvent was removed in vacuo.
General Procedure for the Methylation of a Hydroxy Group (GP 5). Pentane was added to NaH (2 equiv.)
under N2. After stirring for 10 min, the pentane was decanted, and the white solid was dried by streaming N2. A
soln. of the alcohol (1 equiv.) in dry THF was added to the solid at 08. After stirring for 30 min at r.t., MeI
(1.1 equiv.) was added at 08, and the mixture was stirred for additional 2 h at r.t. The reaction was quenched with
H2O, the mixture was extracted (CH2Cl2), the org. phases were dried (MgSO4), and the solvent was removed in
vacuo.
General Procedure for the Substitution of a Hydroxy Group by AcSH Under Mitsunobu Conditions (GP 6).
To a soln. of Ph3P (1.5 equiv.) in dry THF (0.1m), DIAD (1.5 equiv.) was added at 08, and the mixture was stirred
for 30 min, whereas a white solid precipitated. A soln. of the alcohol (1 equiv.) in dry THF (0.16m) was added
dropwise to the mixture, followed by addition of freshly distilled AcSH (2 equiv.). The mixture was stirred for
1 h at 08 and for 2 h at r.t. After addition of Et2O, and washing with H2O and sat. aq. NaCl soln., the aq. phases
were extracted (CH2Cl2), and the combined org. phases were dried (MgSO4) and concentrated in vacuo.
2-Formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (3). To a soln. of 2 (5.00 g, 29mmol) in dry THF
(150 ml), BuLi (1.6m in hexane, 21.4 ml, 34 mmol) was added slowly at À 788. After stirring for 5 min, DMF
(10.5 ml, 137 mmol) was added, and the mixture was stirred for 30 min at À 788 and 1 h at r.t. The mixture was
poured into 2m HCl, neutralized with sat. aq. NaHCO3 soln., and extracted (CH2Cl2). The org. phases were dried
(MgSO4) and concentrated in vacuo. The resulting residue was purified by CC (SiO2; hexane/AcOEt 25 :75) to
give 3 (4.70 g, 81%). Yellowish powder. M.p. 91 ± 928 ([31]: 928). 1H-NMR (300 MHz, CDCl3): 3.01 (s, 6 H); 7.03
(d, J ˆ 1.3, 1 H); 7.58 (dd, J ˆ 1.3, 0.6, 1 H); 9.94 (d, J ˆ 0.6, 1 H).
2-[(1RS)-1-Hydroxy-2-phenylethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-4). Mg (1.01 g,
42 mmol) in Et2O (10 ml) was slowly treated with BnBr (4.1 ml, 35 mmol). The resulting suspension was
added to a soln. of 3 (4.70 g, 23 mmol) in THF (30 ml). After addition, the reaction was carefully quenched with
sat. aq. NH4Cl soln., and the mixture was extracted (CH2Cl2). The org. phases were dried (MgSO4) and
concentrated in vacuo. The resulting residue was purified by CC (SiO2; AcOEt) to give (Æ)-4 (3.87 g, 57%).
Reddish powder. M.p. 72 ± 738. IR (CHCl3): 3580, 3007, 1455, 1420, 1393, 1180, 1160. 1H-NMR (300 MHz,
CDCl3): 2.84 (s, 6 H); 3.16 (dd, J ˆ 13.7, 8.1, 1 H); 3.37 (dd, J ˆ 13.7, 4.7, 1 H); 5.29( dd, J ˆ 8.1, 4.7, 1 H); 7.05 (d,
J ˆ 1.6, 1 H); 7.22 ± 7.32 (m, Ph). 13C-NMR (75 MHz, CDCl3): 38.2; 43.1; 67.9; 119.9; 126.7; 127.6; 128.4; 129.6;
‡
137.5; 150.5. EI-MS: 295.1 (1, M ), 276.1 (16), 204.0 (63), 169.1 (44), 108.0 (100). Anal. calc. for C13H17N3O3S
(295.36): C 52.87, H 5.80, N 14.23; found: C 53.04, H 5.89, N 14.07.
2-((1RS)-1-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-phenylethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide
((Æ)-5). GP 1, starting from (Æ)-4 (10.50 g, 35.5 mmol), gave (Æ)-5 (11.97 g, 82%) after purification through a
plug (SiO2; pentane/AcOEt 67:33) and recrystallization from Et2O. Yellowish crystals. M.p. 70 ± 728. IR
(CHCl3): 2930, 2857, 1472, 1420, 1392, 1255, 1178, 1159. 1H-NMR (300 MHz, CDCl3): À 0.15 (s, 3 H); À 0.14 (s,
3 H); 0.77 (s, 9H); 2.68 ( s, 6 H); 3.06 (dd, J ˆ 13,1, 7.8, 1 H); 3.35 (dd, J ˆ 13.1, 5.9, 1 H); 5.37 (dd, J ˆ 7.8, 5.9,
1 H); 7.08 (d, J ˆ 1.6, 1 H); 7.16 ± 7.24 (m, 6 H). 13C-NMR (75 MHz, CDCl3): À 5.1; 18.2; 25.7; 37.9; 44.4; 69.1;
‡
119.1; 126.4; 128.1; 128.2; 130.0; 138.1; 150.7. MALDI-MS (DHB): 432.2 (72, [M ‡ Na] ), 278.1 (63), 233.0 (12),
‡
‡
215.1 (12), 214.1 (100). MALDI-HR-MS (DHB): 432.1748 ([M ‡ Na] , C19H31N3NaO3SSi ; calc. 432.1748).
Anal. calc. for C19H31N3O3SSi (409.62): C 55.71, H 7.63, N 10.26, S 7.83; found C 55.97, H 7.64, N 10.25, S 7.76.
2-((1RS)-1-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-phenylethyl)-5-formyl-N,N-dimethyl-1H-imidazole-1-sul-
fonamide ((Æ)-6). To a soln. of (Æ)-5 (3.00 g, 7.32 mmol) in dry THF (50 ml), s-BuLi (1.3m in cyclohexane,
8.5 ml, 11 mmol) was slowly added at À 788C. After stirring for 30 min, DMF (2.7 ml, 35 mmol) was added, and
the mixture was stirred for 1 h at À 788. The mixture was poured into 1m HCl, neutralized with sat. aq. NaHCO3
soln., and extracted (CH2Cl2). The org. phases were dried (MgSO4) and concentrated in vacuo. The resulting
residue was purified by CC (SiO2; pentane/AcOEt 75 :25) to give (Æ)-6 (2.15 g, 67%). Colorless oil. IR

Helvetica Chimica Acta ± Vol. 88 (2005)
721
(CHCl3): 3436, 3015, 2956, 2861, 1692, 1671, 1543, 1471, 1394, 1260. 1H-NMR (300 MHz, CDCl3): À 0.13 (s,
3 H); À 0.10 (s, 3 H); 0.79( s, 9H); 2.72 ( s, 6 H); 3.03 (dd, J ˆ 13.1, 7.5, 1 H); 3.40 (dd, J ˆ 13.1, 5.9, 1 H); 5.51
(dd, J ˆ 7.5, 5.9, 1 H); 7.18 ± 7.27 (m, 5 H); 7.89( s, 1 H); 10.00 (s, 1 H). 13C-NMR (75 MHz, CDCl3): À 5.1; 18.2;
25.7; 37.9; 44.4; 69.8; 126.7; 128.3; 128.3; 130.0; 137.4; 139.1; 157.5; 179.8. MALDI-MS (DHB): 460.2 (72, [M ‡
‡
Na] ), 438.2 (14), 393.2 (11), 380.2 (24), 359.2 (21), 358.2 (100). MALDI-HR-MS (DHB): 460.1703 ([M ‡
‡
‡
Na] , C20H31N3NaO4SSi ; calc. 460.1697).
2-((1RS)-1-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-phenylethyl)-5-[(SR)-hydroxy(phenyl)methyl]-N,N-di-
methyl-1H-imidazole-1-sulfonamide ((Æ)-7) and 2-((1RS)-1-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-phenylethyl)-
5-[(RS)-hydroxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-8). GP 2, starting from (Æ)-
5 (17.80 g, 43.45 mmol) and PhCHO, afforded (Æ)-7 (6.23 g, 28%) and (Æ)-8 (8.31 g, 37%) after purification by
CC (SiO2; pentane/AcOEt 75 :25).
Data of (Æ)-7: Colorless crystals. M.p. 127 ± 1288. IR (CHCl3): 3580, 2944, 1600, 1492, 1467, 1451, 1374, 1251,
1185, 1161, 1097. 1H-NMR (300 MHz, CDCl3): À 0.12 (s, 6 H); 0.77 (s, 9H); 2.61 ( s, 6 H); 3.02 (dd, J ˆ 13.1, 7.5,
1 H); 3.12 (d, J ˆ 5.0, 1 H); 3.32 (dd, J ˆ 13.1, 6.2, 1 H); 5.35 (dd, J ˆ 7.5, 6.2, 1 H); 6.06 (s, 1 H); 6.60 (s, 1 H);
7.15 ± 7.42 (m, 5 H); 7.31 ± 7.43 (m, 5 H). 13C-NMR (125 MHz, CDCl3): À 5.0; 18.2; 25.6; 37.5; 44.4; 67.7; 69.6;
126.4; 126.8; 128.1; 128.3; 129.8; 130.0; 136.5; 138.1; 140.4; 153.4 (1 arom. signal overlapping). MALDI-MS
‡
‡
(DHB): 538.2 (30, [M ‡ Na] ), 516.2 (13, MH ), 431.2 (13), 409.2 (17), 391.2 (34), 384.1 (25), 366.1 (100).
‡
‡
MALDI-HR-MS (DHB): 538.2165 ([M ‡ Na] , C26H37N3NaO4SSi ; calc. 538.2166).
Data of (Æ)-8: Colorless crystals. M.p. 127 ± 1288. IR (CHCl3): 3590, 2930, 2857, 1600, 1455, 1376, 1254, 1161,
1102. 1H-NMR (300 MHz, CDCl3): À 0.17 (s, 3 H); À 0.15 (s, 3 H); 0.76 (s, 9H); 2.67 ( s, 6 H); 3.00 (dd, J ˆ 13.1,
8.0, 1 H); 3.32 (dd, J ˆ 13.1, 5.3, 1 H); 5.33 (dd, J ˆ 8.0, 5.3, 1 H); 6.10 (s, 1 H); 6.62 (s, 1 H); 7.18 ± 7.27 (m, 5 H);
7.31 ± 7.43 (m, 5 H). 13C-NMR (125 MHz, CDCl3): À 5.1; 18.2; 25.7; 37.6; 44.6; 67.7; 69.9; 126.6; 126.8; 128.2;
128.4; 129.7; 130.0; 136.6; 138.1; 140.5; 153.5 (1 arom. signal overlapping). MALDI-MS (DHB): 538.2 (33,
‡
‡
[M ‡ Na] ), 516.2 (20, MH ), 431.2 (16), 409.2 (49), 391.2 (100). MALDI-HR-MS (DHB): 538.2168 ([M ‡
‡
‡
Na] , C26H37N3NaO4SSi ; calc. 538.2166). Anal. calc. for C26H37N3O4SSi (515.74): C 60.55, H 7.23, N 8.15; found
C 60.75, H 7.21, N 8.12.
2-[(1RS)-1-Hydroxy-2-phenylethyl]-5-[(SR)-hydroxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sul-
fonamide ((Æ)-11). GP 3, starting from (Æ)-7 (300 mg, 0.58 mmol), afforded (Æ)-11 (177 mg, 76%) after
purification by CC (SiO2; AcOEt). White powder. M.p. 1208. IR (CHCl3): 3587, 3009, 2966, 1717, 1604, 1495,
1454, 1420, 1387, 1262, 1161, 1098. 1H-NMR (300 MHz, CDCl3): 2.81 (s, 6 H); 3.10 (dd, J ˆ 13.7, 7.8, 1 H); 3.35
(dd, J ˆ 13.7, 5.0, 1 H); 5.24 (m, 1 H); 6.12 (s, 1 H); 6.58 (s, 1 H); 7.20 ± 7.40 (m, 10 H). 13C-NMR (75 MHz,
CDCl3): 37.8; 43.3; 67.6; 68.4; 126.5; 126.6; 128.1; 128.2; 128.3; 128.9; 129.5; 136.7; 137.5; 140.6; 153.0. MALDI-
‡
‡
MS (DHB): 424.1 (22, [M ‡ Na] ), 402.1 (48, MH ), 317.1 (22), 304.1 (12), 295.1 (18), 277.1 (100). MALDI-
‡
‡
HR-MS (DHB): 402.1491 (MH , C20H24N3O4S ; calc. 402.1482).
2-[(1RS)-1-Hydroxy-2-phenylethyl]-5-[(SR)-hydroxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sul-
fonamide ((Æ)-12). GP 3, starting from (Æ)-8 (200 mg, 0.39mmol), afforded ( Æ)-12 (135 mg, 86%) after
purification by CC (SiO2; AcOEt). White powder. M.p. 1268. IR (CHCl3): 3582, 3020, 1602, 1495, 1454, 1419,
1
1383, 1323, 1274, 1162, 1099. H-NMR (300 MHz, CDCl3): 2.82 (s, 6 H); 3.06 (dd, J ˆ 13.7, 8.4, 1 H); 3.33 (dd,
J ˆ 13.7, 4.7, 1 H); 5.26 (m, 1 H); 6.09( s, 1 H); 6.48 (s, 1 H); 7.20 ± 7.44 (m, 10 H). 13C-NMR (75 MHz, CDCl3):
38.0; 43.8; 67.5; 68.7; 126.6; 126.7; 128.2; 128.3; 128.3; 129.2; 129.5; 137.0; 137.5; 139.7; 153.4. MALDI-MS
‡
‡
(DHB): 402.1 (48, MH ), 317.1 (7), 295.1 (13), 277.1 (100). MALDI-HR-MS (DHB): 402.1490 (MH ,
‡
C20H24N3O4S ; calc. 402.1482).
(1RS)-1-{5-[(SR)-Hydroxy(phenyl)methyl]-1H-imidazol-2-yl}-2-phenylethanol ((Æ)-15). GP 4, starting
from (Æ)-11 (100 mg, 0.25 mmol), gave (Æ)-15 (39mg, 53%) after purification by CC (SiO 2; CH2Cl2/MeOH
91:9). White powder. M.p. 167 ± 1688. IR (KBr): 3238, 2678, 1947, 1558, 1491, 1452, 1315, 1222, 1194, 1080, 1066,
1024, 996. 1H-NMR (300 MHz, CD3OD): 3.02 (dd, J ˆ 13.7, 7.2, 1 H); 3.14 (dd, J ˆ 13.7, 5.9, 1 H); 4.87 (m, 1 H);
5.72 (s, 1 H); 6.69( s, 1 H); 7.06 ± 7.39( m, 10 H). 13C-NMR (75 MHz, CD3OD): 43.9; 69.9; 71.2; 126.8; 127.5;
127.9; 128.7; 128.7; 130.1; 138.5; 144.2; 151.2 (2 arom. signals overlapping). MALDI-MS (DHB): 317.1 (30,
‡
‡
‡
[M ‡ Na] ), 309.2 (30), 295.1 (37, MH ), 291.1 (13), 277.1 (100). MALDI-HR-MS (DHB): 295.1444 (MH ,
‡
C18H19N2O2 ; calc. 295.1447).
(1RS)-1-{5-[(RS)-Hydroxy(phenyl)methyl]-1H-imidazol-2-yl}-2-phenylethanol ((Æ)-16). GP 4, starting
from (Æ)-12 (100 mg, 0.25 mmol), gave (Æ)-16 (29mg, 40%) after purification by CC (SiO 2; CH2Cl2/MeOH
91:9). White powder. M.p. 179 ± 1808. IR (KBr): 3250, 2672, 1947, 1603, 1564, 1494, 1454, 1401, 1309, 1216, 1116,
1083, 995. 1H-NMR (300 MHz, CD3OD): 3.02 (dd, J ˆ 13.5, 7.6, 1 H); 3.16 (dd, J ˆ 13.5, 6.1, 1 H); 4.87 (m, 1 H);
5.73 (s, 1 H); 6.70 (s, 1 H); 7.08 ± 7.40 (m, 10 H). 13C-NMR (75 MHz, CD3OD): 44.0; 69.9; 71.0; 127.0; 127.5;
128.1; 128.8; 130.2; 138.6; 144.2; 151.3 (3 arom. signals overlapping). MALDI-MS (DHB): 317.1 (22,

722
Helvetica Chimica Acta ± Vol. 88 (2005)
‡
‡
‡
‡
[M ‡ Na] ), 295.1 (21, MH ), 277.1 (100). MALDI-HR-MS (DHB): 295.1454 (MH , C18H19N2O2 ; calc.
295.1447). Anal. calc. for C18H18N2O2 (294.35): C 73.45, H 6.16, N 9.52; found C 73.41, H 6.26, N 9.41.
2-((1RS)-1-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-phenylethyl)-5-[(SR)-methoxy(phenyl)methyl]-N,N-di-
methyl-1H-imidazole-1-sulfonamide ((Æ)-9). GP 5, starting from (Æ)-7 (2.24 g, 4.34 mmol), afforded (Æ)-9
(1.89g, 82%) after purification by CC (SiO 2; pentane/AcOEt 80 :20). Slightly yellow oil. IR (CHCl3): 3019,
1
2929, 2856, 1454, 1380, 1214, 1101, 940. H-NMR (300 MHz, CDCl3): À 0.22 (s, 3 H); À 0.21 (s, 3 H); 0.74 (s,
9H); 2.67 ( s, 6 H); 2.93 (dd, J ˆ 13.1, 8.4, 1 H); 3.29( dd, J ˆ 13.1, 4.4, 1 H); 3.34 (s, 3 H); 5.24 (dd, J ˆ 8.4, 4.4,
1 H); 5.61 (d, J ˆ 0.6, 1 H); 6.58 (d, J ˆ 0.6, 1 H); 7.15 ± 7.37 (m, 10 H). 13C-NMR (75 MHz, CDCl3) À 5.4; 18.3;
25.7; 37.7; 44.8; 56.9; 70.2; 126.9; 127.9; 128.2; 128.3; 128.6; 129.8; 130.0; 134.4; 136.1; 138.4; 152.9(1 aliph. signal
‡
‡
under solvent peak). MALDI-MS (DHB): 552.2 (25, [M ‡ Na] ), 530.3 (6, MH ), 391.2 (100), 366.1 (72),
‡
‡
259.1 (67). MALDI-HR-MS (DHB): 552.2328 ([M ‡ Na] , C27H39N3NaO4SSi ; calc. 552.2323).
2-((1RS)-1-{[(tert-Butyl)(dimethyl)silyl]oxy}-2-phenylethyl)-5-[(RS)-methoxy(phenyl)methyl]-N,N-di-
methyl-1H-imidazole-1-sulfonamide ((Æ)-10). GP 5, starting from (Æ)-8 (3.50 g, 6.79mmol), afforded ( Æ)-10
(3.25 g, 90%) after purification by CC (SiO2; pentane/AcOEt 80 :20). Slightly yellow oil. IR (CHCl3): 3017,
2929, 2857, 1454, 1380, 1218, 1086. 1H-NMR (300 MHz, CDCl3): À 0.16 (s, 6 H); 0.75 (s, 9H); 2.59( s, 6 H); 3.03
(dd, J ˆ 13.1, 7.5, 1 H); 3.33 (s, 3 H); 3.34 (dd, J ˆ 13.1, 5.6, 1 H); 5.32 (t, J ˆ 6.9, 1 H); 5.63 (s,1 H); 6.66 (s, 1 H);
7.15 ± 7.39( m, 10 H). 13C-NMR (75 MHz, CDCl3): À 4.8; 18.3; 25.9; 37.5; 44.6; 57.0; 69.7; 76.9; 126.3; 127.7;
‡
128.1; 128.2; 128.4; 129.5; 129.9; 134.5; 138.2; 138.7; 153.0. MALDI-MS (DHB): 552.2 (25, [M ‡ Na] ), 530.3 (7,
‡
‡
‡
MH ), 391.2 (100), 366.1 (56), 259.1 (47). MALDI-HR-MS (DHB): 552.2327 ([M ‡ Na] , C27H39N3NaO4SSi ;
calc. 552.2323).
2-[(1RS)-1-Hydroxy-2-phenylethyl]-5-[(SR)-methoxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sul-
fonamide ((Æ)-13). GP 3, starting from (Æ)-9 (3.25 g, 6.13 mmol), gave (Æ)-13 (1.97 g, 77%) after purification
by recrystallization from Et2O. Colorless crystals. M.p. 151 ± 1528. IR (CHCl3): 3574; 3064; 2997; 2933; 2826;
1603; 1454; 1391; 1163; 1084; 970. 1H-NMR (300 MHz, CDCl3): 2.90 (s, 6 H); 3.01 (dd, J ˆ 13.7, 8.4, 1 H); 3.29
(dd, J ˆ 13.7, 4.0, 1 H); 3.34 (s, 3 H); 5.25 ± 5.30 (m, 1 H); 5.64 (d, J ˆ 0.9, 1 H); 6.50 (d, J ˆ 0.9, 1 H); 7.17 ± 7.41
(m, 10 H). 13C-NMR (75 MHz, CDCl3): 38.2; 44.1; 56.9; 68.9; 76.1; 126.5; 127.5; 128.3; 128.4; 128.4; 129.2; 129.5;
‡
‡
134.9; 137.7; 138.4; 153.3. MALDI-MS (DHB): 438.2 (6, [ M ‡ Na] ), 416.2 (28, MH ), 277.1 (68), 242.3 (100).
‡
‡
MALDI-HR-MS (DHB): 416.1642 (MH , C21H26N3O4S ; calc. 416.1639).
2-[(1RS)-1-Hydroxy-2-phenylethyl]-5-[(RS)-methoxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sul-
fonamide ((Æ)-14). GP 3, starting from (Æ)-10 (1.76 g, 3.32 mmol), gave (Æ)-14 (1.06 g, 77%) after purification
by CC (SiO2; pentane/AcOEt 50 :50). Colorless crystals. M.p. 1228. IR (CHCl3): 3577; 3025; 3012; 2933; 2826;
1604; 1454; 1385; 1162; 1084; 968. 1H-NMR (300 MHz, CDCl3): 2.68 (s, 6 H); 3.15 (dd, J ˆ 13.7, 7.8, 1 H); 3.35
(s, 3 H); 3.42 (dd, J ˆ 13.7, 5.6, 1 H); 5.21 (t, J ˆ 6.5, 1 H); 5.63 (d, J ˆ 0.9, 1 H); 6.62 (d, J ˆ 0.9, 1 H); 7.18 ± 7.40
(m, 10 H). 13C-NMR (75 MHz, CDCl3): 37.69; 42.61; 57.04; 68.45; 77.17; 126.42; 127.60; 128.22; 128.32; 128.37;
‡
‡
129.17; 129.49; 134.86; 137.65; 138.24; 152.64. MALDI-MS (DHB): 438.1 (6, [M ‡ Na] ), 416.2 (28, MH ),
‡
‡
331.1 (21), 318.1 (17), 277.1 (100), 259.1 (19). MALDI-HR-MS (DHB): 416.1641 (MH , C21H26N3O4S ; calc.
416.1639). Anal. calc. for C21H25N3O4S (415.51): C 60.70, H 6.06, N 10.11; found C 60.86, H 6.12, N 10.04. X-Ray:
see Fig. 3.
(1RS)-1-{5-[(SR)-Methoxy(phenyl)methyl]-1H-imidazol-2-yl}-2-phenylethanol ((Æ)-17). GP 4, starting
from (Æ)-13 (150 mg, 0.36 mmol), afforded (Æ)-17 (68 mg, 61%) after purification by CC (SiO2; AcOEt/MeOH
1
99 :1). White solid. M.p. 108 ± 1098. IR (KBr): 3620, 3018, 2894, 1950, 1520, 1473, 1423, 1334, 1215. H-NMR
(300 MHz, CD3OD): 3.03 (dd, J ˆ 13.7, 7.5, 1 H); 3.15 (dd, J ˆ 13.7, 6.2, 1 H); 3.30 (s, 3 H); 4.92 (dd, J ˆ 6.8, 5.9,
1 H); 5.25 (s, 1 H); 6.65 (s, 1 H); 7.05 ± 7.38 (m, 10 H). 13C-NMR (75 MHz, CD3OD): 44.0; 56.7; 69.9; 80.3; 118.1;
‡
127.0; 127.9; 128.4; 128.8; 128.9; 130.2; 138.5; 139.2; 141.6; 151.6. MALDI-MS (DHB): 331.1 (8, [ M ‡ Na] ),
‡
‡
‡
309.2 (8, MH ), 277.1 (100). MALDI-HR-MS (DHB): 309.1601 (MH , C19H21N2O2 ; calc. 309.1598).
(1RS)-1-{5-[(RS)-Methoxy(phenyl)methyl]-1H-imidazol-2-yl}-2-phenylethanol ((Æ)-18). GP 4, starting
from (Æ)-14 (300 mg, 0.72 mmol), afforded (Æ)-18 (173 mg, 78%) after purification by CC (SiO2; AcOEt/
MeOH 99 :1). White solid. M.p. 132 ± 1338. IR (CHCl3): 3683, 3620, 3018, 2976, 2895, 1521, 1476, 1424, 1216,
1
1047, 929. H-NMR (300 MHz, CDCl3): 2.96 (dd, J ˆ 13.7, 8.4, 1 H); 3.29( dd, J ˆ 13.7, 4.4, 1 H); 3.32 (s, 3 H);
4.96 (dd, J ˆ 8.4, 4.4, 1 H); 5.24 (s, 1 H); 6.58 (s, 1 H); 7.13 ± 7.39( m, 10 H). 13C-NMR (75 MHz, CDCl3): 44.0;
56.7; 70.0; 80.3; 126.9; 127.9; 128.3; 128.8; 128.9; 130.2; 138.6; 141.6; 151.6 (2 arom. signals overlapping).
‡
‡
MALDI-MS (DHB): 331.1 (20, [M ‡ Na] ), 309.2 (12, MH ), 277.1 (100). MALDI-HR-MS (DHB): 331.1420
‡
‡
([M ‡ Na] , C19H20N2NaO2 ; calc. 331.1417).
2-[(RS)-Methoxy(phenyl)methyl]-N,N-dimethyl-5-(2-phenylethyl)-1H-imidazole-1-sulfonamide ((Æ)-19).
NaH (60%, 0.144 g, 3.78 mmol) was suspended in pentane (10 ml) and stirred for 10 min. The solvent was
decanted, and the solid was dried under a stream of N2. A soln. of (Æ)-13 (1.00 g, 2.41 mmol) in dry THF (12 ml)

Helvetica Chimica Acta ± Vol. 88 (2005)
723
was added at 08, and the mixture was stirred for 45 min at r.t. After addition of CS2 (0.32 ml, 5.29mmol), the
soln. turned yellow and was stirred for 30 min, then MeI (0.64 ml, 10.20 mmol) was added, whereupon the soln.
turned red and was stirred for an additional h at r.t. The reaction was quenched with H2O, the mixture was
extracted (CH2Cl2), and the org. phases were dried (MgSO4) and concentrated in vacuo. The obtained
intermediate (yellow oil) was dried overnight and then dissolved in PhH (12 ml). Bu3SnH (0.99 ml, 3.61 mmol)
and AIBN (cat. amount) were added, and the soln. was heated to reflux for 5 h. After addition of CH2Cl2, the
mixture was concentrated in vacuo. Purification by CC (SiO2; pentane/AcOEt 75 :25) gave (Æ)-19 (818 mg,
85%). Colorless oil. IR (CHCl3): 3014, 1731, 1454, 1383, 1223, 1160, 1084, 970. 1H-NMR (300 MHz, CDCl3): 2.81
(s, 6 H); 3.04 ± 3.29( m, 4 H); 3.35 (s, 3 H); 5.65 (s, 1 H); 6.46 (s, 1 H); 7.17 ± 7.40 (m, 10 H). 13C-NMR (75 MHz,
CDCl3): 31.0; 31.6; 34.1; 37.9; 56.9; 126.1; 127.6; 128.2; 128.3; 128.8; 134.8; 138.5; 141.0; 151.0 (2 arom. signals
‡
‡
overlapping). MALDI-MS (DHB): 422.2 (8, [M ‡ Na] ); 400.2 (34, MH ); 315.2 (13); 262.2 (17); 261.1 (100).
‡
‡
MALDI-HR-MS (DHB): 400.1787 (MH , C21H26N3O3S ; calc. 400.1689).
2-[(RS)-Methoxy(phenyl)methyl]-5-(2-phenylethyl)-1H-imidazole ((Æ)-22). GP 4, starting from (Æ)-19
(406 mg, 1.02 mmol), afforded (Æ)-22 (250 mg, 84%) after purification by CC (SiO2; AcOEt/MeOH 99 :1).
1
Slightly yellow oil. IR (CHCl3): 3452, 3020, 2976, 1521, 1454, 1424, 1208, 1086, 1047, 928. H-NMR (300 MHz,
CDCl3): 2.98 (s, 4 H); 3.32 (s, 3 H); 5.23 (s, 1 H); 6.50 (s, 1 H); 7.09± 7.37 ( m, 10 H). 13C-NMR (75 MHz, CDCl3):
30.5; 34.6; 56.8; 79.0; 126.2; 126.9; 127.7; 128.2; 128.4; 140.0; 140.6; 147.8 (3 arom. signals overlapping). MALDI-
‡
‡
‡
MS (DHB): 551.3 (14), 331.2 (4, [M ‡ K] ), 321.2 (20), 315.1 (8, [M ‡ Na] ), 293.2 (4, MH ), 261.1 (100).
‡
‡
MALDI-HR-MS (DHB): 293.1651 (MH , C19H21N2O ; calc. 293.1648).
2-[(RS)-Methoxy(phenyl)methyl]-N,N-dimethyl-5-(phenylacetyl)-1H-imidazole-1-sulfonamide ((Æ)-23).
To a soln. of (Æ)-13 (1.00 g, 2.41 mmol) in CH2Cl2 (50 ml), Dess ± Martin periodinane (15% soln. in CH2Cl2,
7.83 ml, 3.61 mmol) was added, and the mixture was stirred for 2.5 h at r.t. The reaction was quenched with H2O,
the mixture was extracted (CH2Cl2), and the org. phases were dried (MgSO4) and concentrated in vacuo.
Purification by CC (SiO2; pentane/AcOEt 67:33) gave (Æ)-23 (470 mg, 47%). Colorless needles. M.p. 898. IR
1
(CHCl3): 3019, 2975, 2896, 1653, 1616, 1521, 1424, 1222, 1046, 929. H-NMR (300 MHz, CDCl3): 2.91 (s, 6 H);
3.35 (s, 3 H); 4.30 (d, J ˆ 15.5, 1 H); 4.38 (d, J ˆ 15.5, 1 H); 5.73 (s, 1 H); 6.57 (s, 1 H); 7.24 ± 7.39( m, 10 H).
13C-NMR (75 MHz, CDCl3): 38.6; 47.4; 57.0; 77.2; 126.9; 127.9; 128.4; 128.5; 129.5; 129.8; 133.5; 135.2; 138.0;
‡
‡
139.3; 146.8; 196.4. MALDI-MS (DHB): 436.1 (4, [M ‡ Na] ), 414.2 (3, MH ), 356.2 (22), 275.1 (100), 273.0
‡
‡
(37). MALDI-HR-MS (DHB): 436.1305 ([M ‡ Na] , C21H23N3NaO4S ; calc.: 436.1307). Anal. calc. for
C21H23N3O4S (413.49): C 61.00, H 5.61, N 10.16; found C 60.82, H 5.68, N 10.00.
2-(1-Benzylethenyl)-5-[(RS)-methoxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-
25). To a soln. of (Æ)-23 (75 mg, 0.18 mmol) in THF (1.5 ml) at À 788, Tebbe reagent (0.5m in PhMe, 0.43 ml,
0.22 mmol) was added dropwise under Ar. After stirring for 45 min at À 788, the mixture was warmed to À 208
and stirred for 80 min. After cooling to À 508, the reaction was quenched with 10% aq. KOH soln., CH2Cl2 was
added at r.t., the mixture was filtered over Celite, and the solvent was removed in vacuo. Purification by CC
(SiO2; pentane/AcOEt 75 :25) afforded (Æ)-25 (7 mg, 9%). Yellowish oil. IR (CHCl3): 3034, 3022, 2935, 1708,
1454, 1390, 1218, 1085. 1H-NMR (300 MHz, CDCl3): 2.70 (s, 6 H); 3.36 (s, 3 H); 3.71 (d, J ˆ 15.9, 1 H); 3.81 (d,
J ˆ 15.9, 1 H); 5.19 (s, 1 H); 5.39( s, 1 H); 5.67 (s, 1 H); 6.56 (s, 1 H); 7.18 ± 7.42 (m, 10 H). 13C-NMR (75 MHz,
CDCl3): 37.8; 42.6; 56.8; 77.2; 120.3; 126.3; 127.5; 128.1; 128.2; 129.2; 129.5; 135.1; 137.8; 138.4; 140.6; 150.5 (1
‡
‡
arom. signal overlapping). MALDI-MS (DHB): 434.2 (3, [M ‡ Na] ), 412.2 (21, MH ), 379.2 (28), 173.1
‡
‡
(100). MALDI-HR-MS (DHB): 412.1686 (MH , C22H26N3O3S ; calc.: 412.1689).
2-(1-Benzylethenyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (30).
A
mixture of 27 (2.10 g,
10.66 mmol), 26 (8.36 g, 18 mmol), [PdCl2(PPh3)2] (748 mg, 1.06 mmol), and Ag2O (2.47 g, 10.66 mmol) in
DMF (25 ml) was degassed in the ultrasonic bath for 30 min under Ar. The mixture was the stirred for 2 d in a
sealed tube at 1008. The solvent was removed in vacuo. The residue was suspended in CH2Cl2 and filtered over
Celite. Purification by CC (SiO2; pentane/AcOEt 67 :33, then AcOEt) gave 30 (2.36 g, 76%). Yellow oil. IR
(CHCl3): 3162, 2970, 2475, 1948, 1863, 1721, 1602, 1529, 1496, 1454, 1420, 1393, 1281, 1178. 1H-NMR (300 MHz,
CDCl3): 2.58 (s, 6 H); 3.84 (s, 2 H); 5.37 (d, J ˆ 0.9, 1 H); 5.58 (d, J ˆ 0.9, 1 H); 7.01 (d, J ˆ 1.6, 1 H); 7.17 ± 7.28
(m, 6 H). 13C-NMR (75 MHz, CDCl3): 37.9; 42.9; 121.0; 121.2; 126.3; 127.3; 128.3; 129.4; 138.3; 139.1; 147.8.
‡
‡
MALDI-MS (DHB): 314.1 (12, [M ‡ Na] ), 301.2 (12), 292.1 (60, MH ), 273.0 (100). MALDI-HR-MS
‡
‡
(DHB): 314.0941 ([M ‡ Na] , C14H17N3NaO2S ; calc. 314.0939).
2-[(E)-1-Formyl-2-phenylethenyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (31). A mixture of 29
(1.50 g, 6.23 mmol), 26 (3.25 g, 7 mmol), [PdCl2(PPh3)2] (490 mg, 0.71 mmol), and Ag2O (1.62 g, 7.00 mmol)
in DMF (25 ml) was degassed in the ultrasonic bath for 30 min under Ar. The mixture was the stirred for 2 d in a
sealed tube at 1008. The solvent was removed in vacuo. The residue was suspended in CH2Cl2 and filtered over
Celite. Purification by CC (SiO2; pentane/AcOEt 67:33, then AcOEt) gave 31 (951 mg, 50%). Colorless

724
Helvetica Chimica Acta ± Vol. 88 (2005)
crystals. M.p. 131 ± 1328. IR (CHCl3): 3156, 2987, 2831, 2253, 1794, 1688, 1631, 1394, 1176. 1H-NMR (300 MHz,
CDCl3): 2.72 (s, 6 H); 7.09( d, J ˆ 1.3, 1 H); 7.11 ± 7.36 (m, 5 H); 7.43 (d, J ˆ 1.3, 1 H); 7.70 (s, 1 H); 9.73 (s, 1 H).
13C-NMR (75 MHz, CDCl3): 38.1; 120.1; 128.9; 129.5; 130.5; 131.5; 121.7; 132.8; 140.2; 154.1; 191.8. MALDI-MS
‡
‡
‡
(DHB): 328.1 (28.4, [M ‡ Na] ), 306.1 (88, MH ), 273.0 (100). MALDI-HR-MS (DHB): 306.0908 (MH ,
‡
C14H16N3O3S ; calc. 306.0907).
S-((2RS)-2-{1-[(Dimethylamino)sulfonyl]-1H-imidazol-2-yl}-3-phenylpropyl) Ethanethioate ((Æ)-32). To
a soln. of 30 (291 mg, 1.00 mmol) in PhH (2 ml), AIBN (20 mg, 0.13 mmol) and freshly distilled AcSH (0.26 ml,
5.00 mmol) were added. The mixture was heated to reflux for 4 h. The solvent was removed in vacuo, and
purification by CC (SiO2; pentane/AcOEt 67: 33, then AcOEt) afforded (Æ)-32 (365 mg, 99%). Colorless oil.
IR (CHCl3): 3020, 1948, 1883, 1709, 1690, 1607, 1535, 1455, 1419, 1392, 1276, 1179, 1150, 1104. 1H-NMR
(300 MHz, CDCl3): 2.27 (s, 3 H); 2.61 (s, 6 H); 2.9 3 (dd, J ˆ 13.7, 6.7, 1 H); 3.22 (dd, J ˆ 13.4, 8.4, 1 H); 3.31 (dd,
J ˆ 13.7, 8.4, 1 H); 3.36 (dd, J ˆ 13.4, 5.6, 1 H); 3.81 (m, 1 H); 7.03 (d, J ˆ 1.6, 1 H); 7.12 ± 7.24 (m, 6 H). 13C-NMR
(75 MHz, CDCl3): 30.6; 33.3; 37.7; 40.3; 40.7; 119.6; 126.4; 127.4; 128.2; 129.2; 138.7; 149.9; 195.1. MALDI-MS
‡
‡
‡
‡
(DHB): 390.1 (25, [M ‡ Na] ), 368.1 (100, MH ). MALDI-HR-MS (DHB): 368.1100 (MH , C16H22N3O3S2
;
calc. 368.1103).
2-(1-Benzylethenyl)-5-[(RS)-hydroxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-
33). GP 2, starting from 30 (291 mg, 1.0 mmol) and PhCHO, afforded (Æ)-33 (125 mg, 31%) after purification
by CC (SiO2; pentane/AcOEt 60 :40). Colorless oil. IR (CHCl3): 3017, 2927, 2854, 1683, 1602, 1495, 1455, 1362,
1262, 1160, 1011, 959. 1H-NMR (300 MHz, CDCl3): 2.68 (s, 6 H); 3.33 (br. s, 1 H); 3.75 (d, J ˆ 16.0, 1 H); 3.82 (d,
J ˆ 16.0, 1 H); 5.27 (d, J ˆ 0.9, 1 H); 5.45 (d, J ˆ 0.9, 1 H); 6.12 (s, 1 H); 6.48 (s, 1 H); 7.18 ± 7.45 (m, 10 H).
13C-NMR (75 MHz, CDCl3): 37.8; 42.7; 67.8; 120.7; 126.5; 127.9; 128.1; 128.2; 129.4; 129.5; 137.1; 137.8; 140.2;
‡
‡
150.5 (1 arom. signal overlapping). MALDI-MS (DHB): 427.3 (51), 420.1 (4, [M ‡ Na] ), 398.2 (27, MH ),
‡
‡
380.1 (6), 313.1 (8), 291.2 (24), 273.1 (100). MALDI-HR-MS (DHB): 398.1540 (MH , C21H24N3O3S ; calc.
398.1538).
2-[(1RS)-1-Benzyl-2-hydroxyethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-35). To a suspension
of 31 (500 mg, 1.64 mmol) in PhH (15 ml), AcOH (0.8 ml, 13.10 mmol) and [Pd(PPh3)4] (18.5 mg, 0.016 mmol)
were added. Subsequently, Bu3SnH (0.83 ml, 3.36 mmol) was added dropwise, and the mixture was stirred for
14 h at r.t. After addition of CH2Cl2, the mixture was poured into ice-H2O and neutralized with NaHCO3. The
org. phase was washed with sat. aq. NaCl soln., and the combined aq. phases were extracted (CH2Cl2). The
combined org. phases were dried (MgSO4) and concentrated in vacuo. Purification by CC (SiO2; AcOEt)
afforded (Æ)-35 (412 mg, 82%). Slightly yellow oil. IR (CHCl3): 3607, 3402, 3019, 2929, 2857, 1472, 1391, 1207,
899. 1H-NMR (300 MHz, CDCl3): 2.73 (s, 6 H); 3.01 (dd, J ˆ 13.1, 9.0, 1 H); 3.18 (dd, J ˆ 13.1, 5.9, 1 H); 3.48 (br.
s, 1 H); 3.60 ± 3.67 (m, 1 H); 3.81 (s, 2 H); 7.02 (d, J ˆ 1.6, 1 H); 7.15 ± 7.27 (m, 6 H). 13C-NMR (75 MHz, CDCl3):
‡
37.3; 38.0; 42.5; 63.2; 119.4; 126.2; 127.2; 128.3; 128.9; 129.2; 139.3. MALDI-MS (DHB): 332.1 (16, [M ‡ Na] ),
‡
‡
‡
310.1 (100, MH ), 279.1 (27). MALDI-HR-MS (DHB): 310.1215 (MH , C14H20N3O3S ; calc. 310.1220).
2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide
((Æ)-36). GP 1, starting from (Æ)-35 (620 mg, 2.00 mmol), afforded (Æ)-36 (673 mg, 79%) after purification by
CC (SiO2; pentane/AcOEt 25 :75). Slightly yellow oil. IR (CHCl3): 3019, 2929, 2857, 1472, 1391, 1207, 899.
1H-NMR (300 MHz, CDCl3): À 0.01 (s, 3 H); À 0.07 (s, 3 H); 0.85 (s, 9H); 2.51 ( s, 6 H); 3.06 (dd, J ˆ 13.1, 5.0,
1 H); 3.18 (dd, J ˆ 13.1, 8.1, 1 H); 3.66 ± 3.76 (m, 2 H); 3.93 ± 4.00 (m, 1 H); 7.03 (d, J ˆ 1.9, 1 H); 7.12 ± 7.18 (m,
6 H). 13C-NMR (75 MHz, CDCl3): À 5.3; 25.8; 26.0; 37.3; 37.7; 44.3; 65.9; 119.7; 126.0; 127.2; 128.1; 129.2; 140.2;
‡
‡
149.7. MALDI-MS (DHB): 446.2 (17, [M ‡ Na] ), 424.2 (100, MH ), 360.2 (13), 317.2 (32). MALDI-HR-MS
‡
‡
(DHB): 424.2074 (MH , C20H34N3O3SSi ; calc. 424.2085).
2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-5-[(SR)-hydroxy(phenyl)methyl]-N,N-di-
methyl-1H-imidazole-1-sulfonamide ((Æ)-37) and 2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-
5-[(RS)-hydroxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-38). GP 2, starting from
(Æ)-36 (460 mg, 1.09mmol), afforded a mixture of diastereoisomers ( Æ)-37 and (Æ)-38 (ratio ca. 2 :1, total
490 mg, 85%) after purification by CC (SiO2; pentane/AcOEt 75 :25). Colorless crystals. M.p. 142 ± 1438. IR
(CHCl3): 3688, 3587, 3029, 2959, 2928, 2857, 1603, 1495, 1454, 1261, 1101. 1H-NMR (300 MHz, CDCl3): À 0.01 (s,
3 H); 0.01 (s, 3 H); 0.03 (s, 3 H); 0.04 (s, 3 H); 0.85 (s, 9H); 0.88 ( s, 9H); 2.41 ( s, 6 H); 2.54 (s, 6 H); 3.02 ± 3.23
(m, 3 H ‡ 3 H); 3.61 ± 3.74 (m, 2 H ‡ 2 H); 3.94 ± 4.01 (m, 1 H ‡ 1 H); 6.02 ± 6.07 (m, 1 H ‡ 1 H); 6.48 (s, 1 H);
6.54 (s, 1 H); 7.11 ± 7.42 (m, 10 H ‡ 10 H). 13C-NMR (75 MHz, CDCl3): À 5.2; 18.4; 26.0; 37.1; 37.3; 37.7; 44.9;
45.2; 65.8; 66.1; 67.6; 67.9; 125.9; 126.6; 126.7; 127.9; 128.1; 128.2; 129.0; 129.1; 129.2; 136.5; 140.3; 140.5; 144.1;
‡
151.2; 152.3; 155.0 (4 aliph. and 6 arom. signals overlapping). MALDI-MS (DHB): 532.5 (2, [M ‡ Na] ), 530.3
‡
‡
(21, MH ), 445.2 (11), 123.3 (17), 406.4 (29), 44 (100). MALDI-HR-MS (DHB): 530.2492 ( MH ,

Helvetica Chimica Acta ± Vol. 88 (2005)
725
‡
C27H40N3O4SSi ; calc. 530.2503). Anal. calc. for C27H39N3O4SSi (529.77): C 61.21, H 7.42, N 7.93; found C 61.11,
H 7.57, N 7.97.
2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-5-[(SR)-methoxy(phenyl)methyl]-N,N-di-
methyl-1H-imidazole-1-sulfonamide ((Æ)-39) and 2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-
5-[(RS)-methoxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-40). GP 5, starting from a
mixture of (Æ)-37 and (Æ)-38 (ratio ca. 2 :1, 490 mg, 0.93 mmol), afforded a mixture of (Æ)-39 and (Æ)-40 (ratio
ca. 2 :1, 492 mg, 98%). Yellow oil. IR (CHCl3): 3020, 2955, 2930, 2857, 1454, 1382, 1216, 1102. 1H-NMR
(300 MHz, CDCl3): À 0.01 (s, 6 H); 0.02 (s, 6 H); 0.85 (s, 9H); 0.87 ( s, 9H); 2.44 ( s, 6 H); 2.47 (s, 6 H); 2.9 5 ±
3.24 (m, 2 H ‡ 2 H); 3.30 (s, 3 H); 3.35 (s, 3 H); 3.56 ± 3.77 (m, 2 H ‡ 2 H); 3.89± 4.03 ( m, 1 H ‡ 1 H); 5.60 (s,
1 H,); 5.60 (s, 1 H); 6.47 (d, J ˆ 0.9, 1 H); 6.63 (d, J ˆ 0.9, 1 H); 7.01 ± 7.49 (m, 10 H ‡ 10 H). 13C-NMR
(75 MHz, CDCl3): À 5.2; 18.3; 25.7; 25.9; 37.0; 37.2; 37.9; 44.8; 45.3; 56.8; 57.0; 65.8; 66.0; 67.3; 125.9; 127.6;
127.8; 128.0; 128.1; 128.2; 128.6; 129.0; 129.1; 129.2; 134.2; 134.6; 138.6; 138.9; 140.2; 140.7; 151.8; 152.4 (4 arom.
‡
and 4 aliph. signals overlapping). MALDI-MS (DHB): 544.3 (13, MH ), 465.3 (11), 419.3 (27), 406.3 (28), 405.2
‡
‡
(100). MALDI-HR-MS (DHB): 544.2667 (MH , C28H42N3O4SSi ; calc. 544.2660).
2-[(1RS)-1-Benzyl-2-hydroxyethyl]-5-[(SR)-methoxy(phenyl)methyl]-N,N-dimethyl-1H-imidazole-1-sul-
fonamide ((Æ)-20) and 2-[(1RS)-1-Benzyl-2-hydroxyethyl]-5-[(RS)-methoxy(phenyl)methyl]-N,N-dimethyl-
1H-imidazole-1-sulfonamide ((Æ)-21). GP 3, starting from a mixture of (Æ)-39 and (Æ)-40 (ratio ca. 2 :1, 450 mg,
0.83 mmol), afforded (Æ)-20 (220 mg, 62%) and (Æ)-21 (123 mg, 35%) after purification and separation by CC
(SiO2; pentane/AcOEt 50 :50).
Data of (Æ)-20: Colorless crystals. M.p. 127 ± 1288. IR (CHCl3): 3402, 3010, 2933, 1454, 1387, 1161, 1085.
1H-NMR (300 MHz, CDCl3): 2.77 (d, J ˆ 0.9, 6 H); 2.96 (dd, J ˆ 13.1, 9.7, 1 H); 3.13 (dd, J ˆ 13.1, 5.0, 1 H); 3.35
(s, 3 H); 3.51 ± 3.57 (m, 1 H); 3.68 ± 3.79( m, 2 H); 5.65 (s, 1 H); 6.48 (s, 1 H); 7.15 ± 7.40 (m, 10 H). 13C-NMR
(75 MHz, CDCl3): 37.4; 37.8; 43.0; 56.9; 62.7; 126.2; 127.6; 128.2; 128.3; 129.0; 129.2; 134.4; 138.4; 139.4; 153.6 (1
‡
aliph. signal under solvent peak, 1 arom. signal overlapping). MALDI-MS (DHB): 452.2 (25, [M ‡ Na ]),
‡
‡
‡
430.2 (72, MH ), 345.2 (16), 291.2 (100), 273.0 (11). MALDI-HR-MS (DHB): 430.1797 (MH , C22H28N3O4S ;
calc. 430.1801).
Data of (Æ)-21: Colorless crystals. M.p. 126 ± 1278. IR (CHCl3): 3421, 3031, 2933, 1454, 1381, 1162, 1086.
1H-NMR (300 MHz, CDCl3): 2.60 (s, 6 H); 3.02 (dd, J ˆ 13.2, 7.6, 1 H); 3.22 (dd, J ˆ 13.2, 7.0, 1 H); 3.32 (s, 3 H);
3.58 ± 3.63 (m, 1 H); 3.76 ± 3.84 (m, 2 H); 5.62 (d, J ˆ 0.9, 1 H); 6.47 (d, J ˆ 0.9, 1 H); 7.16 ± 7.41 (m, 10 H).
13C-NMR (75 MHz, CDCl3): 37.4; 37.5; 43.2; 56.9; 63.7; 77.0; 126.2; 127.6; 128.2; 128.3; 128.3; 129.1; 129.1; 134.7;
‡
‡
138.3; 139.6; 153.1. MALDI-MS (DHB): 452.2 (25, [M ‡ Na] ), 430.2 (64, MH ), 345.2 (15), 291.2 (100), 273.0
‡
‡
(10). MALDI-HR-MS (DHB): 430.1793 (MH , C22H28N3O4S ; calc. 430.1801).
S-((2RS)-2-{1-[(Dimethylamino)sulfonyl]-5-[(SR)-methoxy(phenyl)methyl]-1H-imidazol-2-yl}-3-phenyl-
propyl) Ethanethioate ((Æ)-41). GP 6, starting from (Æ)-20 (100 mg, 0.23 mmol), afforded (Æ)-41 (109mg,
95%) after purification by CC (SiO2; CH2Cl2/AcOEt 83 :17). Colorless crystals. M.p. 119± 120 8. IR (CHCl3):
3014, 2935, 2825, 1727, 1690, 1456, 1380, 1221, 1159. 1H-NMR (300 MHz, CDCl3): 2.25 (s, 3 H); 2.63 (s, 6 H); 2.80
(dd, J ˆ 13.1, 7.8, 1 H); 3.25 ± 3.32 (m, 3 H); 3.36 (s, 3 H); 3.72 ± 3.76 (m, 1 H); 5.63 (s, 1 H); 6.57 (s, 1 H); 7.14 ±
7.36 (m, 10 H). 13C-NMR (75 MHz, CDCl3): 30.6; 32.9; 37.4; 41.0; 41.3; 57.0; 126.3; 127.6; 128.2; 128.2; 129.2;
124.5; 128.6; 138.6; 138.7; 152.7; 195.1 (1 aliph. and 1 arom. signal overlapping). MALDI-MS (DHB): 210.2 (40,
‡
‡
‡
[M ‡ Na] ), 488.2 (53, MH ), 403.2 (26), 273.1 (100). MALDI-HR-MS (DHB): 488.1667 (MH ,
‡
C24H30N3O4S2 ; calc. 488.1672). Anal. calc. for C24H29N3O4S2 (487.64): C 59.11, H 5.99, N 8.62; found C 59.16,
H 6.13, N 8.65. X-Ray: see Fig. 4.
S-((2RS)-2-{1-[(Dimethylamino)sulfonyl]-5-[(RS)-methoxy(phenyl)methyl]-1H-imidazol-2-yl}-3-phenyl-
propyl) Ethanethioate ((Æ)-42). GP 6, starting from (Æ)-21 (90 mg, 0.210 mmol), afforded (Æ)-42 (95 mg, 93%)
after purification by CC (SiO2; pentane/AcOEt 50 :50). Slightly yellow oil. IR (CHCl3): 3014, 2933, 2826, 1952,
1727, 1690, 1454, 1381, 1217, 1161. 1H-NMR (300 MHz, CDCl3): 2.27 (s, 3 H); 2.51 (s, 6 H); 2.90 (dd, J ˆ 13.4, 6.2,
1 H); 3.14 ± 3.36 (m, 3 H); 3.31 (s, 3 H); 3.70 ± 3.77 (m, 1 H); 5.61 (s, 1 H); 6.51 (s, 1 H); 7.12 ± 7.42 (m, 10 H).
13C-NMR (75 MHz, CDCl3): 30.6; 33.6; 37.2; 40.4; 41.1; 56.7; 76.7; 126.3; 127.3; 128.1; 128.2; 129.2; 134.8; 138.5;
‡
‡
139.1; 152.4; 195.0 (2 arom. signals overlapping). MALDI-MS (DHB): 510.1 (28, [M ‡ Na] ), 488.2 (55, MH ),
‡
‡
350.1 (21), 349.1 (100). MALDI-HR-MS (DHB): 488.1660 (MH , C24H30N3O4S2 ; calc. 488.1672).
(2RS)-2-{5-[(SR)-Methoxy(phenyl)methyl]-1H-imidazol-2-yl}-3-phenylpropan-1-ol ((Æ)-44). GP 4, start-
ing from (Æ)-20 (90 mg, 0.21 mmol), afforded (Æ)-44 (55 mg, 82%) after purification by CC (SiO2; AcOEt/
MeOH 95 :5). Colorless oil. IR (CHCl3): 3440, 3007, 2932, 1951, 1813, 1720, 1603, 1583, 1496, 1454, 1085.
1H-NMR (300 MHz, CDCl3): 2.91 (dd, J ˆ 13.4, 8.4, 1 H); 3.01 (dd, J ˆ 13.4, 7.2, 1 H); 3.04 ± 3.13 (m, 1 H); 3.29
(s, 3 H); 3.70 (dd, J ˆ 10.9, 5.6, 1 H); 3.76 (dd, J ˆ 10.9, 3.7, 1 H); 5.22 (s, 1 H); 6.46 (s, 1 H); 7.03 ± 7.37 (m, 10 H).
13C-NMR (75 MHz, CDCl3): 37.4; 42.8; 56.9; 63.3; 79.4; 126.5; 127.3; 128.0; 128.6; 128.7; 129.2; 139.5; 140.3;

726
Helvetica Chimica Acta ± Vol. 88 (2005)
‡
‡
150.4 (2 arom. signals overlapping). MALDI-MS (DHB): 345.2 (10, [M ‡ Na] ), 323.2 (12, MH ), 291.2 (100).
‡
‡
MALDI-HR-MS (DHB): 323.1753 (MH , C20H23N2O2 ; calc. 323.1760).
2-[(1RS)-1-Benzyl-2-sulfanylethyl]-5-[(SR)-methoxy(phenyl)methyl]-1H-imidazol-3-ium Chloride ((Æ)-
1). A suspension of MeONa (108 mg, 2.00 mmol) in MeOH (10 ml) was degassed in an ultrasonic bath for
30 min under Ar and for 10 min under H2. A soln. of (Æ)-41 (100 mg, 0.20 mmol) in MeOH (10 ml), degassed
for 30 min under Ar, was added to the suspension, and the mixture was stirred for 75 min at r.t. CF3COOH
(0.46 ml, 6.00 mmol) was added, and stirring was continued for 105 min. After addition of CH2Cl2 (80 ml), the
mixture was washed with dil. aq. NaHCO3 soln. The aq. phases were extracted (CH2Cl2), and the combined org.
phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by CC (SiO2; AcOEt/MeOH
99 :1), the resulting product was dissolved in 0.1% methanolic HCl soln., and the solvent was removed in vacuo.
The residue was purified 3 times by reversed-phase CC (RP-18 SiO2; 0.1% aq. HCl soln./MeCN 67 :33) to give
(Æ)-1 (31 mg, 41%). Colorless oil. IR (CHCl3): 2958, 2868, 2728, 2638, 1729, 1635, 1604, 1493, 1454, 1379.
1H-NMR (500 MHz, CDCl3): 1.55 (br. s, 1 H); 2.91 (dd, J ˆ 13.7, 4.9, 1 H); 3.12 ± 3.16 (m, 1 H); 3.19( dd, J ˆ 13.8,
8.2, 1 H); 3.27 (s, 3 H); 3.32 (dd, J ˆ 13.8, 7.9, 1 H); 3.89 ± 3.95 (m, 1 H); 5.34 (s, 1 H); 6.60 (s, 1 H); 7.08 ± 7.16 (m,
5 H); 7.29± 7.34 ( m, 5 H); 14.40 (br. s, 2 H). 13C-NMR (125 MHz, CDCl3): 27.1; 39.0; 43.6; 57.1; 76.3; 115.6;
‡
126.9; 127.1; 128.7; 128.8; 128.9; 128.9; 134.5; 136.9; 137.4; 149.0. MALDI-MS (DHB): 361.1 (5, [ M ‡ Na] ),
‡
‡
‡
339.2 (15, MH ), 321.1 (13), 307.1 (100). MALDI-HR-MS (DHB): 339.1523 (MH , C20H23N2OS ; calc.
339.1526).
2-[(1RS)-1-Benzyl-2-sulfanylethyl]-5-[(RS)-methoxy(phenyl)methyl]-1H-imidazol-3-ium Chloride ((Æ)-
43). Analogous procedure as for ( Æ )-1, starting from ( Æ )-42 (70 mg, 0.14 mmol), afforded ( Æ )-43 (23 mg,
43%). Colorless oil. IR (CHCl3): 2958, 2868, 2728, 2639, 1729, 1634, 1603, 1494, 1455, 1379. 1H-NMR (500 MHz,
CDCl3): 1.56 (br. s, 1 H); 2.91 (dd, J ˆ 14.0, 5.0, 1 H); 3.10 ± 3.15 (m, 1 H); 3.17 (dd, J ˆ 13.8, 8.0, 1 H); 3.26 (s,
3 H); 3.29( dd, J ˆ 13.8, 6.1, 1 H); 3.86 ± 3.92 (m, 1 H); 5.36 (s, 1 H); 6.62 (s, 1 H); 7.08 ± 7.17 (m, 5 H); 7.30 ± 7.35
(m, 5 H); 14.40 (br. s, 2 H). 13C-NMR (125 MHz, CDCl3): 27.0; 39.0; 43.6; 57.1; 76.4; 115.5; 126.9; 127.1; 128.7;
‡
128.8; 128.9; 128.9; 134.5; 136.7; 137.5; 148.9. MALDI-MS (DHB): 361.1 (11, [ M ‡ Na] ), 341.1 (19), 339.2 (17,
‡
‡
‡
MH ), 321.1 (7), 307.1 (100). MALDI-HR-MS (DHB): 361.1344 ([M ‡ Na] , C20H22N2NaOS ; calc. 361.1351).
2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-5-[(SR)-hydroxy(naphthalen-2-yl)methyl]-
N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-47) and 2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}-
ethyl)-5-[(RS)-hydroxy(naphthalen-2-yl)methyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-48). GP 2,
starting from (Æ)-36 (0.500 g, 1.180 mmol) and naphthalene-2-carbaldehyde, afforded (Æ)-47 (269mg, 39%),
(Æ)-48 (157 mg, 23%), and a mixture of (Æ)-47 and (Æ)-48 (231 mg, 34%) after purification by CC (SiO2;
pentane/AcOEt 84 :16).
Data of (Æ)-47: White solid. M.p. 160 ± 1618. IR (CHCl3): 3590, 3062, 2956, 2930, 2885, 2857, 1720, 1603,
1568, 1509, 1495, 1472, 1463, 1454, 1418, 1377. 1H-NMR (300 MHz, CDCl3): À 0.01 (s, 3 H); 0.01 (s, 3 H); 0.90 (t,
J ˆ 2.8, 9H); 2.43 ( s, 6 H); 3.10 (dd, J ˆ 13.1, 4.8, 1 H); 3.20 (dd, J ˆ 13.1, 8.4, 1 H); 3.33 (d, J ˆ 4.9, 1 H); 3.62 ±
3.77 (m, 2 H); 3.92 ± 4.00 (m, 1 H); 6.20 (d, J ˆ 4.9, 1 H); 6.54 (d, J ˆ 0.6, 1 H); 7.09± 7.23 ( m, 5 H); 7.42 ± 7.54 (m,
3 H); 7.83 ± 7.91 (m, 4 H). 13C-NMR (75 MHz, CDCl3): À 5.2; 18.4; 26.0; 37.2; 37.3; 45.2; 66.1; 68.0; 124.9; 125.6;
126.0; 126.1; 126.2; 127.6; 127.9; 128.0; 128.1; 129.1; 129.2; 133.0; 133.0; 136.4; 137.8; 140.5; 152.3. MALDI-MS
‡
‡
(DHB): 602.3 (26, [M ‡ Na] ), 580.3 (25, MH ), 562.3 (10), 495.3 (22), 473.3 (8), 455.3 (100). MALDI-HR-MS
‡
‡
(DHB): 580.2665 (MH , C31H42N3O4SSi ; calc. 580.2660). Anal. calc. for C31H41N3O4SSi (579.83): C 64.22, H
7.13, N 7.25; found C 64.18, H 7.29, N 7.38.
Data of (Æ)-48: White solid. M.p. 163 ± 1648. IR (CHCl3): 3590, 3062, 2956, 2929, 2885, 2857, 1720, 1603,
1568, 1509, 1495, 1472, 1463, 1454, 1418, 1375. 1H-NMR (300 MHz, CDCl3): 0.04 (s, 3 H); 0.05 (s, 3 H); 0.84 (t,
J ˆ 2.9, 9 H); 2.56 (s, 6 H); 3.03 (dd, J ˆ 13.2, 5.5, 1 H); 3.16 (dd, J ˆ 13.2, 7.6, 1 H); 3.33 (d, J ˆ 5.0, 1 H); 3.64 ±
3.72 (m, 2 H); 3.91 ± 3.97 (m, 1 H); 6.24 (d, J ˆ 5.0, 1 H); 6.47 (d, J ˆ 0.6, 1 H); 7.12 ± 7.25 (m, 5 H); 7.42 ± 7.52 (m,
3 H); 7.82 ± 7.87 (m, 3 H); 7.9 6 (s, 1 H). 13C-NMR (75 MHz, CDCl3): À 5.2; 18.4; 26.0; 37.4; 37.7; 45.0; 65.8; 67.6;
124.8; 125.3; 126.1; 126.2; 127.6; 127.8; 128.1; 128.2; 129.2; 129.3; 132.9; 133.0; 136.4; 137.7; 140.2; 152.5 (1 arom.
‡
signal overlapping). MALDI-MS (DHB): 580.3 (1, MH ), 562.3 (6), 455.3 (100). MALDI-HR-MS (DHB):
‡
‡
580.2668 (MH , C31H42N3O4SSi ; calc. 580.2660).
2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-5-[(SR)-methoxy(naphthalen-2-yl)methyl]-
N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-49). GP 5, starting from (Æ)-47 (269mg, 0.464 mmol),
afforded (Æ)-49 (260 mg, 94%) after purification by CC (SiO2; pentane/AcOEt 80 :20). Colorless oil. IR
(CHCl3): 3687, 3062, 3022, 3019, 3016, 2955, 2929, 2857, 1603, 1496, 1472, 1463, 1454, 1419. 1H-NMR (300 MHz,
CDCl3): À 0.02 (s, 3 H); 0.01 (s, 3 H); 0.84 (t, J ˆ 3.0, 9H); 2.52 ( s, 6 H); 2.9 6 (dd, J ˆ 13.1, 6.1, 1 H); 3.14 (dd,
J ˆ 13.1, 7.2, 1 H); 3.38 (s, 3 H); 3.65 ± 3.74 (m, 2 H); 3.98 ± 4.02 (m, 1 H); 5.78 (s, 1 H); 6.63 (d, J ˆ 0.9, 1 H);
7.09± 7.21 ( m, 5 H); 7.45 ± 7.53 (m, 3 H); 7.81 ± 7.86 (m, 4 H). 13C-NMR (75 MHz, CDCl3): À 5.2; 18.4; 26.0; 37.4;

Helvetica Chimica Acta ± Vol. 88 (2005)
727
37.9; 44.8; 57.1; 65.7; 77.2; 125.5; 125.9; 126.1; 126.9; 127.6; 127.9; 128.1; 128.9; 129.1; 132.9; 133.1; 134.2; 136.3;
‡
‡
140.2; 152.5 (2 arom. signals overlapping). MALDI-MS (DHB): 616.3 (3, [M ‡ Na] ), 594.3 (19, MH ), 455.3
‡
‡
(100). MALDI-HR-MS (DHB): 594.2823 (MH , C32H44N3O4SSi ; calc. 594.2816).
2-((1RS)-1-Benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-5-[(SR)-methoxy(naphthalen-2-yl)methyl]-
N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-50). GP 5, starting from (Æ)-48 (150 mg, 0.259mmol),
afforded ((Æ)-50 (149mg, 97%) after purification by CC (SiO 2; pentane/AcOEt 80 :20). Colorless solid. IR
(CHCl3): 3687, 3062, 3022, 3016, 2955, 2929, 2857, 1603, 1496, 1472, 1463, 1454, 1419, 1381. 1H-NMR (300 MHz,
CDCl3): 0.00 (s, 6 H); 0.84 (t, J ˆ 3.0, 9H); 2.45 ( s, 6 H); 3.17 ± 3.21 (m, 2 H); 3.33 (s, 3 H); 3.57 ± 3.66 (m, 2 H);
3.89± 3.94 ( m, 1 H); 5.78 (s, 1 H); 6.49( d, J ˆ 0.9, 1 H); 7.07 ± 7.25 (m, 5 H); 7.48 ± 7.53 (m, 3 H); 7.83 ± 7.88 (m,
4 H). 13C-NMR (75 MHz, CDCl3): À 5.2; 18.3; 26.0; 37.1; 45.5; 56.9; 66.0; 125.5; 125.9; 126.1; 126.6; 127.6; 128.0;
128.1; 128.2; 129.3; 133.1; 133.2; 134.6; 136.1; 140.8; 151.9 (2 aliph. and 2 arom. signals overlapping). MALDI-
‡
‡
‡
MS (DHB): 616.3 (3, [M ‡ Na] ), 594.3 (19, MH ), 455.3 (100). MALDI-HR-MS (DHB): 594.2823 (MH ,
‡
C32H44N3O4SSi ; calc. 594.2816).
2-[(1RS)-1-Benzyl-2-hydroxyethyl]-5-[(SR)-methoxy(naphthalen-2-yl)methyl]-N,N-dimethyl-1H-imida-
zole-1-sulfonamide ((Æ)-51). GP 3, starting from (Æ)-49 (260 mg, 0.438 mmol), afforded (Æ)-51 (168 mg, 80%)
after purification by CC (SiO2; pentane/AcOEt 25 :75). Colorless oil. IR (CHCl3): 3679, 3387, 3027, 2935, 2824,
1603, 1497, 1454, 1419, 1382, 1161. 1H-NMR (300 MHz, CDCl3): 2.82 (s, 6 H); 2.9 6 (dd, J ˆ 13.1, 10.0, 1 H); 3.13
(dd, J ˆ 13.1, 4.8, 1 H); 3.40 (s, 3 H); 3.52 ± 3.60 (m, 1 H); 3.70 ± 3.80 (m, 3 H); 5.83 (s, 1 H); 6.48 (d, J ˆ 0.9, 1 H);
7.16 ± 7.30 (m, 5 H); 7.49± 7.54 ( m, 3 H); 7.84 ± 7.90 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 37.5; 38.1; 43.2; 57.1;
62.9; 76.9; 125.6; 126.5; 127.0; 127.9; 128.2; 128.5; 128.6; 129.5; 133.3; 133.5; 134.6; 136.2; 139.7; 154.0 (3 arom.
‡
‡
signals overlapping). MALDI-MS (DHB): 502.2 (16, [M ‡ Na] ), 480.2 (34, MH ), 395.2 (18), 341.2 (100).
‡
‡
MALDI-HR-MS (DHB): 480.1958 (MH , C26H30N3O4S ; calc. 480.1952).
2-[(1RS)-1-Benzyl-2-hydroxyethyl]-5-[(RS)-methoxy(naphthalen-2-yl)methyl]-N,N-dimethyl-1H-imida-
zole-1-sulfonamide ((Æ)-52). GP 3, starting from (Æ)-50 (149mg, 0.251 mmol), afforded ( Æ)-52 (91 mg, 76%)
after purification by CC (SiO2; pentane/AcOEt 33 :66). Colorless solid. M.p. 648. IR (CHCl3): 3681, 3416, 3023,
3016, 2931, 2823, 2398, 2360, 1602, 1497, 1454, 1379, 1224. 1H-NMR (300 MHz, CDCl3): 2.61 (s, 6 H); 3.04 (dd,
J ˆ 13.1, 7.5, 1 H); 3.25 (dd, J ˆ 13.1, 7.5, 1 H); 3.37 (s, 3 H); 3.40 (s, 1 H); 3.61 ± 3.66 (m, 1 H); 3.79(br. s, 2 H);
5.81 (s, 1 H); 6.49( s, 1 H); 7.17 ± 7.30 (m, 5 H); 7.49± 7.54 ( m, 3 H); 7.86 ± 7.90 (m, 4 H). 13C-NMR (75 MHz,
CDCl3): 37.5; 37.7; 43.5; 57.1; 64.1; 76.8; 125.6; 126.5; 127.0; 127.9; 128.3; 128.5; 128.6; 129.5; 129.6; 133.3; 133.5;
‡
135.0; 136.1; 140.0; 153.4 (2 arom. signals overlapping). MALDI-MS (DHB): 502.2 (17, [M ‡ Na] ), 480.2 (31,
‡
‡
‡
MH ), 395.2 (21), 341.2 (100). MALDI-HR-MS (DHB): 480.1956 (MH , C26H30N3O4S , calc. 480.1952). Anal.
calc. for C26H29N3O4S (479.59): C 65.11, H 6.09, N 8.76; found C 65.17, H 6.16, N 8.72.
S-((2RS)-2-{1-[(Dimethylamino)sulfonyl]-5-[(SR)-methoxy(naphthalen-2-yl)methyl]-1H-imidazol-2-yl}-
3-phenylpropyl) Ethanethioate ((Æ)-53). GP 6, starting from (Æ)-51 (168 mg, 0.350 mmol), gave (Æ)-53
(156 mg, 83%) after purification by CC (pentane/AcOEt 80 :20). Yellow oil. IR (CHCl3): 3058, 3031, 3026, 3020,
3010, 2987, 2938, 2825, 1690, 1615, 1571, 1496, 1454, 1418, 1370. 1H-NMR (300 MHz, CDCl3): 2.24 (s, 3 H); 2.61
(s, 6 H); 2.79( dd, J ˆ 13.4, 8.1, 1 H); 3.20 ± 3.33 (m, 3 H); 3.39( s, 3 H); 3.70 ± 3.80 (m, 1 H); 5.80 (s, 1 H); 6.57 (d,
J ˆ 0.9, 1 H); 7.12 ± 7.26 (m, 5 H); 7.46 ± 7.52 (m, 3 H); 7.80 ± 7.87 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 30.6;
32.8; 37.6; 41.1; 41.4; 57.0; 69.9; 125.4; 126.2; 126.4; 126.8; 127.6; 128.0; 128.1; 128.2; 129.2; 133.0; 133.2; 134.5;
‡
136.0; 138.7; 152.8; 156.4; 195.2 (1 arom. signal overlapping). MALDI-MS (DHB): 560.2 (30, [M ‡ Na] ),
‡
‡
538.2 (23, MH ), 453.2 (37), 399.2 (100), 323.2 (27). MALDI-HR-MS (DHB): 560.1643 ([M ‡ Na] ,
‡
C28H31N3NaO4S2 ; calc. 560.1648).
S-((2RS)-2-{1-[(Dimethylamino)sulfonyl]-5-[(RS)-methoxy(naphthalen-2-yl)methyl]-1H-imidazol-2-yl}-
3-phenylpropyl) Ethanethioate ((Æ)-54). GP 6, starting from (Æ)-52 (0.091 g, 0.190 mmol), gave (Æ)-54 (89mg,
87%) after purification by CC (SiO2; pentane/AcOEt 75 :25). Yellowish oil. IR (CHCl3): 3061, 3031, 3019, 3010,
1
2987, 2937, 2825, 1690, 1602, 1571, 1496, 1454, 1418, 1380. H-NMR (300 MHz, CDCl3): 2.26 (s, 3 H); 2.52 (s,
6 H); 2.92 (dd, J ˆ 13.4, 6.2, 1 H); 3.23 (dd, J ˆ 13.4, 7.5, 1 H); 3.29± 3.35 ( m, 2 H); 3.36 (s, 3 H); 3.73 ± 3.80 (m,
1 H); 5.80 (s, 1 H); 6.55 (d, J ˆ 0.9, 1 H); 7.13 ± 7.29 (m, 5 H); 7.48 ± 7.54 (m, 3 H); 7.84 ± 7.89( m, 4 H). 13C-NMR
(75 MHz, CDCl3): 30.7; 33.8; 37.4; 40.4; 41.1; 57.1; 77.0; 125.7; 126.5; 126.6; 127.0; 127.9; 128.3; 128.4; 128.6;
129.5; 129.6; 133.3; 133.5; 135.0; 136.3; 139.5; 152.8; 195.5 (1 arom. signal overlapping). MALDI-MS (DHB):
‡
‡
560.2 (29, [M ‡ Na] ), 538.2 (25, MH ), 453.2 (35), 399.2 (100), 323.2 (36). MALDI-HR-MS (DHB): 560.1642
‡
‡
([M ‡ Na] , C28H31N3NaO4S2 ; calc. 560.1648).
(2RS)-2-{5-[(SR)-Methoxy(naphthalen-2-yl)methyl]-1H-imidazol-2-yl}-3-phenylpropan-1-ol ((Æ)-55).
GP 4, starting from (Æ)-51 (261 mg, 0.54 mmol), afforded (Æ)-55 (151 mg, 75%) after purification by CC
(SiO2; AcOEt/MeOH/NEt3 97 :2 :1). Colorless oil. IR (CHCl3): 3440, 3014, 2936, 2829, 1955, 1888, 1818, 1600,
1
1497, 1452, 1323, 1080, 1018. H-NMR (300 MHz, CDCl3): 2.95 (dd, J ˆ 13.4, 8.1, 1 H); 3.03 (dd, J ˆ 13.4, 7.5,

728
Helvetica Chimica Acta ± Vol. 88 (2005)
1 H); 3.09± 3.15 ( m, 1 H); 3.37 (s, 3 H); 3.77 (dd, J ˆ 10.6, 5.6, 1 H); 3.87 (dd, J ˆ 10.6, 3.4, 1 H); 5.40 (s, 1 H);
6.56 (s, 1 H); 7.10 ± 7.25 (m, 5 H); 7.45 ± 7.51 (m, 3 H); 7.80 ± 7.85 (m, 4 H). 13C-NMR (75 MHz, CDCl3): 37.4;
42.6; 56.9; 63.7; 77.2; 124.9; 125.8; 125.9; 126.1; 126.4; 127.6; 127.9; 128.2; 128.6; 128.9; 133.0; 133.1; 137.5; 139.2;
‡
‡
149.9 (2 arom. signals overlapping). MALDI-MS (DHB): 401.2 (10), 395.2 (20, [M ‡ Na] ), 373.2 (7, MH ),
‡
‡
‡
341.2 (100, [M À MeO] ). MALDI-HR-MS (DHB): 373.1906 (MH , C24H25N2O2 ; calc. 373.1910).
2-[(1RS)-1-Benzyl-2-sulfanylethyl]-5-[(SR)-methoxy(naphthalen-2-yl)methyl]-1H-imidazol-3-ium Chlor-
ide ((Æ)-45). GP 6, starting from (Æ)-55 (70 mg, 0.19mmol), afforded an Ac-protected intermediate that was
purified by CC (SiO2; CH2Cl2/AcOEt 60 :40). The purified intermediate was dissolved in MeOH (4 ml), and the
soln. was degassed under Ar for 30 min. The soln. was added to a suspension of MeONa (63 mg, 1.16 mmol) in
MeOH (4 ml) that was degassed for 30 min under Ar and for 10 min under H2. The mixture was stirred for 2 h at
r.t. After addition of sat. aq. NH4Cl soln. and extraction (CH2Cl2), the org. phases were dried (MgSO4) and
concentrated in vacuo. The residue was immediately purified by CC (SiO2; AcOEt). The resulting product was
dissolved in 0.1% methanolic HCl soln., and the solvent was removed in vacuo. Purification by reversed-phase
CC (RP-18 SiO2; 0.1% aq. HCl soln./MeCN 67:33) gave ((Æ)-45 (17 mg, 21% over 2 steps). White solid. M.p.
80 ± 818. IR (CHCl3): 3675, 3064, 2969, 2829, 2700, 1812, 1756, 1715, 1631, 1600, 1544, 1497, 1457, 1334, 1088.
1H-NMR (300 MHz, CDCl3): 1.53 (t, J ˆ 9.1, 1 H); 2.84 ± 2.93 (m, 1 H); 3.06 ± 3.18 (m, 2 H); 3.24 ± 3.33 (m, 1 H);
3.26 (s, 3 H); 3.85 ± 3.95 (m, 1 H); 5.47 (s, 1 H); 6.60 (s, 1 H); 6.98 ± 7.13 (m, 5 H); 7.24 ± 7.48 (m, 3 H); 7.71 ± 7.82
(m, 4 H). 13C-NMR (75 MHz, CDCl3): 27.2; 39.0; 43.6; 57.2; 76.4; 115.4; 124.0; 126.4; 126.5; 126.7; 126.8; 127.6;
‡
128.0; 128.5; 128.7; 128.8; 132.9; 133.3; 134.2; 134.5; 136.8; 148.9. MALDI-MS (DHB): 411.2 (5, [ M ‡ Na] ),
‡
‡
‡
‡
389.2 (5, MH ), 357.1 (100, [M À MeO] ). MALDI-HR-MS (DHB): 389.1683 (MH , C24H25N2OS ; calc.
389.1682).
5-Benzyl-2-((1RS)-1-benzyl-2-{[(tert-butyl)(dimethyl)silyl]oxy}ethyl)-N,N-dimethyl-1H-imidazole-1-sul-
fonamide ((Æ)-56). At À 788, s-BuLi (1.3m in cyclohexane, 1.1 ml, 1.42 mmol) was added dropwise to a soln. of
(Æ)-36 (0.5 g, 1.18 mmol) in dry THF (30 ml), and the mixture was stirred for 30 min. BnBr (0.42 ml, 3.54 mmol)
was added, followed by stirring for 2 h at À 788 and for 1 h at r.t. The reaction was quenched by addition of 1n
aq. HCl soln., and the mixture was neutralized with sat. aq. NaHCO3 soln. and extracted (CH2Cl2). The org.
phases were dried (MgSO4) and concentrated in vacuo. Purification by CC (SiO2; pentane/AcOEt 80 :20)
afforded (Æ)-56 (407 mg, 67%). Yellow oil. IR (CHCl3): 3693, 3328, 3064, 3033, 3010, 2956, 2929, 1949, 1603,
1495, 1472, 1454, 1377. 1H-NMR (300 MHz, CDCl3): 0.01 (s, 3 H); 0.02 (s, 3 H); 0.87 (s, 9H); 2.33 ( s, 6 H); 3.07
(dd, J ˆ 13.0, 5.3, 1 H); 3.17 (dd, J ˆ 13.0, 8.4, 1 H); 3.69± 3.79( m, 2 H); 3.98 (m, 1 H); 4.02 (d, J ˆ 16.5, 1 H);
4.09( d, J ˆ 16.5, 1 H); 6.59( s, 1 H); 7.10 ± 7.32 (m, 10 H). 13C-NMR (75 MHz, CDCl3): À 5.2; 26.1; 26.5; 32.6;
37.2; 37.8; 45.1; 66.2; 125.7; 126.2; 126.8; 128.4; 128.6; 129.1; 129.6; 132.6; 138.3; 140.8; 152.1. MALDI-MS
‡
‡
(DHB): 536.3 (15, [M ‡ Na] ), 514.3 (100, MH ), 497.3 (38), 407.3 (55). MALDI-HR-MS (DHB): 514.2559
‡
‡
(MH , C27H40N3O3SSi ; calc. 514.2554).
5-Benzyl-2-[(1RS)-1-benzyl-2-hydroxyethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide ((Æ)-57). GP 3,
starting from (Æ)-56 (0.407 g, 0.79mmol), afforded ( Æ)-57 (257 mg, 81%) after purification by CC (SiO2;
pentane/AcOEt 33 :67). Colorless oil. IR (CHCl3): 3394, 3008, 2993, 2883, 1950, 1877, 1810, 1733, 1604, 1577,
1496, 1454, 1379.. 1H-NMR (300 MHz, CDCl3): 2.57 (s, 6 H); 3.06 (dd, J ˆ 13.1, 8.8, 1 H); 3.18 (dd, J ˆ 13.1, 5.9,
1 H); 3.61 ± 3.74 (m, 2 H); 3.77 ± 3.80 (m, 2 H); 4.08 (t, J ˆ 17.7, 2 H); 6.51 (t, J ˆ 1.2, 1 H); 7.17 ± 7.35 (m, 10 H).
13C-NMR (75 MHz, CDCl3): 28.9; 32.5; 37.7; 43.3; 63.4; 126.5; 127.0; 128.2; 128.6; 128.7; 129.1; 129.6; 132.8;
‡
‡
137.7; 139.9; 153.4. MALDI-MS (DHB): 422.2 (20, [M ‡ Na] ), 400.2 (100, MH ), 355.1 (36), 293.2 (62).
‡
‡
MALDI-HR-MS (DHB): 400.1692 (MH , C21H26N3O3S ; calc. 400.1689).
S-((2RS)-2-{5-Benzyl-1-[(dimethylamino)sulfonyl]-1H-imidazol-2-yl}-3-phenylpropyl) Ethanethioate
((Æ)-58). GP 6, starting from (Æ)-57 (0.132 g, 0.330 mmol), afforded (Æ)-58 (139mg, 92%) after purification
by CC (SiO2; pentane/AcOEt 75 :25). Colorless oil. IR (CHCl3): 3688, 3065, 3030, 3023, 3010, 2972, 2360, 1951,
1
1690, 1378, 1226, 1220.. H-NMR (300 MHz, CDCl3): 2.26 (s, 3 H); 2.41 (s, 6 H); 2.90 (dd, J ˆ 13.1, 6.9, 1 H);
3.24 (dd, J ˆ 13.4, 8.4, 1 H); 3.29( dd, J ˆ 13.4, 7.8, 1 H); 3.35 (dd, J ˆ 13.1, 5.6, 1 H); 3.83 ± 3.92 (m, 1 H); 4.06 (s,
2 H); 6.58 (s, J ˆ 0.9, 1 H); 7.13 ± 7.33 (m, 10 H). 13C-NMR (75 MHz, CDCl3): 30.6; 32.3; 33.4; 37.1; 41.0; 41.1;
126.3; 126.5; 128.2; 128.2; 128.3; 128.6; 129.2; 132.5; 137.7; 139.0; 152.1; 195.1. MALDI-MS (DHB): 480.1 (13,
‡
‡
‡
‡
[M ‡ Na] ), 458.2 (78, MH ), 351.2 (100). MALDI-HR-MS (DHB): 458.1571 (MH , C23H28N3O3S2 ; calc.
458.1567).
5-Benzyl-2-[(1RS)-1-benzyl-2-sulfanylethyl]-1H-imidazol-3-ium Chloride ((Æ)-46). To a soln. of (Æ)-58
(80 mg, 0.175 mmol) in MeOH (5 ml), conc. aq. HCl soln. (37%, 0.5 ml) was added, and the mixture was heated
to reflux for 4 h. After cooling to r.t., CH2Cl2 (15 ml) was added, and the mixture was washed with dil. aq.
NaHCO3 soln. The aq. phases were extracted (CH2Cl2), and the combined org. phases were dried (MgSO4) and
concentrated in vacuo. Purification by CC (SiO2; AcOEt/MeOH 99 :1) gave a product, which was dissolved in

Helvetica Chimica Acta ± Vol. 88 (2005)
729
CHCl3. HCl (g) was bubbled through the soln. for 10 min. Concentration in vacuo and purification by reversed-
phase CC (RP-18 SiO2; 0.1% aq. HCl soln./MeCN 67:33) gave (Æ)-46 (15 mg, 46%). Colorless solid. M.p. 53 ±
548. IR (CHCl3): 3089, 3066, 2971, 2862, 2786, 2720, 2654, 1951, 1636, 1604, 1496, 1455. 1H-NMR (300 MHz,
CDCl3): 1.50 (t, J ˆ 8.4, 1 H); 2.88 ± 2.98 (m, 1 H); 3.06 ± 3.24 (m, 2 H); 3.32 (dd, J ˆ 13.7, 7.2, 1 H); 3.85 (br. s,
1 H); 3.94 (s, 2 H); 6.52 (s, 1 H); 7.10 ± 7.26 (m, 10 H); 14.19(br. s, 1 H); 14.48 (br. s, 1 H). 13C-NMR (75 MHz,
CDCl3): 27.6; 31.0; 40.1; 46.2; 116.8; 127.7; 127.8; 129.0; 129.2; 129.4; 129.5; 133.7; 137.6; 138.0; 149.3. MALDI-
‡
‡
‡
MS (DHB): 309.1 (100, MH ). MALDI-HR-MS (DHB): 309.1422 (MH , C19H21N2S ; calc. 309.1420).
X-Ray Crystal Structures. Copies of the data can be obtained free of charge on application to Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033;
e-mail: deposit@ccdc.cam.ac.uk).
Compound (Æ)-14. Crystal data at 293(2) K for C21H25N3O4S (Mr 415.50): monoclinic, space group P2(1)/c,
Dc ˆ 1.268 g cmÀ3, Z ˆ 4, a ˆ 9.787(2), b ˆ 19.841(3), c ˆ 11.365(3) Š, b ˆ 99.56(2)8, Vˆ 2176.3(8) Š3. Enraf
Nonius CAD-4 diffractometer with CuKa radiation (graphite monochromator, l ˆ 1.54184 Š). The structure
was solved by direct methods (SIR97) [60]. The non-H-atoms were refined anisotropically (SHELXL-97) [61].
The H-atoms were calculated at idealized positions and refined with constrained isotropic displacement
parameters. The H(O) atom was located from a difference Fourier map and refined isotropically. Final R(F) ˆ
0.0433, wR(F2) ˆ 0.1522 for 266 parameters, 0 restraints, and 3276 reflections with I > 2s(I) and 4.46 < q <
66.948. Deposition No. CCDC-256717.
Å
Compound (Æ)-41. Crystal data at 202 K for C24H29N3O4S2 (Mr 487.64): triclinic, space group P1, Dc ˆ
1.324 g cmÀ3, Z ˆ 2, a ˆ 9.3213(2), b ˆ 11.5643(2), c ˆ 12.1363(2) Š, a ˆ 83.9220(8)8, b ˆ 74.6721(8)8, g ˆ
76.0488(7)8, Vˆ 1223.23(4) Š3. Bruker-Nonius Kappa CCD diffractometer, MoKa radiation, l ˆ 0.71073. The
structure was solved by direct methods (SIR97) [60]. The non-H-atoms were refined anisotropically (SHELXL-
97) [61]. The H-atoms were calculated at idealized positions and refined with constrained isotropic
displacement parameters. Final R(F) ˆ 0.067, wR(F2) ˆ 0.161 for 414 parameters, 0 restraints, and 5810
reflections with I > 2s(I) and 0.10 < q < 28.708. Deposition No. CCDC-256718.
REFERENCES
[1] A. J. Turner, K. Tanzawa, FASEB J. 1997, 11, 355.
[2] N. D. Rawlings, D. P. Tolle, A. J. Barrett, Nucleic Acids Res. 2004, 32, D160.
[3] M. A. Kerr, A. J. Kenny, Biochem. J. 1974, 137, 477.
Â
Â
[4] B. P. Roques, F. Noble, V. Dauge, M.-C. Fournie-Zaluski, A. Beaumont, Pharmacol. Rev. 1993, 45, 87.
[5] B. Malfroy, J. P. Swerts, A. Guyon, B. P. Roques, J. C. Schwartz, Nature 1978, 276, 523.
[6] R. Matsas, I. S. Fulcher, A. J. Kenny, A. J. Turner, Proc. Natl. Acad. Sci. U.S.A. 1983, 80, 3111.
[7] E. G. Erdös, R. A. Skidgel, FASEB J. 1989, 3, 145.
[8] A. J. Kenny, S. L. Stephenson, FEBS Lett. 1988, 232, 1.
[9] M. A. Shipp, G. E. Tarr, C.-Y. Chen, S. N. Switzer, L. B. Hersh, H. Stein, M. E. Sunday, E. L. Reinherz,
Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 10662.
[10] A. J. Turner, R. E. Isaac, D. Coates, BioEssays 2001, 23, 261.
[11] N. Iwata, S. Tsubuki, Y. Takaki, K. Watanabe, M. Sekiguchi, E. Hosoki, M. Kawashima-Morishima, J.-L.
Lee, E. Hama, J. Sekine-Aizawa, T. C. Saido, Nat. Med. 2000, 6, 143.
[12] N. Iwata, S. Tsubuki, Y. Takaki, K. Shirotani, B. Lu, N. P. Gerard, C. Gerard, E. Hama, H.-J. Lee, T. C.
Saido, Science 2001, 292, 1550.
Â
[13] B. P. Roques, F. Noble, P. Crine, M.-C. Fournie-Zaluski, Methods Enzymol. 1995, 248, 263.
Â
[14] M.-C. Fournie-Zaluski, P. Coric, V. Thery, W. Gonzalez, H. Meudal, S. Turcaud, J.-B. Michel, B. P. Roques,
J. Med. Chem. 1996, 39, 2594.
[15] R. Bohacek, S. De Lombaert, C. McMartin, J. Priestle, M. Grütter, J. Am. Chem. Soc. 1996, 118, 8231.
[16] J. Bralet, J.-C. Schwartz, Trends Pharmacol. Sci. 2001, 22, 106.
[17] J. D. Belluzzi, N. Grant, V. Garsky, D. Sarantakis, C. D. Wise, L. Stein, Nature 1976, 260, 625.
Â
[18] B. P. Roques, M.-C. Fournie-Zaluski, E. Soroca, J. M. Lecomte, B. Malfroy, C. Llorens, J.-C. Schwartz,
Nature 1980, 288, 286.
[19] C. Oefner, A. DꢀArcy, M. Hennig, F. K. Winkler, G. E. Dale, J. Mol. Biol. 2000, 296, 341.
Â
[20] C. Oefner, B. P. Roques, M.-C. Fournie-Zaluski, G. E. Dale, Acta Crystallogr. Sect. D 2004, 60, 392.
[21] F. Hof, F. Diederich, Chem. Commun. 2004, 477.
[22] K. Schärer, M. Morgenthaler, P. Seiler, F. Diederich, D. W. Banner, T. Tschopp, U. Obst-Sander, Helv.
Chim. Acta 2004, 87, 2517.

730
Helvetica Chimica Acta ± Vol. 88 (2005)
[23] R. Paulini, C. Lerner, R. Jakob-Roetne, G. Zürcher, E. Borroni, F. Diederich, ChemBioChem 2004, 5, 1270.
[24] V. Snieckus, Chem. Rev. 1990, 90, 879; V. Snieckus, Pure Appl. Chem. 1990, 62, 2047.
[25] S. Sahli, B. Stump, T. Welti, D. Blum-Kaelin, J. D. Aebi, C. Oefner, H.-J. Böhm, F. Diederich,
ChemBioChem 2004, 5, 996.
[26] S. Sahli, B. Frank, W. B. Schweizer, F. Diederich, D. Blum-Kaelin, J. D. Aebi, H.-J. Böhm, C. Oefner, G. E.
Dale, Helv. Chim. Acta 2005, 88, 731.
[27] P. R. Gerber, K. Müller, J. Comput.-Aided Mol. Des. 1995, 9, 251; Gerber Molecular Design (http://
www.moloc.ch).
Â
[28] N. Dion, H. Le Moual, M.-C. Fournie-Zaluski, B. P. Roques, P. Crine, G. Boileau, Biochem. J. 1995, 311, 623.
Â
[29] C. Marie-Claire, E. Ruffet, S. Antonczak, A. Beaumont, M. OꢀDonohue, B. P. Roques, M.-C. Fournie-
Zaluski, Biochemistry 1997, 36, 13938.
[30] H.-J. Böhm, G. Klebe, Angew. Chem. 1996, 108, 2750; Angew. Chem., Int. Ed. 1996, 35, 2588.
[31] E. A. Meyer, R. K. Castellano, F. Diederich, Angew. Chem. 2003, 115, 1244; Angew. Chem., Int. Ed. 2003,
42, 1210.
[32] S. De Lombaert, L. Blanchard, J. Tan, Y. Sakane, C. Berry, R. D. Ghai, Bioorg. Med. Chem. Lett. 1995, 5, 145.
[33] D. Bur, G. E. Dale, C. Oefner, Protein Eng. 2001, 14, 337.
[34] D. J. Chadwick, R. I. Ngochindo, J. Chem. Soc., Perkin Trans. 1 1984, 481.
[35] B. L. Eriksen, P. Vedsù, S. Morel, M. Begtrup, J. Org. Chem. 1998, 63, 12.
[36] J.-W. Kim, S. M. Abdelaal, L. Bauer, N. E. Heimer, J. Heterocycl. Chem. 1995, 32, 611.
[37] D. H. R. Barton, S. W. McCombie, J. Chem. Soc., Perkin Trans. 1 1975, 1574.
[38] D. S. Noyce, G. T. Stowe, W. Wong, J. Org. Chem. 1974, 39, 2301.
[39] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277.
Â
[40] G. Darzens, C. R. Hebd. Seances Acad. Sci. 1904, 139, 1214; for a recent review on such homologations, see
N. F. Badham, Tetrahedron 2004, 60, 11.
[41] D. J. Peterson, J. Org. Chem. 1968, 33, 780.
[42] G. Wittig, G. Geissler, Liebigs Ann. Chem. 1953, 580, 44; J. M. Hornback, G. S. Proehl, J. Am. Chem. Soc.
1979, 101, 7367.
[43] F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc. 1978, 100, 3611.
[44] T. N. Mitchell, in ꢂMetal-Catalyzed Cross-Coupling Reactions, 2nd edn. Vol. 1ꢀ, Eds. A. de Meijere, F.
Diederich, Wiley-VCH, Weinheim, 2004, p. 125 ± 161.
[45] A. J. Gutierrez, T. J. Terhorst, M. D. Matteucci, B. C. Froehler, J. Am. Chem. Soc. 1994, 116, 5540.
[46] J. Malm, P. Björk, S. Gronowitz, A.-B. Hörnfeldt, Tetrahedron Lett. 1992, 33, 2199.
[47] P. Four, F. Guibe, Tetrahedron Lett. 1982, 23, 1825.
[48] O. Mitsunobu, Synthesis 1981, 1.
[49] L. Zervas, I. Photaki, N. Ghelis, J. Am. Chem. Soc. 1963, 85, 1337.
[50] E. J.-G. Anctil, V. Snieckus, in ꢂMetal-Catalyzed Cross-Coupling Reactions, 2nd. edn. Vol. 2ꢀ, Eds. A. de
Meijere, F. Diederich, Wiley-VCH, Weinheim, 2004, p. 761 ± 813.
[51] G. Parkin, Chem. Rev. 2004, 104, 699.
[52] U. Obst, V. Gramlich, F. Diederich, L. Weber, D. W. Banner, Angew. Chem. 1995, 107, 1874; Angew. Chem.,
Int. Ed. 1995, 34, 1739.
[53] B. Masjost, P. Ballmer, E. Borroni, G. Zürcher, F. K. Winkler, R. Jakob-Roetne, F. Diederich, Chem.±Eur. J.
2000, 6, 971.
[54] E. A. Meyer, R. Brenk, R. Castellano, M. Furler, G. Klebe, F. Diederich, ChemBioChem 2002, 3, 250.
[55] D. Carcache, S. Hörtner, A. Bertogg, C. Binkert, D. Bur, H. P. Märki, A. Dorn, F. Diederich,
ChemBioChem 2002, 3, 1137.
[56] J. v. Braun, M. Kühn, Chem. Ber. 1925, 58, 2168.
[57] H. Suzuki, M. Aihara, H. Yamamoto, Y. Takamoto, T. Ogawa, Synthesis 1988, 236.
[58] C. F. H. Allen, C. O. Edens, Org. Synth., Coll. Vol. III 1955, 731.
[59] K. M. Carvalho, G. Boileau, A. C. M. Camargo, L. Juliano, Anal. Biochem. 1996, 237, 167.
[60] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli, J. Appl.
Crystallogr. 1994, 27, 435.
[61] G. M. Sheldrick, ꢂSHELX-97, Program for the Refinement of Crystal Structuresꢀ, University of Göttingen,
Germany, 1997.
Recevied December 20, 2004