Synthesis of a benzolactone collection using click chemistry

Article abstract of DOI:10.1002/ejoc.200600681

A collection of benzotriazoles consisting of seven compounds was prepared from the propynyl-substituted benzolactone 1 and various azides using click chemistry. The lactone 1 was obtained through a short route by direct esterification of the allylbenzoic

Full text of DOI:10.1002/ejoc.200600681

FULL PAPER
DOI: 10.1002/ejoc.200600681
Synthesis of a Benzolactone Collection using Click Chemistry
Jan Ritschel,[a] Florenz Sasse,[b] and Martin E. Maier*[a]
Keywords: Benzolactones / Triazoles / Click chemistry / Azides / 1,3-Dipole / Natural product analogs
A collection of benzotriazoles consisting of seven compounds
was prepared from the propynyl-substituted benzolactone 1
and various azides using click chemistry. The lactone 1 was
obtained through a short route by direct esterification of the
allylbenzoic acid 9 with the alkynol 7 giving the benzoate 2.
by removal of the silicon protecting group furnished the lac-
tone 1. Two of the benzotriazoles, 17a and 17b, were also
converted into the corresponding phenols to probe the role
of the phenolic OH on the biological activity. All nine benzo-
triazoles showed cytotoxic activity in a L929 mouse fibroblast
The homopropargyl alcohol 7 in turn was obtained by open- assay with IC50 values in the low micromolar range.
ing the epoxide 6 with triisopropylsilyl acetylide. Ring-clos-
ing metathesis of the ester 2 using Grubbs catalyst II followed
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
One goal of chemical genetics is to find a selective small
molecule inhibitor for the most important proteins.[1] This
should be achieved by populating the corresponding chemi-
cal space in a well-balanced manner.[2] In a brute force ap-
proach large numbers of small molecules would be re-
quired, which however might pose enormous technological
and financial challenges. In order to increase the hit rate
and to populate the complementary biological space, re-
course has been taken to natural product libraries which
have shown some promising results. For example, a library
based on the carpanone core structure led to the discovery
of compounds that inhibit vesicular trafficking. Thus, while
carpanone itself is devoid of useful biological activity,[3] the
analog CLL-19 obtained from a combinatorial synthesis
campaign turned out to inhibit exocytosis from Golgi (Fig-
ure 1).[4]
Figure 1. A natural product library based on carpanone and two
priveledged core structures.
Many other natural product-like libraries which are
known are based on so-called privileged structures. This very prominent structural motif among the polyketides is
term refers to molecular subunits, that are associated with the benzolactone core. Several representative examples are
a high degree of biological activity across more than one shown in Figure 2. Frequently, they have a 14-membered
biological target. Representative examples include benzopy- macrolactone ring with various degree of functionalization.
rans and benzolactones (Figure 1). One might argue that Common to the 14-membered benzolactones is the acetate
privileged structures are a consequence of the biosynthetic starter unit resulting in a methyl side chain. Zearalenone is
machinery, meaning they are available by well-established a fungal metabolite with oestrogenic activity.[5] Radicicol
pathways, such as polyketide or terpene biosynthesis. One has antifungal and antibiotic properties which are due to
inhibition of the HSP90.[6] The lactone LL-783,277 turned
out to be a MEK inhibitor,[7] whereas aigialomycin blocks
[a] Universität Tübingen, Institut für Organische Chemie,
Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax: +49-7071-295137
cyclin dependent kinases.[8] While it seems that these ben-
E-mail: martin.e.maier@uni-tuebingen.de
[b] Helmholtz-Zentrum für Infektionsforschung GmbH, Chemis-
che Biologie,
zolactones have a propensity for protein kinases, there is a
selectivity for individual kinase targets.
The ring size in benzolactones may vary. For example in
several benzolactone enamides, the lactone ring is smaller
but the side chain is longer and functionalized. Salicylihala-
mide A, apicularen A and oximidine II are typical examples
Inhoffenstrasse 7, 38124 Braunschweig, Germany
Fax: +49-531-6181-1096
E-mail: florenz.sasse@helmholtz-hzi.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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in drug discovery,[14] chemical biology,[15,16] and other
fields.[17] As the macrolactone core we chose the simplified
salicylihalimide compound 1. This selection was based on
the facile construction of the salicylihalamide core by a
ring-closing metathesis reaction of a suitable ester having a
double bond at both termini. In a previous paper we illus-
trated the synthesis of lactone 1 from the propynyl-6-hep-
tenyl benzoate 2.[18] However, in order for the ring-closing
metathesis reaction with the second generation Grubbs cat-
alyst to succeed, the triple bond required protection with a
bulky triisopropylsilyl group.
In this paper we illustrate a shorter synthesis of the ben-
zoate 2 and also the derivatization of the triple bond of the
lactone 1 by CuI-catalyzed 1,3-dipolar cycloaddition reac-
tions with several azides.
Figure 2. Typical 14-membered benzolactones with a methyl sub-
stituent.
for benzolactone enamides (Figure 3).[9] The enamide side
chain is essential for the biological activity, which is due to
Results
inhibition of V-ATPase,
a membrane bound proton
Synthesis
pump.[10] The functionalized side chain inspired us to de-
sign simplified benzolactones that would carry different res-
idues in this region. The idea was to possibly generate novel
dual mode binding natural product analogs. For this pur-
pose a suitable, easily accessible benzolactone core was re-
quired together with a functional group in the side chain
that has a high diversity potential. In this regard a propynyl
side chain seemed ideal since with the terminal alkyne many
different conjugation reactions seem to be possible. Thus,
Sonogashira couplings or Reppe–Vollhardt reactions are
ideal methods. Another very powerful method for per-
forming ligation-type reactions on terminal alkynes is the
CuI-catalyzed 1,3-dipolar cycloaddition reaction yielding
difunctionalized triazoles.[11–13] This reaction has found use
As described previously,[18] opening of (S)-epichlorohyd-
rin[19] (3) with 4-pentenylmagnesium bromide (4) in pres-
ence of copper cyanide led to the chlorohydrin 5 in 90%
yield (Scheme 1). Epoxide formation under basic conditions
provided the (S)-oxirane 6 in almost quantitative yield as a
colorless oil. In the next step the epoxide 6 was opened with
the lithium anion of triisopropylacetylene in the presence
of boron trifluoride–diethyl ether resulting in the chiral sec-
ondary alcohol 7. This reaction worked quite well and gave
a much higher yield than the corresponding opening with
lithium trimethylsilylacetylide. Esterification of the homo-
propargyl alcohol 7 with the 2-allylbenzoic acid 9 had to be
performed under Mitsunobu conditions in order to reach
the salicylihalamide configuration. While in related cases
this reaction works quite well, in the present situation it
required optimized conditions in order to give a reasonable
yield. Reliable result were obtained with recrystallized
(from MeOH) triphenylphosphane and diisopropyl diazo-
dicarboxylate (DIAD) in toluene as solvent. In contrast, the
Mitsunobu esterification of the alcohol 8, obtained from
the TIPS-alkynol 7 by treatment with tetrabutylammonium
fluoride, gave the corresponding ester in 84% yield.[18]
While we have not further investigated the reason for this
difference one might speculate that the intermediate ox-
aphosphonium salt is attacked intramolecularly by the tri-
ple bond leading to a cylobutenyl cation, stabilized by hy-
perconjugation from the C–Si bond as indicated with struc-
ture A (Scheme 1). Alternatively, a cyclopropane may form.
In both cases, reaction of the cation with a nucleophile
(water etc.) could produce the corresponding ketone. Some-
what related cases from the literature support this hypothe-
sis.[20] In comparison, deprotonation of the alkyne 10 with
nBuLi followed by trapping of the anion with triisopro-
pylsilyl chloride provided the benzoate 2 in 78% yield.[18]
Nevertheless, the direct condensation of alkynol 7 with
acid[21] 9 still was the best option.
Figure 3. Design of dual domain benzolactone analogs utilizing
click chemistry on alkyne 1.
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J. Ritschel, F. Sasse, M. E. Maier
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Figure 4. X-ray structure of macrolactone E-12.
methods. The azide 13a was obtained from the bromide,[22]
whereas for the azide 13b the chloride served as starting
material.[23] For the azides 13c–f the two-step procedure via
the corresponding tosylate followed by SN2 substitution
with sodium azide in DMF, turned out to be more reli-
able.[24] A third method is based on the reaction of an
alcohol with nicotinoyl azide under Mitsunobu conditions
(Ph3P, DEAD).[25] Using this method the azide 13g
(Scheme 3) was prepared from 2-(1H-indol-3-yl)ethanol
(16).
Scheme 1. Synthesis of the benzoate 2 via Mitsunobu esterification
of acid 9 with alkynol 7.
The crucial ring-closing metathesis of 2 was performed
in refluxing toluene (1.1 m) using the Grubbs catalyst 11
(0.05 equiv.) (Scheme 2). The two isomers E-12 and Z-12
could be separated by flash chromatography. They were
formed in an E/Z-ratio of 6:1. Recrystallization of the E
isomer from EtOH gave crystals suitable for X-ray analysis.
A rendering of this structure is shown in Figure 4. One can
clearly see the bent shape of the macrolactone and the ori-
entation of the carboxyl group more or less orthogonal to
the aromatic ring. Finally, treatment of the macrolactone
E-12 with tetrabutylammonium fluoride (TBAF) in THF
induced cleavage of the carbon–silicon bond with liberation
of the terminal alkyne 1.
Scheme 3. Synthesis of the azides 13a–g by SN2 reactions.
With the azide 13a–g in hand, the 1,3-dipolar cycload-
dition reaction of the alkyne 1 leading to the triazoles 17a–
g could be investigated. Accordingly, using conditions put
Scheme 2. Ring-closing metathesis of benzoate 2 using Grubbs cat-
alyst II (11).
The idea in this project was to connect the privileged forward by Sharpless et al.,[12a,26] a solution of the alkyne 1
benzolactone fragment by click chemistry to other subunits (1 equiv.) and an azide (1.2–1.4 equiv.) in degassed ethanol
in order to see whether the new conjugates can be steered was treated with a copper(II) sulfate solution (1.18 equiv.)
to other dual domain binding sites. For this purpose a small and a sodium ascorbate solution (1.5 equiv.) as reducing
collection of azides was prepared according to known agent. In general, the CuI-catalyzed 1,3-dipolar cycload-
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Synthesis of a Benzolactone Collection using Click Chemistry
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dition was complete within 20 h at room temperature. As 17g (Scheme 5). In order to check for the role of the meth-
can be seen in Scheme 4, a range of benzylic azides reacted oxy group as compared to a hydroxy group, the two com-
smoothly under these conditions. The reaction is also com- pounds 17a and 17b were treated with 9-I-9-BBN in
patible with a pyridine ring (cf. structure 17b) and aryl bro- CH2Cl2 for a short time resulting in the hydroxylactones
mides (cf. structures 17d and 17e).
18a (96%) and 18b (67%), respectively. The aromatic pro-
Further examples that successfully could be obtained, in- ton of the triazole typically appears at around 7.40–7.60
clude the piperidine derivative 17f and the indole derivative ppm in CDCl3 as solvent. The two carbon atoms in the
triazole ring resonate at around δ = 122 (C-5Ј) and δ = 144
(C-4Ј) ppm.
Biological Studies
The biological activity of the compounds were tested by
a growth inhibition assay with fibroblast cells of the mouse
cell line L929 (ACC2, DSMZ). The cells were cultivated in
Dulbeco’s modified Eagle medium with high glucose and
10% fetal calf serum at 37 °C and 10% CO2. Aliquots of
120 µL of suspended cells (50,000 mL–1) were given to
60 µL of serial dilutions of the compounds in 96-well micro-
plates. After 5 d the reduction of MTT (3-[4,5-dimethylthi-
azol-2-yl]-2,5-diphenyltetrazolium bromide) was measured
as a parameter of growth and metabolic activity of the cells
and related to control cells that were incubated with the
solvent only. The IC50 values obtained are given in Table 1.
Among the compounds tested the triazole 17f was the most
active one (entry 6). The other compounds were almost
equally active except for 17b and 18b which contain a pyri-
dine moiety in the side chain and were clearly less effi-
cacious in inhibiting cell propagation.
Table 1. Results of a cytotoxicity assay of benzotrialzoles 17a–17g,
18a, and 18b with L929 mouse fibroblasts.
Entry
Compound
IC50 [µgmL–1]
IC50 [µmolL–1]
1
2
3
4
5
6
7
8
9
17a
17b
17c
17d
17e
17f
17g
18a
18b
6
20
9
9
7
5
6
6
20
14
46
19
18
18
10
12
14
48
Scheme 4. Synthesis of the triazoles 17a–e using the corresponding
benzylic azides and lactone 1.
The more active compounds 17a, 17c–g, 18a were
checked for special phenotypic effects with PtK2 potoroo
cells at 12 to 20 µg mL–1. Cells (ATCC CCL-56) grown on
glass coverslips (13 mm diameter) in four well plates were
incubated with the compounds overnight, fixed with cold
(–20 °C) acetone/methanol (1:1) for 10 min and labelled for
endoplasmatic reticulum (ER) with a primary antibody
against GRP-94 (1:1000; Affinity BioReagents) and a sec-
ondary goat anti-rat IgG antibody conjugated with Alexa
Fluor 448 (10 µg mL–1; Molecular Probes). Other cells were
fixed in 4% formalin and stained with Alexa Fluor 594
phalloidin (2 U mL–1; Molecular Probes) for the actin cyto-
skeleton.
Living cells were also stained for lysosomes with an azi-
dotropic reagent (50 nM LysoTracker Red DND-99; Mo-
lecular Probes) at 37 °C for 30 min after they had been in-
Scheme 5. Synthesis of the triazoles 17f and 17g from lactone 1.
Cleavage of the aromatic methyl ether to give the lactone-triazole
conjugates 18a and 18b.
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J. Ritschel, F. Sasse, M. E. Maier
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After addition of boron trifluoride–diethyl ether (3.90 mL, 4.36 g,
30.7 mmol) the mixture was stirred for another h and then slowly
treated with a solution of the epoxide 6 (2.50 g, 19.81 mmol) in
THF (60 mL). The temperature was kept for 1.5 h, and the reaction
was quenched by addition of saturated NH4Cl solution (5 mL).
The mixture was poured into a saturated NH4Cl solution (120 mL)
and extracted with diethyl ether (3ϫ100 mL). The combined or-
ganic extracts were washed with saturated NaHCO3 solution
(240 mL), brine (240 mL), and dried with MgSO4. After filtration
and evaporation of the solvent the crude product was purified by
cubated with the inhibitor for 3.5 h, and examined under
the fluorescent microscope.
We did not find alteration in the ER system that are typi-
cal for V-ATPase inhibitors and no sign that the acidifica-
tion of the lysosomes that is accomplished by the action of
V-ATPases is inhibited. Thus, we do not assume that toxic-
ity of the compounds is due to V-ATPase inhibition. Com-
pared to the control, it seemed that in the treated cells the
actin cortex was more rigid and distinct, pointing to an in-
creased actin polymerization. Whether this is a direct effect flash chromatography (petroleum ether/ethyl acetate, 9:1) to afford
the hydroxyalkyne 7 (6.44 g, 90%) as a light yellow oil. Rf = 0.43
(petroleum ether/ethyl acetate, 9:1). [α]D = +0.67 (c = 2.0, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 1.01–1.05 [m, 21 H, CH(CH3)2],
1.30–1.60 (m, 6 H, CH2), 1.99–2.07 (m, 3 H, OH, 8-H), 2.37 (dd,
J = 16.7, 6.6 Hz, 1 H, 3-H), 2.48 (dd, J = 16.8, 4.9 Hz, 1 H, 3-H),
3.69–3.76 (m, 1 H, CHOH), 4.92 (dd, J = 10.1, 0.8 Hz, 1 H,
CH=CH2), 4.98 (dd, J = 17.1, 1.6 Hz, 1 H, CH=CH2), 5.78 (ddt,
J = 17.1, 10.2, 5.1 Hz, 1 H, CH=CH2) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.2 [CH(CH3)2], 18.6 [CH(CH3)2], 25.0 (C-6), 28.8
(C-3), 28.9 (C-7), 33.6 (C-8), 36.0 (C-5), 69.9 (C-4), 83.5 (C-1),
of the triazoles or just a side effect has to be elucidated.
Conclusions
In this paper we describe a straightforward synthesis of
the benzolactone 1 which carries a propynyl side chain. The
benzolactone was designed with the polyketide-derived nat-
ural product salicylihalamide A as a lead structure. Key re-
actions in the synthesis of THE lactone 1 include opening
of the terminal epoxide 6 with lithium triisopropylsilylace-
tylide giving the homopropargyl alcohol 7. A subsequent
Mitsunobu esterification of 7 with the acid 9 led to the ester
2 which served as a substrate for a ring-closing metathesis
reaction. The bulky triisopropyl group protects the alkyne
during the metathesis reaction. The derived benzolactone 1
was combined with several azides leading to the corre-
sponding triazoles. Growth inhibition assay showed moder-
ate cytotoxicity (IC50 down to 10 µ) for these compounds.
Nevertheless, the concept of combining sophisticated privi-
ledged structures derived from natural products with other
pharmacophores by click chemistry could be of broad inter-
est.
104.7 (C-2), 114.4 (C-10), 138.8 (C-9) ppm. IR (film): ν = 1463,
˜
1641, 2172, 2360, 2865, 2940, 3383 cm–1. MS (EI): m/z (%) = 265
(3), 247 (18), 139 (44), 131 (86), 111 (45), 103 (100), 92 (36), 83
(50), 75 (40), 69 (22). HRMS (EI): [M – CH3]+ calcd. for
C16H29OSi 265.1988, found 265.2038.
(4S)-9-Decen-1-yn-4-ol (8): To a solution of the alkyne 7 (200 mg,
0.65 mmol) in THF (2 mL) was added TBAF (1.94 mL, 1.94 mmol,
1  in THF) at 0 °C. After being stirred for 2 h at room tempera-
ture, the solution was treated with saturated aqueous NaHCO3
solution (10 mL) and the mixture extracted with Et2O (2ϫ10 mL).
The combined extracts were dried (MgSO4), filtered, and concen-
trated. The residue was purified by flash chromatography (petro-
leum ether/ethyl acetate, 9:1) to provide the desired alkynol 8
(89 mg, 90%) as a colorless wax. Rf = 0.23 (petroleum ether/ethyl
1
acetate, 9:1). [α]D = –2.44 (c = 1.0, CH2Cl2). H NMR (400 MHz,
CDCl3): δ = 1.30–1.48 (m, 4 H, 6-H, 7-H), 1.51–1.56 (m, 2 H, 5-
H), 1.94 (br., 1 H, OH) 2.03–2.07 (m, 3 H, CH2=CHCH2, 1-H),
2.27–2.45 (m, 2 H, 3-H), 3.72–3.78 (m, 1 H, CHOH), 4.92–5.01 (m,
2 H, CH2=CH), 5.74–5.84 (m, 1 H, CH2=CH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.0 (C-6), 27.3 (C-3), 28.7 (C-7), 33.6 (C-
8), 36.0 (C-5), 69.8 (C-4), 70.8 (C-1), 80.9 (C-2), 114.5 (C-10), 138.8
(C-9) ppm.
Experimental Section
General: 1H and 13C NMR: Bruker Avance 400 spectrometer; spec-
tra were recorded at 295 K in CDCl3; chemical shifts are calibrated
to the residual proton and carbon resonance of the solvent or to
added TMS: CDCl3 (δH = 7.25, δC = 77.0 ppm), C6D6 (δH = 7.16,
δC = 128.0 ppm). Melting points: Büchi Melting Point B-540, un-
corrected. IR: Jasco FT/IR-430 apparatus (cm–1). MS: Finnigan
Triple-Stage-Quadrupole TSQ-70 (ionizing voltage of 70 eV).
HRMS: Intectra AMD MAT-711A (EI) mass spectrometers. Flash
chromatography: J. T. Baker silica gel, 43–60 µm. Thin-layer
chromatography: Macherey–Nagel Polygram Sil G/UV254 plates.
All solvents used in the reactions were distilled before use. Dry
tetrahydrofuran and toluene were distilled from sodium and benzo-
phenone, whereas dry dichloromethane was distilled from CaCO3.
Acetone was dried by distillation from phosphorus pentoxide. Pe-
troleum ether with a boiling range of 40–60 °C was used. Reactions
were generally run under argon. All commercially available com-
pounds were used as received, unless stated otherwise. (2S)-1-
Chloro-7-octen-2-ol (5) and (2S)-2-(5-hexenyl)oxirane (6) were pre-
pared according to Herb et al.[18] Benzyl azide (13a) was prepared
according to Alvarez.[22]
(1R)-1-[3-(Triisopropylsilyl)-2-propynyl]-6-heptenyl 2-Methoxy-6-(2-
propenyl)benzoate (2): To
a solution of alcohol 7 (3.80 g,
12.31 mmol) and triphenylphosphane (4.84 g, 18.47 mmol, recrys-
tallized from methanol) in toluene (45 mL) was added dropwise a
solution of acid[21] 9 (6.62 g, 34.46 mmol) and diisopropyl azodicar-
boxylate (DIAD) (3.64 mL, 3.74 g, 18.47 mmol) in toluene
(20 mL). After 1.5 h of stirring at room temperature, the solvent
was removed in vacuo and the residue purified by flash chromatog-
raphy (petroleum ether/ethyl acetate, 15:1). Ester 2 (3.03 g, 51%)
was isolated as a colorless oil. Rf = 0.65 (petroleum ether/ethyl
1
acetate, 9:1). [α]D = +33.5 (c = 1.0, CH2Cl2). H NMR (400 MHz,
CDCl3): δ = 1.01–1.05 [m, 21 H, CH(CH3)2], 1.37–1.52 (m, 4 H,
CH2), 1.73–1.97 (m, 2 H, 2Ј-H), 2.07 (br. dt, J = 6.3, 6.3 Hz, 2 H,
5Ј-H), 2.58 (dd, J = 16.8, 8.0 Hz, 1 H, 1ЈЈ-H), 2.73 (dd, J = 16.7,
4.3 Hz, 1 H, 1ЈЈ-H), 3.35 (br. d, J = 6.3 Hz, 2 H, CH2CH=CH2),
3.79 (s, 3 H, OCH3), 4.93 (br. d, J = 10.1 Hz, 1 H, CH=CH2), 5.00
(br. d, J = 17.1 Hz, 1 H, CH=CH2), 5.05 (br. d, J = 10.4 Hz, 1 H,
CH2CH=CH2), 5.05 (br. d, J = 17.2 Hz, 1 H, CH2CH=CH2), 5.13–
5.20 (m, 1 H, 1Ј-H), 5.80 (ddt, J = 17.1, 10.1, 6.7 Hz, 1 H,
CH=CH2), 5.86–5.97 (m, 1 H, CH2CH=CH2), 6.77 (d, J = 8.3 Hz,
(4S)-1-(Triisopropylsilyl)-9-decen-1-yn-4-ol (7): A cooled (–78 °C)
solution of (triisopropylsilyl)acetylene (5.78 g, 31.7 mmol) in THF
(200 mL) was treated with nBuLi (19.8 mL, 31.7 mmol, 1.6  in
hexane) and the suspension was stirred for 1 h at that temperature.
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Synthesis of a Benzolactone Collection using Click Chemistry
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1 H, 3-H), 6.82 (d, J = 7.7 Hz, 1 H, 5-H), 7.27 (m, 1 H, 4-H)
(487 mg, 1.071 mmol) in THF (10 mL) was added TBAF (5.4 mL,
ppm. 13C NMR (100 MHz, CDCl3): δ = 11.2 [CH(CH3)2], 18.55 5.4 mmol, 1  in THF) at 0 °C. After being stirred for 5 h at room
[CH(CH3)2], 24.5 (C-3Ј), 25.4 (C-1ЈЈ), 28.6 (C-4Ј), 32.8 (C-2Ј), 33.6
(C-5Ј), 37.4 (CH2CH=CH2), 55.8 (OCH3), 70.5 (C-3Ј), 73.0 (C-1Ј), NaHCO3 solution (10 mL) and the mixture extracted with Et2O
83.1 (C-3ЈЈ), 103.7 (C-2ЈЈ), 108.9 (C-3), 114.5 (CH=CH2), 116.4 (2ϫ15 mL). The combined extracts were dried (MgSO4), filtered,
(CH2CH=CH2), 121.6 (C-5), 123.8 (C-1), 130.3 (C-4), 136.4 and concentrated. The residue was purified by flash chromatog-
(CH2CH=CH2), 138.3 (C-6), 138.7 (C-6Ј), 156.4 (C-2), 167.7 raphy (petroleum ether/ethyl acetate, 15:1) to provide the desired
(C=O) ppm. IR (film): ν = 1469, 1640, 1727, 2174, 2362, 2864, alkyne 1 (234 mg, 73%) as a colorless wax. Rf = 0.58 (petroleum
temperature, the solution was treated with saturated aqueous
˜
1
2942 cm–1. MS (EI): m/z (%) = 439 (4), 306 (23), 305 (100), 175
ether/ethyl acetate, 9:1). [α]D = –21.9 (c = 1.0, CH2Cl2). H NMR
(42), 147 (23). HRMS (EI): [M – iPr]+ calcd. for C27H39SiO3 (400 MHz, CDCl3): δ = 0.97–1.05 (m, 1 H, 4-H, 5-H, 6-H), 1.16–
439.2668, found 439.2655.
1.26 (m, 1 H, 4-H, 5-H, 6-H), 1.37–1.47 (m, 1 H, 4-H, 5-H, 6-H),
1.51–1.64 (m, 3 H, 4-H, 5-H, 6-H), 1.72–1.81 (m, 1 H, 4-H), 1.95
(br. s, 1 H, 3Ј-H), 2.12–2.21 (m, 1 H, 7-H), 2.55 (d, J = 2.02 Hz, 2
H, 1Ј-H), 3.08 (dd, J = 14.2, 1.3 Hz, 1 H, 10-H), 3.64 (dd, J = 14.0,
10.5 Hz, 1 H, 10-H), 3.79 (s, 1 H, OCH3), 5.07–5.14 (m, 3 H, 3-
H), 5.24–5.32 (m, 1 H, 9-H), 5.35–5.45 (m, 1 H, 8-H), 6.71 (d, J =
7.0 Hz, 1 H, 11-H), 6.79 (d, J = 7.7 Hz, 1 H, 13-H), 7.23 (m, 1 H,
12-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.7 (C-6), 23.9 (C-
5), 24.6 (C-4), 31.4 (C-1Ј), 32.7 (C-7), 37.8 (C-10), 55.8 (OCH3),
69.7 (C-3), 70.2 (C-3Ј), 80.1 (C-2Ј), 109.6 (C-13), 122.4 (C-11),
123.9 (C-14a), 128.9 (C-9), 130.3 (C-12), 132.6 (C-8), 139.4 (C-10a),
14-Methoxy-3-[3-(triisopropylsilyl)-2-propynyl]-3,4,5,6,7,10-hexahy-
dro-1H-2-benzoxacyclododecin-1-one (12): The Grubbs II catalyst
11 (40 mg, 0.047 mmol, 0.05 equiv.) was added under argon to a
solution of the dienoate 2 (450 mg, 0.932 mmol) in toluene
(850 mL). Upon addition of the catalyst the solution turned violet
and after warming became golden-yellow. The mixture was refluxed
for 2 h. After complete reaction (TLC control) and cooling to room
temperature, the solvent was removed in vacuo. The residue was
purified by flash chromatography (petroleum ether/diethyl ether,
30:1) to provide the benzolactones E-12 (319 mg, 75%) and Z-12
(54 mg, 13%) as colorless solids. Recrystallization of E-12 from
ethanol gave crystals suitable for X-ray analysis. CCDC-624498 con-
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
156.9 (C-14), 167.9 (C-1) ppm. IR (film): ν = 1069, 1118, 1278,
˜
1470, 1584, 1723, 2864, 2939, 3291, 3547 cm–1. MS (EI): m/z (%)
= 298 (15), 177 (20), 131 (91), 103 (100), 75 (89), 61 (38). HRMS
(EI): [M]+ calcd. for C19H22O3 298.1569, found 298.1557.
2-(Azidomethyl)pyridine (13b): A solution of 2-(chloromethyl)pyri-
dine hydrochloride (500 mg, 3.05 mmol) in water (18 mL) was
treated with sodium azide (0.79 g, 12.1 mmol), followed by re-
fluxing the mixture for 2 d. After cooling to room temperature,
the mixture was neutrilized with solid NaHCO3. The mixture was
extracted with CH2Cl2 (3ϫ20 mL). The combined organic extracts
were dried with MgSO4, filtered, and concentrated in vacuo. The
residue, a brown oil, was purified by flash chromatography (petro-
leum ether/ethyl acetate, 4:1) to yield azide 13b as a colorless oil
(220.8 mg, 54%). Rf = 0.2 (petroleum ether/ethyl acetate, 9:1).
E-12 (main product): M.p. 104–105 °C. Rf = 0.38 (petroleum ether/
diethyl ether, 15:1). [α]D = –28.3 (c = 1.0, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 0.97–1.10 [m, 22 H, CH(CH3)2, 5-H], 1.21–
1.34 (m, 1 H, 6-H), 1.44–1.55 (m, 1 H, 6-H), 1.58–1.68 (m, 2 H, 5-
H, 7-H), 1.70–1.79 (m, 1 H, 1Ј-H), 1.81–1.91 (m,1 H, 1Ј-H), 2.13–
2.22 (m, 1 H, 7-H), 2.53 (dd, J = 16.4, 9.4 Hz, 1 H, 4-H), 2.83 (dd,
J = 16.4, 4.1 Hz, 1 H, 4-H), 3.15 (d, J = 14.3 Hz, 1 H, 10-H), 3.72
(dd, J = 14.3, 10.3 Hz, 1 H, 10-H), 3.77 (s, 3 H, OCH3), 5.05–5.14
(m, 1 H, 3-H), 5.24–5.34 (m, 1 H, 9-H), 5.36–5.47 (m, 1 H, 8-H),
6.78 (d, J = 7.3 Hz, 1 H, 11-H), 6.78 (d, J = 8.7 Hz, 1 H, 13-H),
7.24 (m, 1 H, 12-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.2
[CH(CH3)2], 18.6 [CH(CH3)2], 19.8 (C-6), 24.4 (C-5), 25.3 (C-4),
31.3 (C-1Ј), 32.7 (C-7), 37.8 (C-10), 55.9 (OCH3), 70.6 (C-3), 82.9
(C-3Ј), 104.0 (C-2Ј), 109.6 (C-13), 122.4 (C-11), 124.0 (C-14a),
128.9 (C-9), 130.3 (C-12), 132.6 (C-8), 139.4 (C-10a), 156.9 (C-14),
General Procedure for the Preparation of Benzylic Tosylates 15c–f:
To a solution of the alcohol in THF (0.25 ) was added nBuLi
(1.6  in hexane, 1.1 equiv.) at 0 °C. After being stirred for 15 min
at 0 °C, TsCl (1.5 equiv.) was added. The resulting mixture was
stirred at 70 °C for 15 h which results in the precipitation of a col-
orless solid. The reaction mixture was diluted with water (15 mL/
mmol of alcohol) and extracted with CH2Cl2 (3ϫ10 mL/mmol of
alcohol). Drying of the organic phase with MgSO4, followed by
filtration and evaporation of the solvent in vacuo, gave the crude
tosylate which was used for the next step without further purifica-
tion.
167.8 (C-1) ppm. IR (KBr): ν = 1069, 1117, 1256, 1275, 1470, 1726,
˜
2864, 2941 cm–1. MS (EI): m/z (%) = 412 (34), 411 (100), 393 (8),
378 (9), 305 (33), 263 (23), 175 (31), 131 (33), 103 (51), 75 (32).
HRMS (EI): [M – iPr]+ calcd. for C25H35SiO3 411.2355, found
411.2383.
Z-12 (minor product): Rf = 0.19 (petroleum ether/diethyl ether,
15:1). [α]D = –3.5 (c = 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3):
δ = 1.05 [br. s, 21 H, CH(CH3)2], 1.37–1.53 (m, 4 H, 5-H, 6-H),
1.85–2.09 (m, 3 H, 1Ј-H, 7-H), 2.31–2.42 (m, 1 H, 7-H), 2.57–2.63
(m, 2 H, 4-H), 3.20 (br. d, J = 15.0 Hz, 1 H, 10-H), 3.51 (dd, J =
15.0, 10.2 Hz, 1 H, 10-H), 3.79 (s, 3 H, OCH3), 5.13–5.22 (m, 1 H,
8-H), 5.29–5.36 (m, 1 H, 3-H), 5.43–5.51 (m, 1 H, 9-H), 6.75 (d, J
= 8.3 Hz, 1 H, 13-H), 6.89 (d, J = 7.7 Hz, 1 H, 11-H), 7.28 (dd, J
= 8.3, 7.7 Hz, 1 H, 12-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
11.2 [CH(CH3)2], 17.8 (C-6), 18.6 [CH(CH3)2], 23.6 (C-4), 24.4 (C-
7), 26.3 (C-5), 28.5 (C-1Ј), 31.6 (C-10), 55.8 (OCH3), 73.3 (C-3),
82.9 (C-3Ј), 103.6 (C-2Ј), 108.6 (C-13), 121.9 (C-11), 123.9 (C-14a),
129.5 (C-8), 130.0 (C-9), 130.4 (C-12), 139.4 (C-10a), 156.2 (C-14),
167.7 (C-1) ppm.
(1,3-Benzodioxol-5-yl)methyl
4-Methylbenzenesulfonate
(15c):
Alcohol 14c (200 mg, 1.31 mmol) in THF (5 mL) was converted to
tosylate 13c using nBuLi (1.6  in hexane, 0.9 mL, 1.45 mmol) and
tosyl chloride (288 mg, 1.51 mmol). Rf = 0.76 (petroleum ether/
ethyl acetate, 2:1). The crude tosylate was used immediately for the
subsequent substitution with sodium azide. Attempted chromatog-
raphy led to decomposition of this tosylate.
(3-Bromophenyl)methyl
4-Methylbenzenesulfonate:
(3-Bro-
mophenyl)methanol (245 mg, 1.31 mmol) in THF (5 mL) was con-
verted to tosylate 15d using nBuLi (1.6  in hexane, 0.9 mL,
1.45 mmol) and tosyl chloride (288 mg, 1.51 mmol). Rf = 0.80 (pe-
troleum ether/ethyl acetate, 3:1).
(4-Bromophenyl)methyl
(3R)-14-Methoxy-3-(2-propynyl)-3,4,5,6,7,10-hexahydro-1H-2-benzo- mophenyl)methanol (245 mg, 1.31 mmol) in THF (5 mL) was con-
xacyclododecin-1-one (1): To a solution of TIPS-alkyne E-12 verted to tosylate 15e using nBuLi (1.6  in hexane, 0.9 mL,
4-Methylbenzenesulfonate:
(4-Bro-
Eur. J. Org. Chem. 2007, 78–87
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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83

J. Ritschel, F. Sasse, M. E. Maier
FULL PAPER
1.45 mmol) and tosyl chloride (288 mg, 1.51 mmol). Rf = 0.80 (pe-
troleum ether/ethyl acetate, 3:1).
(1.2 equiv.) in degassed ethanol (0.04 ) was added a degassed solu-
tion of CuSO4 (1  in degassed water, 1.18 equiv.) plus the degassed
sodium ascorbate solution (2  in degassed water, 1.5 equiv.) at
room temperature. The reaction mixture was stirred at room tem-
perature for several h (TLC control). Typical reaction times are
from 14 to 24 h. After dissapearence of alkyne 1, the solvent was
removed in vacuo and the residue purified by flash chromatography
to give the triazoles.
1-Benzyl-4-piperidinyl 4-Methylbenzenesulfonate: 1-Benzyl-4-piperi-
dinol (251 mg, 1.31 mmol) in THF (5 mL) was converted to tosyl-
ate 15f using nBuLi (1.6  in hexane, 0.9 mL, 1.45 mmol) and tosyl
chloride (288 mg, 1.51 mmol). Rf = 0.72 (petroleum ether/ethyl ace-
tate, 3:1).
General Procedure for the Preparation of the Azides 13c–13f: A mix-
ture of the crude tosylate in dry DMF (0.16 ) and NaN3
(2.6 equiv.) was stirred at 90 °C for 5 h which results in a white
precipitate. The mixture was diluted with water (40 mL/mmol of
tosylate) and extracted with CH2Cl2 (3ϫ15 mL/mmol of tosylate).
The combined organic extracts were dried with MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography to yield azides as colorless oils.
(3R)-14-Methoxy-3-{[1-(phenylmethyl)-1H-1,2,3-triazol-4-yl]meth-
yl}-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one (17a):
Prepared from alkyne 1 (54 mg, 0.181 mmol) and azide 13a (29 mg,
0.218 mmol), yield of lactone 17a 75 mg (96%), colorless amorph-
ous solid. Rf = 0.50 (petroleum ether/ethyl acetate, 1:2). [α]D
=
1
–2.93 (c = 1.0, CH2Cl2). H NMR (600 MHz, CDCl3): δ = 0.94–
1.00 (m, 1 H, 5-H), 1.14–1.21 (m, 1 H, 6-H), 1.33–1.40 (m, 1 H, 6-
H), 1.46–1.61 (m, 4 H, 4-H, 5-H, 7-H), 2.06–2.11 (m, 1 H, 7-H),
3.06–3.10 (m, 3 H, 10-H, CH2-triazole), 3.43 (br. s, 3 H, OCH3),
3.66 (dd, J = 14.3, 10.4 Hz, 1 H, 10-H), 5.17–5.24 (m, 2 H, 3-H,
9-H), 5.30–5.35 (m, 1 H, 8-H), 5.40 (d, J = 15.1 Hz, 1 H, CH2Ph),
5.49 (d, J = 15.1 Hz, 1 H, CH2Ph), 6.67 (d, J = 8.4 Hz, 1 H, 11-
H), 6.72 (d, J = 7.4 Hz, 1 H, 13-H), 7.16–7.20 (m, 3 H, aromatic
H), 7.24–7.26 (m, 3 H, aromatic H), 7.43 (br. s, 1 H, 5Ј-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 19.6 (C-6), 24.5 (C-5), 30.9
(CH2-triazole), 31.8 (C-7), 32.5 (C-4), 37.8 (C-10), 53.9 (CH2Ph),
55.4 (OCH3), 71.7 (C-3), 109.7 (C-13), 122.1 (C-5Ј), 122.7 (C-11),
123.8 (C-14a), 127.8 (C aromatic), 128.5 (C aromatic), 128.7 (C-
9), 128.9 (C aromatic), 130.3 (C aromatic), 132.6 (C-8), 134.9 (C
aromatic), 139.8 (C-10a), 144.4 (C aromatic), 156.7 (C-14), 167.8
(1,3-Benzodioxol-5-yl)methyl Azide (13c): The crude tosylate 14c
(1.31 mmol) in DMF (8 mL) was converted to azide 13c using
NaN3 (221 mg, 3.40 mmol) according to the above procedure. Puri-
fication of the crude product by flash chromatography (petroleum
ether/ethyl acetate) gave 107 mg (46%) of azide 13c. Rf = 0.91 (pe-
troleum ether/ethyl acetate, 1:1). 1H NMR (400 MHz, CDCl3): δ =
4.02 (s, 2 H, CH2N3), 5.77 (s, 2 H, OCH2O), 6.52–6.67 (m, 3 H,
aromatic H) ppm. 13C NMR (100 MHz, CDCl3): δ = 54.6 (CH2),
101.2 (OCH2O), 108.7 (C-7), 121.9 (C-6), 128.9 (C-5), 147.6 (C-
3a), 148.0 (C-7a) ppm.
1-(Azidomethyl)-3-bromobenzene (13d): The crude tosylate 14d
(1.31 mmol) in DMF (8 mL) was converted to azide 13d using
NaN3 (221 mg, 3.40 mmol) according to the above procedure. Puri-
fication of the crude product by flash chromatography (petroleum
ether/ethyl acetate) gave 148 mg (46%) of azide 13d. Rf = 0.92 (pe-
troleum ether/ethyl acetate, 1:1). 13C NMR (100 MHz, CDCl3): δ
= 54.0 (CH2), 122.8 (C-3), 126.6 (C-6), 130.4 (C-5), 131.1 (C-2),
131.4 (C-4), 137.6 (C-1) ppm.
(C-1) ppm. IR (film): ν = 1272, 1461, 1585, 1716, 2931, 3436 cm–1.
˜
MS (EI): m/z (%) = 431 (13), 173 (22), 91 (100), 78 (76). HRMS
(ESI): [M + H]+ calcd. for C26H29N3O3 432.2282, found 432.2282.
(3R)-14-Methoxy-3-{[1-(2-pyridinylmethyl)-1H-1,2,3-triazol-4-
yl]methyl}-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one
(17b): Prepared from alkyne 1 (54 mg, 0.181 mmol) and azide 13b
(29 mg, 0.218 mmol), yield of lactone 17b 69 mg (89%), colorless
amorphous solid. Rf = 0.45 (petroleum ether/ethyl acetate, 1:2).
1-(Azidomethyl)-4-bromobenzene (13e): The crude tosylate 14e
(1.31 mmol) in DMF (8 mL) was converted to azide 13e using
NaN3 (221 mg, 3.40 mmol) according to the above procedure. Puri-
fication of the crude product by flash chromatography (petroleum
ether/ethyl acetate) gave 111 mg (40%) of azide 13e. Rf = 0.92 (pe-
troleum ether/ethyl acetate, 1:1). 13C NMR (100 MHz, CDCl3): δ
= 54.0 (CH2), 122.3 (C-4), 129.8 (C-5, C-3), 131.9 (C-6, C-2), 134.3
(C-1) ppm.
1
[α]D = –3.6 (c = 1.0, CH2Cl2). H NMR (600 MHz, CDCl3): δ =
0.95–1.02 (m, 1 H, 5-H), 1.15–1.22 (m, 1 H, 6-H), 1.34–1.41 (m, 1
H, 6-H), 1.49–1.61 (m, 3 H, 4-H, 5-H, 7-H), 2.07–2.12 (m, 1 H, 4-
H), 3.06–3.11 (m, 3 H, 10-H, CH2-triazole), 3.61 (br. s, 3 H,
OCH3), 3.66 (dd, J = 14.3, 10.7 Hz, 1 H, 10-H), 5.17–5.26 (m, 2
H, 3-H, 9-H), 5.30–5.35 (m, 1 H, 8-H), 5.61 (d, J = 15.4 Hz, 1 H,
CH2Ph), 5.65 (d, J = 15.4 Hz, 1 H, CH2Ph), 6.71 (d, J = 8.5 Hz, 1
H, 11-H), 6.72 (d, J = 7.7 Hz, 1 H, 13-H), 7.09 (d, J = 7.7 Hz, 1
H, 3ЈЈ-H), 7.16–7.21 (m, 2 H, 12-H, 5ЈЈ-H), 7.57 (ddd, J = 7.7, 7.7,
1.5 Hz, 1 H, 4ЈЈ-H), 7.65 (br. s, 1 H, 5Ј-H), 8.49 (d, J = 4.4 Hz, 1
H, 6ЈЈ-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.6 (C-6), 24.5
(C-5), 30.8 (CH2-triazole), 31.9 (C-7), 32.6 (C-4), 37.8 (C-10), 55.4
(CH2-pyridyl), 55.6 (OCH3), 71.8 (C-3), 109.7 (C-13), 122.1 (C-3ЈЈ),
122.7 (C-11), 122.8 (C-5Ј), 123.2 (C-5ЈЈ), 123.8 (C-14a), 128.7 (C-
12), 130.3 (C-4ЈЈ), 132.6 (C-9), 137.3 (C-8), 139.8 (C-10a), 144.5
(C-4Ј), 149.4 (C-6ЈЈ), 154.7 (C-14), 156.7 (C-2ЈЈ), 167.8 (C-1) ppm.
MS (EI): m/z (%) = 432 (18), 340 (42), 187 (22), 174 (47), 145 (84),
93 (100). HRMS (EI): [M + H]+ calcd. for C25H29N4O3 433.2234,
found 433.2233.
4-Azido-1-(phenylmethyl)piperidine (13f): The crude tosylate 14f
(1.31 mmol) in DMF (8 mL) was converted to azide 13f using
NaN3 (221 mg, 3.40 mmol) according to the above procedure. Puri-
fication of the crude product by flash chromatography (petroleum
ether/ethyl acetate) gave 136 mg (48%) of azide 13f. Rf = 0.60 (pe-
troleum ether/ethyl acetate, 1:1). 13C NMR (100 MHz, CDCl3): δ
= 30.9 (C-3, C-5), 51.2 (C-2, C-6), 57.6 (C-4), 62.9 (CH2Ph), 127.1,
128.2, 129.0 138.3 (aromatic C) ppm.
3-(2-Azidoethyl)-1H-indole (13g): DEAD (133 mg, 0.35 mL of a
40% solution in toluene, 0.77 mmol) was added dropwise to a solu-
tion of 2-(1H-indol-3-yl)ethanol (82 mg, 0.51 mmol) and Ph3P
(203 mg, 0.77 mmol) in THF (5 mL) at 0 °C. After stirring for
15 min at 0 °C, the nicotinyol azide (98 mg, 0.66 mmol) was added
in one portion to the stirred mixture. The reaction mixture was
stirred for 12 h during which the mixture reached room tempera-
ture. Then all the volatiles were removed in vacuo and the residue
subjected to flash chromatography (petroleum ether/ethyl acetate,
1:1), providing the azide 13g (96 mg, 49%) as a yellow oil.
(3R)-3-{[1-(1,3-Benzodioxol-5-ylmethyl)-1H-1,2,3-triazol-4-yl]-
methyl}-14-methoxy-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclo-
dodecin-1-one (17c): Prepared from alkyne 1 (30 mg, 0.10 mmol)
and azide 13c (25 mg, 0.14 mmol), yield of lactone 17c 31 mg
(66%), colorless oil. Rf = 0.55 (petroleum ether/ethyl acetate, 2:1).
[α]D = –32.33 (c = 1.3, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ =
0.97–1.07 (m, 1 H, 5-H), 1.18–1.28 (m, 1 H, 6-H), 1.37–1.47 (m, 1
General Procedure for the 1,3-Dipolar CuI-Catalyzed Cycloaddition
Reaction: To a solution of the alkyne (1 equiv.) and the azide
84
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Eur. J. Org. Chem. 2007, 78–87

Synthesis of a Benzolactone Collection using Click Chemistry
FULL PAPER
H, 6-H), 1.53–1.65 (m, 4 H, 4-H, 5-H, 7-H), 2.11–2.18 (m, 1 H, 7-
dodecin-1-one (17f): Prepared from alkyne 1 (30 mg, 0.10 mmol)
H), 3.12–3.16 (m, 3 H, 10-H, CH2-triazole), 3.59 (s, 3 H, OCH3), and azide 13f (30 mg, 0.14 mmol), yield of lactone 17f 32 mg
3.71 (dd, J = 14.5, 10.2 Hz, 1 H, 10-H), 5.24–5.29 (m, 2 H, 3-H, (62%), colorless oil. Rf = 0.15 (petroleum ether/ethyl acetate, 1:1).
9-H), 5.35–5.40 (m, 1 H, 8-H), 5.34 (d, J = 14.8 Hz, 1 H, CH2- [α]D = –28.4 (c = 1.3 in CH2Cl2). H NMR (400 MHz, CDCl3): δ
1
aryl), 5.43 (d, J = 14.8 Hz, 1 H, CH2-aryl), 5.92 (d, J = 7.1 Hz, 2
H, OCH2O), 6.70 (s, 1 H, 4ЈЈ-H), 6.73 (s, 2 H, 6ЈЈ-H, 7ЈЈ-H), 6.76
(d, J = 8.8 Hz, 1 H, 13-H), 6.79 (d, J = 8.1 Hz, 1 H, 11-H), 7.22–
= 0.93–1.03 (m, 1 H, 5-H), 1.15–1.26 (m, 1 H, 6-H), 1.31–1.44 (m,
1 H, 6-H), 1.48–1.60 (m, 4 H, 4-H, 5-H, 7-H), 1.94–2.05 (m, 2 H,
3ЈЈ-H, 5ЈЈ-H), 2.05–2.15 (m, 5 H, 7-H, 2ЈЈ-H, 6ЈЈ-H, 3ЈЈ-H, 5ЈЈ-H),
7.26 (m, 1 H, 12-H), 7.46 (s, 1 H, 5Ј-H) ppm. 13C NMR (100 MHz, 2.93–2.95 (m, 2 H, 2ЈЈ-H, 6ЈЈ-H), 3.06–3.14 (m, 3 H, 10-H, CH2-
CDCl3): δ = 19.7 (C-6), 24.6 (C-5), 31.0 (CH2-triazole), 31.9 (C-7), triazole), 3.48 (s, 2 H, CH2-Ph), 3.66–3.75 (m, 4 H, 10-H, OCH3),
32.6 (C-4), 37.9 (C-10), 53.9 (CH2-aryl), 55.7 (OCH3), 71.8 (C-3), 4.34–4.42 (m, 1 H, 4ЈЈ-H), 5.18–5.26 (m, 2 H, 3-H, 9-H), 5.30–5.39
101.3 (OCH2O), 108.4 (C-13), 108.5 (C-4ЈЈ), 109.8 (C-7ЈЈ), 121.7 (m, 1 H, 8-H), 6.73–6.76 (m, 2 H, 11-H, 13-H), 7.17–7.28 (m, 6 H,
(C-6ЈЈ), 121.9 (C-5Ј), 122.8 (C-11), 123.9 (C-14a), 128.6 (C-5ЈЈ), 12-H, aromatic H), 7.49 (s, 1 H, 5Ј-H) ppm. 13C NMR (100 MHz,
128.8 (C-9), 130.4 (C-8), 132.7 (C-12), 139.9 (C-10a), 144.5 (C-4Ј), CDCl3): δ = 19.8 (C-6), 24.6 (C-5), 31.0 (CH2-triazole), 31.9 (C-7),
147.9 (C-7aЈЈ), 148.3 (C-3aЈЈ), 156.8 (C-14), 167.9 (C-1) ppm.
HRMS (EI): [M + H]+ calcd. for C27H30N3O5 476.2180, found
476.2177.
32.6 (C-4), 32.7 (C-3ЈЈ), 32.8 (C-5ЈЈ), 37.9 (C-10), 52.0 (C-2ЈЈ, C6ЈЈ),
56.0 (OCH3), 58.2 (C-4ЈЈ), 62.7 (CH2-Ph), 71.8 (C-3), 109.9 (C-13),
121.9 (C-5Ј), 122.8 (C-11), 124.0 (C-14a), 127.2 (C-5ЈЈ), 128.3 (C-
5ЈЈЈ, C-3ЈЈЈ), 128.8 (C-8), 129.0 (C-2ЈЈЈ, C-6ЈЈЈ), 130.4 (C-12), 132.7
(C-9), 138.1 (C-1ЈЈЈ), 139.8 (C-10a), 143.7 (C-4Ј), 156.9 (C-14),
167.9 (C-1) ppm. HRMS (EI): [M + H]+ calcd. for C31H39N4O3
515.3017, found 515.3021.
(3R)-3-({1-[(3-Bromophenyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-
14-methoxy-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-
one (17d): Prepared from alkyne 14 (30 mg, 0.10 mmol) and azide
13d (30 mg, 0.14 mmol), yield of lactone 17d 47 mg (92%), color-
less oil. Rf = 0.32 (petroleum ether/ethyl acetate, 1:2). [α]D = –15.1
(c = 2.4, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.99–1.08 (m,
1 H, 5-H), 1.20–1.31 (m, 1 H, 6-H), 1.37–1.48 (m, 1 H, 6-H), 1.54–
1.68 (m, 4 H, 4-H, 5-H, 7-H), 2.12–2.19 (m, 1 H, 7-H), 3.12–3.19
(m, 3 H, 10-H, CH2-triazole), 3.56 (s, 3 H, OCH3), 3.73 (dd, J =
14.1, 10.8 Hz, 1 H, 10-H), 5.22–5.33 (m, 2 H, 3-H, 9-H), 5.36–5.42
(m, 1 H, 8-H), 5.43 (d, J = 15.3 Hz, 1 H, CH2-aryl), 5.53 (d, J =
15.3 Hz, 1 H, CH2-aryl), 6.77 (d, J = 8.4 Hz, 1 H, 13-H), 6.80 (d,
J = 7.6 Hz, 1 H, 11-H), 7.13–7.20 (m, 2 H, 5ЈЈ-H, 6ЈЈ-H), 7.25 (t,
J = 7.9 Hz, 1 H, 12-H), 7.39–7.45 (m, 2 H, 2ЈЈ-H, 4ЈЈ-H), 7.52 (s,
1 H, 5Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.7 (C-6), 24.6
(C-5), 31.0 (CH2-triazole), 31.9 (C-7), 32.5 (C-4), 37.9 (C-10), 53.2
(CH2-aryl), 55.6 (OCH3), 71.6 (C-3), 109.8 (C-13), 122.2 (C-5Ј),
122.8 (C-11), 123.0 (C-3ЈЈ) 123.8 (C-14a), 126.4 (C-6ЈЈ), 128.7 (C-
8), 130.4 (C-12), 130.6 (C-5ЈЈ) 130.8 (C-4ЈЈ), 131.7 (C-2ЈЈ), 132.8
(C-9), 137.2 (C-1ЈЈ), 139.9 (C-10a), 144.8 (C-4Ј), 156.7 (C-14), 167.8
(C-1) ppm. HRMS (EI): [M + H]+ calcd. for C26H29BrN3O3
510.1387, found 510.1389.
(3R)-3-({1-[2-(1H-Indol-3-yl)ethyl]-1H-1,2,3-triazol-4-yl}methyl)-
14-methoxy-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-
one (17g): Prepared from alkyne 1 (30 mg, 0.10 mmol) and azide
13g (19 mg, 0.12 mmol), yield of lactone 17g 28 mg (58%), color-
less amorphous solid. Rf = 0.48 (petroleum ether/ethyl acetate, 2:1).
[α]D = –22.7 (c = 1.3, CH2Cl2). 1H NMR (400 MHz, C6D6): δ =
0.87–0.96 (m, 1 H, 5-H), 1.23–1.68 (m, 6 H, 4-H, 5-H, 6-H, 7-H),
1.99–2.06 (m, 1 H, 7-H), 2.94–3.14 (m, 6 H, 10-H, OCH3, 2ЈЈ-H),
3.18 (dd, J = 14.9, 6.1 Hz, 1 H, CH2-triazole), 3.32 (dd, J = 14.9,
5.8 Hz, 1 H, CH2-triazole), 4.03 (dd, J = 14.2, 10.4 Hz, 1 H, 10-
H), 4.11 (t, J = 6.7 Hz, 1 H, 1ЈЈ-H), 5.21–5.33 (m, 1 H, 9-H), 5.38–
5.51 (m, 2 H, 3-H, 8-H), 6.32 (s, 1 H, 2ЈЈЈ-H), 6.33 (d, J = 8.3 Hz,
1 H, 13-H), 6.60 (d, J = 7.3 Hz, 1 H, 11-H), 6.72 (s, 1 H, 5Ј-H),
6.97 (t, J = 8.0 Hz, 1 H, 12-H), 7.07 (d, J = 7.8 Hz, 1 H, 7ЈЈЈ-H),
7.12–7.25 (m, 2 H, 5ЈЈЈ-H, 6ЈЈЈ-H), 7.34 (s, 1 H, NH), 7.40 (d, J =
7.3 Hz, 1 H, 4ЈЈЈ-H) ppm. 13C NMR (100 MHz, C6D6): δ = 20.0
(C-4), 24.9 (C-3), 26.7 (C-2ЈЈ), 31.3 (CH2-triazole), 32.4 (C-6), 33.2
(C-7), 38.2 (C-10), 50.3 (C-1ЈЈ), 55.3 (OCH3), 72.6 (C-3), 110.0 (C-
13), 111.2 (C-3ЈЈЈ), 111.7 (C-7ЈЈЈ), 118.5 (C-4ЈЈЈ), 119.7 (C-5ЈЈЈ),
122.2 (C-6ЈЈЈ), 122.6 (C-5Ј), 122.8 (C-2ЈЈЈ), 123.1 (C-11), 125.0 (C-
14a), 127.3 (C-3aЈЈЈ), 129.4 (C-9), 130.3 (C-12), 132.7 (C-8), 136.7
(C-7aЈЈЈ), 140.2 (C-10a), 143.6 (C-4Ј), 157.4 (C-14), 167.9 (C-1)
ppm. HRMS (EI): [M+ Na]+ calcd. for C29H32N4O3Na 507.2365,
found 507.2366.
(3R)-3-({1-[(4-Bromophenyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)-
14-methoxy-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-
one (17e): Prepared from alkyne 1 (30 mg, 0.10 mmol) and azide
13e (30 mg, 0.14 mmol), yield of lactone 17e 34 mg (67%), colorless
oil. Rf = 0,11 (petroleum ether/ethyl acetate, 1:1). [α]D = –29.3 (c =
1.7, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.97–1.07 (m, 1 H,
5-H), 1.18–1.29 (m, 1 H, 6-H), 1.36–1.47 (m, 1 H, 6-H), 1.52–1.69
(m, 4 H, 4-H, 5-H, 7-H), 2.12–2.19 (m, 1 H, 7-H), 3.10–3.17 (m, 3
H, 10-H, CH2-triazole), 3.52 (s, 3 H, OCH3), 3.72 (dd, J = 14.1,
10.6 Hz, 1 H, 10-H), 5.21–5.31 (m, 2 H, 3-H, 9-H), 5.33–5.42 (m,
1 H, 8-H), 5.40 (d, J = 15.3 Hz, 1 H, CH2-aryl), 5.49 (d, J =
15.3 Hz, 1 H, CH2-aryl), 6.75 (d, J = 8.4 Hz, 1 H, 13-H), 6.79 (d,
J = 7.4 Hz, 1 H, 11-H), 7.08 (d, J = 7.9 Hz, 2 H, 2ЈЈ-H, 6ЈЈ-H),
7.25 (t, J = 8.1 Hz, 1 H, 12-H), 7.40 (d, J = 8.1 Hz, 2 H, 3ЈЈ-H,
5ЈЈ-H), 7.47 (s, 1 H, 5Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 19.7 (C-6), 24.6 (C-5), 31.1 (CH2-triazole), 32.0 (C-7), 32.5 (C-
4), 37.9 (C-10), 53.3 (CH2-aryl), 55.6 (OCH3), 71.7 (C-3), 109.8 (C-
13), 122.2 (C-5Ј), 122.7 (C-4ЈЈ), 122.8 (C-11), 123.7 (C-14a), 128.7
(C-8), 129.5 (C-2ЈЈ, C-6ЈЈ), 130.5 (C-12), 132.1 (C-3ЈЈ, C-5ЈЈ), 132.8
(C-9), 134.0 (C-1ЈЈ), 139.9 (C-10a), 144.8 (C-4Ј), 156.7 (C-14), 167.8
(C-1) ppm. HRMS (EI): [M + H]+ calcd. for C26H29BrN3O3
510.1387, found 510.1390.
(3R)-14-Hydroxy-3-{[1-(phenylmethyl)-1H-1,2,3-triazol-4-yl]-
methyl}-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one
(18a): To a stirred solution of the macrolactone 17a (89 mg,
0.206 mmol) in dry CH2Cl2 (4 mL) was added quickly 9-iodo-9-
BBN (0.82 mL, 0.82 mmol, 1  in hexane, 4 equiv.). After 90 s, the
reaction was quenched with methanol (12 mL) and the mixture
stirred for 1 h. The solvent was removed in vacuo. In order to re-
move the formed methyl borinate, high vacuum (oil pump) was
applied to the flask. This operation (addition of methanol and
evaporation of the volatiles) was repeated twice more. Purification
of the residue by flash chromatography (petroleum ether/ethyl ace-
tate, 2:1) provided the phenol derivative 18a (83 mg, 96%) as a
colorlessamorphoussolid.Rf=0.53(petroleumether/ethylacetate,2:1).
[α]D = –5.18 (c = 1.0, CH2Cl2). 1H NMR (600 MHz, C6D6): δ =
0.89–0.99 (m, 1 H, 5-H), 1.12–1.24 (m, 2 H, 4-H, 6-H), 1.28–1.37
(m, 1 H, 6-H), 1.39–1.47 (m, 2 H, 4-H, 5-H), 1.48–1.55 (m, 1 H,
7-H), 2.00–2.06 (m, 1 H, 7-H), 2.50 (dd, J = 14.9, 2.8 Hz, 1 H,
(3R)-14-Methoxy-3-({1-[1-(phenylmethyl)-4-piperidinyl]-1H-1,2,3- CH2-triazole), 2.65 (dd, J = 14.9, 9.0 Hz, 1 H, CH2-triazole), 3.09–
triazol-4-yl}methyl)-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclo- 3.12 (m, 1 H, 10-H), 4.10 (dd, J = 14.0, 10.3 Hz, 1 H, 10-H), 4.78
Eur. J. Org. Chem. 2007, 78–87
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
85

J. Ritschel, F. Sasse, M. E. Maier
FULL PAPER
[3]
For total syntheses of carpanone, see: a) O. L. Chapman, M. R.
Engel, J. P. Springer, J. C. Clardy, J. Am. Chem. Soc. 1971, 93,
6696–6698; b) I. R. Baxendale, A.-L. Lee, S. V. Ley, J. Chem.
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(br. s, 2 H, CH2Ph), 5.22–5.31 (m, 2 H, 3-H, 9-H), 5.38–5.43 (m, 1
H, 8-H), 6.46 (s, 1 H, 5Ј-H), 6.53 (d, J = 7.0 Hz, 1 H, aromatic H),
6.82 (m, 2 H, aromatic H), 6.98–7.02 (m, 4 H, aromatic H), 7.10
(d, J = 7.7 Hz, 1 H, aromatic H), 7.27 (br. s, 3 H, aromatic H, OH)
ppm. 13C NMR (150 MHz, C6D6): δ = 20.0 (C-6), 25.3 (C-5), 30.5
(CH2-triazole), 32.7 (C-7), 33.4 (C-4), 38.7 (C-10), 53.8 (CH2Ph),
70.3 (C-3), 117.8 (C aromatic), 120.8 (C-14a), 121.6 (C-11), 121.7
(C-5Ј), 128.3 (C aromatic), 128.5 (C-9), 129.0 (C-12), 129.9 (C-8),
131.7 (C aromatic), 132.7 (C aromatic), 135.2 [C aromatic (quater-
nary)], 140.7 (C-10a), 144.0 (C-4Ј), 157.5 (C-14), 167.7 (C-1) ppm.
MS (EI): m/z (%) = 417 (26), 226 (6), 173 (22), 91 (100). HRMS
(ESI): [M + H]+ calcd. for C25H28N3O3 418.2125, found 418.2125.
[4]
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B. C. Goess, R. N. Hannoush, L. K. Chan, T. Kirchhausen,
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[8]
(3R)-14-Hydroxy-3-{[1-(2-pyridinylmethyl)-1H-1,2,3-triazol-4-
yl]methyl}-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one
(18b): To a stirred solution of the macrolactone 17b (64 mg,
0.148 mmol) in dry CH2Cl2 (3 mL) was added quickly 9-iodo-9-
BBN (0.59 mL, 0.59 mmol, 1  in hexane, 4 equiv.). After 90 s, the
reaction was quenched with methanol (9 mL) and the mixture
stirred for 1 h. The solvent was removed in vacuo. In order to re-
move the formed methyl borinate, high vacuum (oil pump) was
applied to the flask. This operation (addition of methanol and
evaporation of the volatiles) was repeated twice more. Purification
of the residue by flash chromatography (ethyl acetate) provided the
phenol derivative 18b (42 mg, 67%) as a colorless amorphous solid.
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L. Yet, Chem. Rev. 2003, 103, 4283–4306.
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[11]
[12]
[13]
[14]
1
Rf = 0.51 (ethyl acetate). [α]D = –5.05 (c = 2.1, CH2Cl2). H NMR
(600 MHz, C6D6): δ = 0.90–0.98 (m, 1 H, 5-H), 1.11–1.17 (m, 1 H,
6-H), 1.17–1.24 (m, 1 H, 4-H), 1.27–1.34 (m, 1 H, 6-H), 1.39–1.46
(m, 2 H, 4-H, 5-H), 1.48–1.54 (m, 1 H, 7-H), 2.01–2.06 (m, 1 H,
7-H), 2.53 (dd, J = 14.9, 2.8 Hz, 1 H, CH2-triazole), 2.66 (dd, J =
14.9, 9.0 Hz, 1 H, CH2-triazole), 3.10 (ddd, J = 14.0, 5.2, 2.6 Hz,
1 H, 10-H), 4.10 (dd, J = 14.0, 10.3 Hz, 1 H, 10-H), 5.04 (d, J =
15.4 Hz, 1 H, CH2-pyridyl), 5.08 (d, J = 15.4 Hz, 1 H, CH2-pyr-
idyl), 5.20–5.30 (m, 2 H, 3-H, 9-H), 5.38–5.43 (m, 1 H, 8-H), 6.51–
6.54 (m, 2 H, 5ЈЈ-H, 11-H), 6.66 (d, J = 7.7 Hz, 1 H, 3ЈЈ-H), 6.84
(s, 1 H, 5Ј-H), 6.92 (ddd, J = 7.7, 7.7, 1.8 Hz, 1 H, 4ЈЈ-H), 7.00
(dd, J = 8.1, 7.4 Hz, 1 H, 12-H), 7.08 (dd, J = 8.1, 0.7 Hz, 1 H,
13-H), 8.27 (d, J = 4.4 Hz, 1 H, 6ЈЈ-H) ppm. 13C NMR (100 MHz,
C6D6): δ = 19.9 (C-6), 25.2 (C-5), 30.4 (CH2-triazole), 32.7 (C-7),
33.3 (C-4), 38.7 (C-10), 55.4 (CH2-pyridyl), 70.3 (C-3), 117.7 (C-
13), 121.1 (C-14a), 121.5 (C-5ЈЈ), 122.3 (C-3ЈЈ), 122.7 (C-5Ј), 123.0
(C-11), 129.8 (C-9), 131.6 (C-12), 132.8 (C-8), 137.0 (C-4ЈЈ), 140.6
(C-10a), 143.9 (C-4Ј), 149.5 (C-6ЈЈ), 155.0 (C-14), 157.3 (C-2ЈЈ),
167.7 (C-1) ppm. MS (EI): m/z (%) = 418 (30), 174 (16), 145 (83),
109 (31), 93 (100). HRMS (ESI): [M + H]+ calcd. for C24H27N4O3
419.2078, found 419.2077.
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[15]
Supporting Information Available: (see also the footnote on the first
page of this article): Copies of 1H and 13C NMR spectra of the
alcohols 7, 8, and all triazoles.
Acknowledgments
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Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged.
We also thank the students Christine Wintterle and Jochen Neumaier
for skilful assistance. Finally, we want to thank Bettina Hinkel-
mann for excellent technical assistance. Partial support from COST
D28 is acknowledged as well.
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86
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 78–87

Synthesis of a Benzolactone Collection using Click Chemistry
FULL PAPER
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Received: August 4, 2006
Published Online: November 9, 2006
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