A convenient entry to new C-7-modified colchicinoids through azide alkyne [3+2] cycloaddition: Application of ring-contractive rearrangements

Article abstract of DOI:10.3987/COM-10-S(E)117

Reliable procedures for the preparation of azides derived from colchicine (1), allocolchicine (3) and N-acetylcolchinol (4a) were developed. These azides were then employed in Cu-catalyzed Huisgen-Sharpless [3+2] cycloaddition ("click") reactions with alkynes under microwave irradiation. The method developed opens a convenient and efficient access to libraries of new C-7-modified colchicinoids (triazole derivatives). In addition, a plausible mechanistic rationale for the colchicine-allocolchicine rearrangement is suggested. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)117

HETEROCYCLES, Vol. 82, No. 2, 2011
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HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1585 - 1600. © The Japan Institute of Heterocyclic Chemistry
Received, 30th August, 2010, Accepted, 13th October, 2010, Published online, 28th October, 2010
DOI: 10.3987/COM-10-S(E)117
A CONVENIENT ENTRY TO NEW C-7-MODIFIED COLCHICINOIDS
THROUGH AZIDE ALKYNE [3+2] CYCLOADDITION: APPLICATION
OF RING-CONTRACTIVE REARRANGEMENTS
Norman Nicolaus,a Jens Reball,a Nikolay Sitnikov,b Janna Velder,a Andreas
Termath,a Alexey Yu. Fedorov,b and Hans-Günther Schmalza*
a Department für Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
b
E-mail: schmalz@uni-koeln.de. Department of Chemistry, Nizhny Novgorod
State University, 23 Gagarin Avenue, 603950 Nizhny Novgorod, Russia
Abstract – Reliable procedures for the preparation of azides derived from
colchicine (1), allocolchicine (3) and N-acetylcolchinol (4a) were developed.
These azides were then employed in Cu-catalyzed Huisgen-Sharpless [3+2]
cycloaddition (“click”) reactions with alkynes under microwave irradiation. The
method developed opens a convenient and efficient access to libraries of new
C-7-modified colchicinoids (triazole derivatives). In addition, a plausible
mechanistic rationale for the colchicine-allocolchicine rearrangement is
suggested.
INTRODUCTION
Colchicine (1), the main alkaloid of Colchicum autumnale (known as meadow saffron or Herbstzeitlose in
german-speeking countries), was first isolated in pure form by Pelletier and Caventou in 18201 and its
correct structure was proposed by Dewar only in 1945.2 Colchicine is a powerful mitosis-inhibiting and
anti-inflammatory agent used as a drug in the treatment of gout and Mediterranean fever.3 Its unique
constitutional and stereostructural features, comprising a tropolone methyl ether (fused to a second
seven-membered ring) and a chiral biaryl axis, configurationally “programmed” by the stereocenter at
C-7, has challenged organic chemists for many decades.4 The first total synthesis of colchicine was
accomplished by Eschenmoser and coworkers in 19595 and since then various synthetic strategies were
elaborated, mirroring the evolution of organic synthesis over the past 50 years.6
Interesting aspects of the chemistry of colchicine (1) are its facile acidic hydrolysis to colchiceine (2)7 and
its base-induced ring-contractive rearrangement to its constitutional isomer allocolchicine (3) (Figure 1).8
This paper is dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday.

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HETEROCYCLES, Vol. 82, No. 2, 2011
In addition, oxidative rearrangement/degradation of 2 leads to N-acetylcolchinol (4a)9 the phosphate of
which (4b) has received much attention in recent years as a drug candidate named ZD6126.10
MeO
MeO
MeO
MeO
MeO
MeO
7
NHAc
O
NHAc
NHAc
MeO
MeO
MeO
CO2Me
OR
OR
1: R = Me (colchicine)
2: R = H (colchiceine)
3 (allocolchicine)
4a: R = H (N-acetylcolchinol)
4b: R = PO(OH)2 (ZD6126)
Figure 1
The biological activity of colchicine (and other colchinoids) is mainly connected to the inhibition of
microtubule formation (tubulin polymerization), which leads to cell-cycle arrest and subsequent apoptosis.
Therefore, 1 also represents a lead structure in the search for new anti-tumoral drugs.11 While
colchicine (1) itself is too toxic to be used in cancer therapy, the search for new derivatives with lower
toxicity still represents a relevant challenge, and allocolchicine and colchinol derivatives (with a
benzenoid ring C) are of particular interest in this context.12
In the course of our own research in the field of colchicine chemistry13 we recently disclosed a
click-conjugation approach allowing for a simple and fast diversification of the natural product 1 in
position 7 (Scheme 1).14 The method is based on the colchicine-derived azide 5 which smoothly reacts
with various alkynes in a Huisgen [3+2] cycloaddition15 under Cu-catalysis16 and microwave
acceleration.17 The resulting triazoles of type 6 exhibited encouraging biological properties, and some
were even more active than colchicine itself. We therefore were interested in a further expansion of the
method and report herein efficient procedures also for the preparation of azides derived from
allocolchicine (3) and N-acetylcolchinol (4a) and their use in the synthesis of the corresponding triazoles.
MeO
MeO
MeO
MeO
N
Rdiv
N
N
N3
O
Rdiv
Cu-catalyst, !W
MeO
MeO
O
"click"
OMe
5
OMe
6
Scheme 1. Synthesis of C-7 derivatives of colchicine through click chemistry

HETEROCYCLES, Vol. 82, No. 2, 2011
1587
RESULTS AND DISCUSSION
Starting from commercially available colchicine (1) the three azides 5, 8 and 11 were prepared as shown
in Scheme 2. As previously reported,14 the colchicine-related azide 5 was obtained via
desacetylcolchicine (7)18 through direct diazo transfer with a freshly prepared solution of triflyl azide
(TfN3).19 The conversion of 5 into the allocolchicine-related azide 8 proceeded smoothly under the
“classical conditions” of the colchicine-allocolchicine rearrangement, i.e. by heating with NaOMe in
MeOH.8,20 The synthesis of the colchinol-related azide 11 started with the hydrolysis of 1 to colchiceine
(2) by heating with HCl and AcOH.7 The oxidative degradation of 2 to the iodo-colchinol 9 was then
achieved in high yield under the Windaus conditions9 (I2, KI, NaOH).21 After reductive deiodination of 9
with Zn in AcOH and subsequent acidic hydrolysis of the amide function, the resulting colchinol
hydrochloride (10) was converted into the azide 11 using TfN3 in the presence of a Cu(II)-catalyst.
MeO
MeO
MeO
MeO
MeO
MeO
a, b, c
(ref. 18)
N3
NH2
O
N3
O
d
e
80%
60%
54%
MeO
MeO
MeO
CO2Me
OMe
OMe
1
7
5
8
f
97%
MeO
MeO
MeO
MeO
MeO
MeO
NHAc
NHR'
N3
g
h
j
2
93%
85%
62%
MeO
MeO
MeO
OH
OH
OH
I
9
11
4a (R' = Ac)
10 (R' = H2Cl)
i
99%
Scheme 2. Preparation of the azides 5, 8 and 11 starting from colchicine (1). Reagents and conditions:
a) NEt3, Boc2O, DMAP, CH3CN, reflux, 3 h; b) NaOMe (20 mol%), MeOH, RT, 45 min; c) TFA, RT, 15
min; d) TfN3, CuSO4 (1 mol%), K2CO3, H2O, MeOH, CH2Cl2 24 h; e) MeOH, NaOMe (2 equiv.), 75 °C,
1 h; f) 0.1 M HCl, AcOH, 100 °C, 3 h; g) NaOH, I2, KI, H2O, 0 °C, 1.5 h; h) Zn, AcOH, 120 °C, 1 h; i)
0.2 M HCl, MeOH, 120 °C, 65 h; j) TfN3, CuSO4 (1 mol%), NaHCO3, H2O, MeOH, 2h.
The three azides 5, 8, and 11 were then employed in the Cu-catalyzed cycloaddition reactions with
alkynes (compare Scheme 1) to give new C7-derivatives of colchicine, allocolchicine and colchinol
(Figure 2). Under the previously optimized conditions (1 mol % CuSO4·5H2O, 10 mol % sodium
ascorbate, H2O/tert-BuOH = 1 : 1, µW, 300W, 85 °C, 20 min) the triazoles 12 to 20 were obtained in
typical yields of 80-95% after purification. As alkynes, we here used propargylic alcohol and some of its
esters because our previous investigation14 suggested that the resulting products, especially the fatty acid
derivatives (oleates, palmitates and laurates), should exhibit particularly interesting biological activities.

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HETEROCYCLES, Vol. 82, No. 2, 2011
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
N
N
N
N
N
OH
MeO
MeO
MeO
O
O
C17H33
C15H31
O
O
O
O
O
OMe
OMe
OMe
12 (94%)a
13 (96%)
14 (89%)
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
N
N
N
N
N
OH
MeO
16 (90%)
MeO
O
MeO
O
C17H33
C15H31
CO2Me
CO2Me
CO2Me
O
O
15 (95%)a
17 (92%)
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
N
N
N
N
N
O
MeO
O
MeO
MeO
O
C11H23
Fe
OH
OH
OH
O
O
O
OAc
18 (80%)
19 (93%)
20 (43%)
Figure 2. Triazoles prepared from the azides 5, 8 and 11 through click-conjugation according to
Scheme 1. aIn these cases 5 mol% (instead of 1 mol%) of CuSO4 were used.
Having successfully exploited the long-known ring contractions in the synthesis of 8 and 11 as described
above, we recognized that a satisfying mechanistic rationalization has never been published for these
transformations.22 Therefore, we allow ourselves to suggest here a plausible mechanism for the
colchicine-allocolchicine rearrangement (Scheme 3). We assume a (reversible) attack of a methoxide at
the tropolone carbonyl group of 5 leading to a dearomatized intermediate 21, which then undergoes a
thermal disrotatory 6! electrocyclization to form a norcaradiene derivative (22). The cyclopropane ring is
then fragmented in a Favorsky-type process to yield the aromatic product 8 under methoxide elimination,
probably via an anionic Meisenheimer-type intermediate (not shown). 23
MeO
MeO
MeO
MeO
N3
O
N3
cat. MeONa
75°C
MeO
MeO
CO2Me
OMe
5
8
+ MeO–
- MeO–
MeO
MeO
MeO
MeO
6! DIS
N3
N3
OMe
O–
MeO
MeO
OMe
O–
OMe
MeO
21
22
Scheme 3. Proposed mechanism of the colchicine-allocolchine rearrangement (5 to 8)

HETEROCYCLES, Vol. 82, No. 2, 2011
1589
In a related fashion, the oxidative transformation of colchiceine (2) leading to colchinol derivatives is
supposed to be initiated by a nucleophilic attack of a hydroxide ion to the tropolone carbonyl group and
subsequent disrotatory 6! electrocyclization (Scheme 4). In this case, however, opening of the resulting
norcaradiene intermediate (23) can lead to an iodinated species of type 24, which under elimination of
CO2 (and aromatization) would yield colchinol (4a). Indeed, if the reaction of 2 is performed only with
one equivalent of iodine, significant amounts of colchinol (4a) are formed. To achieve high preparative
yields, however, it is much more efficient to run the reaction under the Windaus conditions with an
excess of iodine and to take into account the formation of the iodinated product 9 (compare Scheme 2),
which then has to be de-iodinated in a separate additional operation.
MeO
MeO
MeO
MeO
NHAc
O
NHAc
NaOH, I2
MeO
MeO
OH
9 (R = I)
R
OH
4a (R = H)
2
MeO
MeO
MeO
NHAc
NHAc
I2
MeO
MeO
O–
O
OH
O–
MeO
OH
OH
I
23
24
Scheme 4. Proposed mechanism of the ring-contractive fragmentation of colchiceine (2) to colchinols
CONCLUSION
Taking the “old” colchicine structure as a lead, the application of modern synthetic methodology opens
new avenues to libraries of C-7-modified colchicinoids as promising molecules for biological
investigations. In this context, we have developed reliable protocols for the preparation of azides derived
from colchicine (1), allocolchicine (3) and N-acetylcolchinol (4a) and demonstrated their use in
1,3-dipolar cycloadditions with alkynes (click chemistry). Furthermore, we have suggested a consistent
mechanistic rationale for the long-known ring-contractive rearrangements exploited in the semi-synthesis
of allocolchicine and colchinol derivatives starting from 1.
EXPERIMENTAL
General: NMR spectra were recorded on Bruker DRX 500 or Bruker DPX 300 instruments. Chemical
shifts (!) are given in ppm relative to the solvent reference as an internal standard (CDCl3, ! = 7.24 ppm

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HETEROCYCLES, Vol. 82, No. 2, 2011
(1H), ! = 77.0 ppm (13C)). The assignments are supported by HMBC, HMQC and H,H-COSY spectra.
Fourier transform infrared spectra (FT-IR) were recorded on a Perkin Elmer FT-IR Paragon 1000
spectrometer. Melting points (mp) were measured on Büchi B-545 melting point apparatus and are
uncorrected. Mass spectra (MS) were recorded on a Finnigan Incos 50 Galaxy System (DIP-MS), high
resolution mass spectra (HRMS) were recorded on a Finnigan MAT 900 (HR-EI-MS). Microwave
promoted reactions were carried out in a CEM Discover microwave synthesizer in sealed microwave
flasks equipped with a stir bar. Flash chromatography was performed using silica 60 (230-400 mesh)
supplied by Merck.
(aR,7S)-7-Azido-1,2,3,10-tetramethoxy-6,7-dihydrobenzo[a]heptalene-9(5H)-one (5)
To a solution of NaN3 (4.44 g, 68.3 mmol) in 11 mL of water were added 18 mL of CH2Cl2 and the
resulting suspension was cooled to 0 °C. After 5 min, 2.3 mL (13.7 mmol, 3.85 g) of Tf2O were added
dropwise. The mixture was stirred for 2 h at 0 °C before the phases were separated and the aqueous phase
was re-extracted twice with 9 mL of CH2Cl2. The combined organic solutions of triflyl azide were washed
with sat. aqueous Na2CO3 and used directly in the next step.
A solution of the crude amine 7 (2.44 g, 6.83 mmol) in 20 mL of MeOH was diluted with 20 mL of water
before 17.1 mg of CuSO4·5H2O (68 !mol, 1 mol%) and 1.41 g of K2CO3 (10.2 mmol) were added
followed by additional 20 mL of MeOH. Then, the solution of triflyl azide (prepared as described above)
was added dropwise. The resulting suspension was diluted with additional MeOH (ca. 10 mL) until a
clear solution was formed. After 24 h the organic solvents were removed under reduced pressure and the
remaining residue was poured into water and extracted with EtOAc (4x). The combined organic layers
were washed with brine and dried over MgSO4 and concentrated. The crude product was purified by
column chromatography (EtOAc/cy-hex = 10:1) to give 1.58 g (4.12 mmol, 60 %) of the azide 5 as a
yellowish solid. 1H NMR (300 MHz, CDCl3): " [ppm] = 1.80-1.85 (m, 1 H, H-6), 2.31-2.50 (m, 3 H, H-6,
2 x H-5), 3.62 (s, 3 H, OMe), 3.86 (s, 6 H, 2 x OMe), 4.23 (dd, 3J = 11.4 Hz, 3J = 6.0 Hz, 1 H, H-7), 6.49
(s, 1 H, H-4), 6.75 (d, 3J = 11.1 Hz, 1 H, H-11), 7.16 (d, 3J = 11.0 Hz, 1 H, H-12), 7.59 (s, 1 H, H-8). 13C
NMR (75 MHz, CDCl3): " [ppm] = 29.62 (t), 36.74 (t), 55.95 (q), 56.22 (q), 60.97 (q), 61.01 (q), 62.87
(d), 107.08 (d), 111.64 (d), 124.74 (s), 132.48 (d), 133.91 (s), 134.82 (s), 134.97 (d), 141.30 (s), 147.25
(s), 150.67 (s), 153.55 (s), 164.00 (s), 179.17 (s). MS (EI, 70 eV): m/z (%) = 383 (13) [M]+, 355 (11), 340
(100), 312 (45), 284 (86), 268 (24), 181 (34). HRMS (EI): calcd for: [M]+ (C20H21N3O5): 383.1481;
found: 383.148. IR (ATR): # (cm-1) = 2934, 2832, 2232, 2099, 1728, 1613, 1566, 1484, 1454, 1394, 1344,
1318, 1244, 1135, 1086, 1020, 907, 841, 722, 642. Mp 159 °C. [!]D -265.9; [!]546 -356.3 (CHCl3, c 0.57,
20 °C).

HETEROCYCLES, Vol. 82, No. 2, 2011
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(aR,5S)-Methyl azido-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7]annulene-3-carboxylate (8)
Sodium (24 mg, 1.04 mmol) was dissolved in 4 mL of dry MeOH at 0 °C (clear solution) and 200 mg
(0.52 mmol) of azide 5 were added. The mixture was heated to 75 °C in an oil bath for 30 min. After
cooling to room temperature the red solution was poured into water and the aqueous layer was extracted
with EtOAc (3x). The combined organic solutions were washed with brine and dried over MgSO4. After
removal of all volatiles the crude product was purified by column chromatography (cy-hex/EtOAc = 6:1)
1
to yield compound 8 (108 mg, 0.28 mmol, 54%) as a colorless oil. H NMR (300 MHz, CDCl3): " =
1.93-2.03 (m, 1 H, H-6), 2.16-2.27 (m, 1 H, H-5), 2.45-2.61 (m, 2 H, H-5, H-6), 3.62 (s, 3 H, OMe), 3.88
3
3
(s, 3 H, OMe), 3.89 (s, 3 H, OMe), 3.92 (s, 3 H, OMe), 4.45 (dd, J = 11.1 Hz, J = 6.6 Hz, 1 H, H-7),
3
3
6.58 (s, 1 H, H-4), 7.53 (d, J = 8.1 Hz, 1 H, H-11), 8.00 (d, J = 8.3 Hz, 1 H, H-10), 8.21 (s, 1 H, H-8).
13C NMR (75 MHz, CDCl3): " = 30.16 (t), 38.76 (t), 52.08 (q), 55.97 (q), 60.66 (d), 61.00 (q), 107.60 (d),
123.32 (s), 124.97 (d), 128.02 (d), 128.98 (s), 130.27 (d), 134.73 (s), 137.45 (s), 138.79 (s), 141.17 (s),
150.90 (s), 153.49 (s), 166.87 (s). MS (ESI, pos., 70 eV): m/z (%) = 406 [M + Na]+. HRMS (ESI): calcd
for: [M + Na]+ (C20H21NaN3O5): 406.1379; found: 406.138. IR (ATR): # (cm-1) = 2936, 2860, 2826, 2246,
2226, 2099, 1715, 1594, 1550, 1483, 1433, 1399, 1343, 1399, 1293, 1229, 1193, 1088, 997, 909, 823, 726.
[!]D -57.9; [!]546 -74.1; [!]405 -258.0; [!]365 -490.9 (CHCl3, c 0.14, 20 °C).
(aR,7S)-7-Acetylamino-10-hydroxy-1,2,3-trimethoxy-6,7-dihydro-5H-benzo[a]heptalene-9-one (2)7
A solution of colchicine (1) (520 mg, 1.30 mmol) in 5 mL of acetic acid was treated with 30 mL of 0.1 M
hydrochloric acid and the mixture was heated to 100 °C for 3 h. The solution was cooled to room
temperature and adjusted to pH = 6 by portionwise addition of solid Na2CO3. The yellowish-green
solution was extracted (3x) with CHCl3, the organic layers were washed with brine and dried over
Na2SO4. After evaporation of the solvent and removal of all volatiles in vacuum, 486 mg of colchiceine
(2) (1.26 mmol, 97%) were obtained as a greenish foam and directly used in the next step. 1H NMR (300
MHz, DMSO-d6): " = 1.86 (s, 3H, H-2´), 1.90-2.20 (m, 4 H, H-5 and H-6), 3.52 (s, 3 H, OMe), 3.78 (s, 3
3
H, OMe), 3.84 (s, 3 H, OMe), 4.31-4.39 (m, 1 H, H-7), 6.79 (s, 1 H, H-4), 7.16 (d, J = 11.8 Hz, 1 H,
H-11), 7.31 (s, 1 H, H-8), 7.34 (d, 3J = 11.8 Hz, 1 H, H-12) 8.62 (d, 3J = 7.3 Hz, 1 H, NH). 13C NMR (75
MHz, CDCl3): " = 29.64 (t), 37.26 (t), 52.61 (q), 55.94 (q), 61.22 (q), 61.27 (q), 107.22 (d), 119.95 (d),
122.53 (d), 125.71 (s), 134.31 (s), 136.37 (s), 141.32 (d), 150.69 (s), 151.57 (s), 153.47 (s), 170.36 (s),
175.59 (s). MS (ESI, pos., 70 eV): m/z (%) = 1181 (5), 807 (6), 532 (6), 492 (10), 424 (10) [M+K]+,
422 (22), 408 (96) [M+Na]+, 400 (33), 386 (100) [M+H]+, 382 (6), 344 (22), 328 (6),
327 (17) [M-NHAc]+, 299 (14). IR (ATR): # (cm-1) = 3254, 3045, 2993, 2934, 2849, 2830, 1706, 1654,
1605, 1592, 1540, 1485, 1449, 1400, 1358, 1345, 1319, 1273, 1227, 1191, 1133, 1090, 1042, 1006, 983,

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HETEROCYCLES, Vol. 82, No. 2, 2011
954, 924, 918, 902, 853, 840, 797, 771, 726. Mp 150 °C.
(aR,5S)-N-(3-Hydroxy-2-iodo-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-5-yl)-
acetamide (9)
A suspension of colchiceine (2) (486 mg, 1.26 mmol) in 10 mL of water was cooled to 0 °C and NaOH
(504 mg, 12.6 mmol) was added followed by the dropwise addition of a solution of iodine (960 mg,
3.78 mmol) and KI (3.4 g, 20.5 mmol) in 32 mL of water. The resulting orange solution was stirred for
90 min at 0 °C and then allowed to warm to room temperature. Then SO2 was bubbled through the
reaction mixture until the brown color disappeared. After 30 min the solution was acidified with conc.
hydrochloric acid (pH = 2). The yellowish solid formed was isolated by filtration, washed with water
1
(4 mL) and dried in vacuo (60 °C) to give 567 mg of 9 (1.17 mmol, 93%). H NMR (300 MHz,
DMSO-d6): " = 1.81-2.15 (m, 4 H, H-5 and H-6), 1.87 (s, 3 H, H-2´), 3.48 (s, 3 H, OMe), 3.77 (s, 3 H,
OMe), 3.82 (s, 3 H, OMe), 4.33-4.41 (m, 1 H, H-7), 6.76 (s, 1 H, H-4), 6.87 (s, 1 H, H-11), 7.56
13
(s, 1 H, H-8), 8.37 (d, 3J = 7.9 Hz, 1 H, NH), 10.27 (s, 1 H, OH). C NMR (75 MHz, DMSO-d6): " =
22.51 (q), 29.87 (t), 37.78 (t), 48.13 (d), 55.72 (q), 60.41 (q), 81.29 (s), 107.98 (d), 109.96 (d), 123.14 (s),
126.49 (s), 134.65 (s), 139.06 (d), 140.41 (s), 142.30 (s), 150.06 (s), 152.10 (s), 155.52 (s), 168.20 (s).
MS (ESI, pos., 70 eV): m/z (%) = 1005 (3) [M2+K]+, 1004 (5), 1003 (23), 987 (31), 965 (3), 879 (4), 878
(10), 862 (14), 847 (2), 779 (3), 664 (2), 648 (5), 636 (5), 633 (21), 632 (100), 566 (6), 551 (17), 538 (54),
524 (3), 508 (54), 507 (4), 506 [M+Na]+ (52), 425 (6), 368 (4). IR (ATR): # (cm-1) = 3254, 3058, 2986,
2932, 2849, 2830, 2745, 2614, 2248, 2117, 1703, 1649, 1594, 1537, 1478, 1452, 1433, 1402, 1371, 1348,
1322, 1289, 1276, 1257, 1238, 1218, 1191, 1156, 1135, 1100, 1087, 1048, 1019, 1003, 954, 928, 911, 888,
862, 823, 791, 758, 726. Mp 238 °C.
(aR,5S)-N-(3-Hydroxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-5-yl)acetamide
(4a)
To a solution of 9 (567 mg, 1.17 mmol, 1 eq) in 11.3 mL of acetic acid was added zinc powder (1.69 g,
25.80 mmol, 22 eq) and the mixture was heated to 120 °C for 1 h. After cooling to room temperature the
remaining solid was filtered off and washed with 3 mL of acetic acid. The filtrate was diluted with 14 mL
of cold water and extracted with CHCl3 (3x). The organic layers were washed with water (2x) and dried
over Na2SO4, and the residue was purified by column chromatography (EtOAc, Rf = 0.3). After
evaporation of the solvent in vacuo N-acetyl-colchinol (4a) (358 mg, 1.0 mmol, 85%) was isolated as a
1
colorless solid. H NMR (300 MHz, DMSO-d6): " = 1.81-1.86 (m, 1 H, H-6), 1.87 (s, 3 H, H-2´),
1.99-2.18 (m, 3 H, H-5 and H-6), 3.45 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 4.41-4.52
(m, 1 H, H-7), 6.67 (dd, 4J = 2.5 Hz, 3J = 8.3 Hz, 1 H, H-10), 6.74 (s, 1 H, H-4), 6.75 (d, 4J = 2.5 Hz, 1 H,

HETEROCYCLES, Vol. 82, No. 2, 2011
1593
3
13
H-8), 7.11 (d, J = 8.3 Hz, 1 H, H-11), 8.33 (d, 3J = 8.4 Hz, 1 H, NH), 9.39 (s, 1 H, OH). C NMR (75
MHz, DMSO-d6): " = 22.60 (q), 30.34 (t), 38.36 (t), 48.04 (d), 55.70 (q), 60.42 (q), 107.85 (d), 110.10 (d),
112.79 (d), 124.30 (s), 124.60 (s), 130.33 (d), 134.62 (s), 140.42 (s), 141.58 (s), 150.22 (s), 151.73 (s),
156.35 (s), 168.12 (s). GC-MS (EI, 70 eV): m/z (%) = 498 (2), 463 (1), 442 (1), 425 (2), 403 (1), 385 (2),
357 (45) [M]+, 342 (2), 326 (2), 298 (44), 283 (17), 267 (23), 240 (17), 225 (12), 207 (9), 189 (4), 168 (7),
153 (8), 134 (6), 115 (6), 99 (2), 82 (4), 59 (9), 43 (100). HRMS (EI, 70 eV): calcd for: [M]+
(C20H23NO5): 357.1576; found: 357.157. IR (ATR): # (cm-1) = 3288, 3065, 2986, 2932, 2849, 2830, 2679,
2588, 2150, 1996, 1882, 1703, 1644, 1605, 1579, 1540, 1478, 1449, 1429, 1401, 1351, 1322, 1289, 1273,
1234, 1221, 1191, 1172, 1152, 1141, 1099, 1081, 1048, 1002, 960, 948, 926, 908, 866, 830, 818, 791, 755,
729. [!]D -55.8; [!]546 -73.0; [!]405 -243.3; [!]365 -421.3 (CHCl3, c 0.135, 20 °C).
(aR,5S)-5-Amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-ol-hydrochloride
(10)
To a solution of N-acetyl-colchinol (4a) (574 mg, 1.61 mmol) in 5.5 mL of MeOH were added 5.5 mL of
0.2 M hydrochloric acid and the reaction mixture was heated to reflux for 65 hours. After cooling to RT a
colorless solid was formed which was filtered off, washed with Et2O (2x) and dried in vacuo to give the
1
hydrochloride 10 (563 mg, 1.6 mmol, 99%). H NMR (300 MHz, DMSO-d6): " = 1.96-2.12 (m, 2 H,
H-5), 2.42-2.58 (m, 2 H, H-6), 3.52 (s, 3 H, OMe), 3.75 (s, 3 H, OMe), 3.82 (s, 3 H, OMe), 4.36-4.42 (m,
1 H, H-7), 6.80 (s, 1 H, H-4), 6.84-6.87 (m, 2 H, H-8 and H-10), 7.19 (d, 3J = 9.0 Hz, 1 H, H-11), 8.79
13
(s, 3 H, NH), 9.83 (s, 1 H, OH). C NMR (75 MHz, DMSO-d6): " = 29.38 (t), 36.87 (t), 50.14 (d),
55.77 (q), 60.43 (q), 60.49 (q), 108.09 (d), 110.08 (d), 113.97 (d), 123.69 (s), 124.24 (s), 131.04 (d),
133.92 (s), 135.86 (s), 140.64 (s), 150.26 (s), 152.19 (s), 156.52 (s). MS (ESI, pos., 70 eV): m/z (%) =
673 (2), 500 (2), 400 (2), 316 (21) [M-HCl]+, 300 (19), 299 (100) [M-NH3Cl]+, 271 (5), 268 (10). IR
(ATR): # (cm-1) = 3302, 3049, 2929, 2624, 2070, 1611, 1567, 1556, 1535, 1503, 1485, 1446, 1429, 1401,
1382, 1354, 1333, 1294, 1273, 1230, 1195, 1173, 1145, 1134, 1102, 1087, 1053, 1028, 1014, 1000, 992,
982, 943, 925, 904, 847, 819, 790. Mp 243 °C. [!]D -92.2; [!]546 -121.5; [!]405 -451.6; [!]343 -820.8
(DMSO, c 1.15, 20 °C).
(aR,5S)-5-Azido-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-3-ol (11)
At first, a ca. 1.14 M solution of TfN3 in toluene was freshly prepared from NaN3 and Tf2O (following the
procedure described above for the synthesis of 5, however, replacing CH2Cl2 by toluene). Then, 2.78 mL
(3.17 mmol) of this solution (TfN3 in toluene) were added to a stirred mixture of hydrochloride 10
(200 mg, 0.57 mmol) in 0.4 mL of water, CuSO4·5H2O (7.4 mg, 0.03 mmol) and NaHCO3 (201 mg,

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HETEROCYCLES, Vol. 82, No. 2, 2011
2.39 mmol). The resulting mixture was diluted with 12.2 mL of MeOH and stirred for 2 hours at room
temperature before the solvents were removed in vacuo. The crude product was purified by column
chromatography (EtOAc/cy-hex = 1:4; Rf = 0.3) to give 122 mg (0.36 mmol, 63 %) of azide 11 as a
1
brownish solid. H NMR (300 MHz, acetone-d6): " = 1.81-1.92 (m, 1 H, H-5), 2.14-2.24 (m, 1 H, H-6),
2.40-2.51 (m, 2 H, H-5 and H-6), 3.53 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 3.82 (s, 3 H, OMe), 4.36-4.42
(m, 1 H, H-7), 6.70 (s, 1 H, H-4), 6.81 (dd, 4J = 2.5 Hz, 3J = 8.4 Hz, 1 H, H-10), 7.00 (d, 4J = 2.5 Hz, 1 H,
H-8), 7.25 (d, 3J = 8.4 Hz, 1 H, H-11). 13C NMR (75 MHz, acetone-d6): " = 31.78 (t), 40.41 (t), 57.19 (q),
61.84 (q), 61.89 (q), 62.72 (d), 109.72 (d), 112.04 (d), 115.48 (d), 126.06 (s), 126.93 (s), 133.12 (d),
136.35 (s), 140.47 (s), 143.08 (s), 152.53 (s), 154.47 (s), 158.40 (s). GC-MS (EI, 70 eV): m/z (%) = 313
(100) [M-N2]+, 298 (6), 282 (8), 267 (7), 240 (6), 225 (6), 199 (3), 184 (5), 154 (4), 128 (6), 102 (2), 78
(3), 57 (3), 41 (4). HRMS (EI, 70 eV): calcd for: [M-N2]+ (C18H19N3O4): 313.1314; found: 313.132.
IR (ATR): # (cm-1) = 3234, 3056, 3000, 2936, 2858, 2829, 2645, 2226, 2099, 1684, 1606, 1592, 1578,
1482, 1450, 1429, 1382, 1347, 1322, 1290, 1269, 1230, 1187, 1152, 1141, 1106, 1088, 1046, 996, 950,
932, 914, 868, 815, 790, 773, 758, 734, 702, 670, 634. Mp 114 °C. [!]D -63.8; [!]546 -82.3; [!]405
-245.9; [!]365 -417.2 (MeOH, c 0.75, 20 °C).
General procedure for the [3+2] cycloaddition:
In a microwave vial 50 mg (130 !mol, 1 eq.) of azide 5 (or the allo-congeners 8 or 11, respectively) were
dissolved in 0.25 mL of t-BuOH. To this solution 0.25 mL of water were added followed by the addition
of 130 !mol of the corresponding alkyne (1 eq.). Then 10 !L (1 mol%) of a catalyst solution (prepared
from 32.4 mg of CuSO4·H2O in 1 mL of water) and 2.6 mg of sodium ascorbate (13 !mol, 10 mol %)
were added. The microwave vial was sealed and placed in a microwave reactor and heated to 85 °C for
20 min (300 W). After cooling to room temperature the reaction mixture was poured into water, followed
by extraction of the aqueous phase with EtOAc (4x), washing the combined organic layers with brine and
by drying over MgSO4. The crude product (triazole) was purified by column chromatography. (For yield
see Figure 2).
Triazole 12 (derived from azide 5 and propargylic alcohol)
1H NMR (300 MHz, CDCl3): " = 7.69 (s, 1 H, H-5’), 7.26 (d, 1 H, d, 3J = 11 Hz, H-12), 6.79 (d, 1 H, 3J =
11 Hz, H-11), 6.57 (s, 1 H, H-8), 6.43 (s, 1 H, H-4), 5.39 (dd, 1 H, 3J = 11.8 Hz, 3J = 5.2 Hz, H-7), 4.75 (s,
2 H, CH2OH), 3.93 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 3.88 (s, 3 H, OMe), 3.71 (s, 3 H, OMe), 2.76 –
13
2.68 (m, 2 H, H-5), 2.58 – 2.52 (m, 2 H, H-6). C NMR (75 MHz, CDCl3): " = 178.80 (s), 164.18 (s),
153.92 (s), 150.94 (s), 148.31 (s), 147.85 (s), 141.62 (s), 135.54 (d), 134.57 (s), 133.51 (s), 131.65 (d),

HETEROCYCLES, Vol. 82, No. 2, 2011
1595
124.81 (s), 122.26 (d), 112.03 (d), 107.38 (d), 62.62 (d), 61.16 (q, 2C), 56.59 (t), 56.37 (q), 56.09 (q),
35.32 (t), 29.64 (t). MS (ESI, pos., 70 eV): m/z (%) = 439 (88) [M]+, 424 (16), 340 (17), 324 (78), 312
(100), 297 (70), 281 (60), 267 (38), 254 (38), 239 (37), 224 (30), 211 (36), 195 (37), 181 (54). HRMS
(ESI): calcd for: [M]+ (C23H25N3O6): 439.1743; found: 439.175. IR (ATR) # (cm-1): 3366, 2986, 2933,
2833, 1613, 1583, 1560, 1483, 1456, 1396, 1346, 1320, 1252, 1136, 1093, 1016, 743. Mp 150 °C. [!]D
-121.6; [!]546 -174.4 (CHCl3, c 0.502, 20 °C).
Triazole 13 (derived from azide 5 and propargyl oleate)
1H NMR (500 MHz, CDCl3): " = 7.62 (s, 1 H, H-5’), 7.25 (d, 1 H, 3J = 11.0 Hz, H-12), 6.77 (d, 1 H, 3J =
11.0 Hz, H-11), 6.55 (s, 1 H, s, H-8), 6.46 (s, 1 H, s, H-4), 5.39 – 5.29 (m, 3 H, H-7, CH=CH), 5.20 (s,
2 H, CH2O), 3.94 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 3.87 (s, 3 H, OMe), 3.73 (s, 3 H, OMe), 2.78 – 2.68
3
(m, 2 H, H-5), 2.60 – 2.49 (m, 2 H, H-6), 2.27 (t, 2 H, J = 7.6 Hz), 1.97 – 1.94 (m, 4 H, CH2CH=CH),
1.60 – 1.52 (m, 2 H), 1.33 – 1.17 (m 20 H, CH2), 0.83 (t, 3 H, 3J = 6.7 Hz, CH2CH3). 13C NMR (75 MHz,
CDCl3): " = 178.75 (s), 173.70 (s), 164.20 (s), 153.88 (s), 150.92 (s), 147.41 (s), 143.10 (s), 141.58 (s),
135.37(d), 134.30 (s), 133.44 (s), 131.76 (d), 129.89 (d), 129.66 (d), 124.79 (s), 124.22 (d), 111.69 (d),
107.26 (d), 62.63 (d), 61.24 (q), 61.13 (q), 57.36 (t), 56.35 (q), 56.05 (q), 35.30 (t), 34.03 (t), 31.82 (t),
29.68 (t, 2C), 29.61 (t), 29.44 (t), 29.24 (t, 2C), 29.07 (t), 29.02 (t), 29.00 (t), 27.13 (t), 27.09 (t), 24.71 (t),
22.60 (t), 14.06 (q). MS (EI, 70 eV) m/z (%): 704 (1) [M]+, 589 (1), 342 (98), 314 (100), 297 (23), 282
(35), 267 (17), 251 (12), 239 (12), 224 (9), 211 (9), 195 (8), 181 (15). HRMS (EI): calcd for [M]+
(C41H57N3O7): 703.4197; found: 703.421. IR (ATR) # (cm-1): 2997, 2922, 2850, 1735, 1618, 1585, 1486,
1459, 1398, 1348, 1321, 1251, 1138, 1095, 1019, 842 cm-1. [!]D -76.1; [!]546 -107.4 (CHCl3, c 0.602,
20 °C).
Triazole 14 (derived from azide 5 and propargyl palmitate)
1H NMR (300 MHz, CDCl3): " = 7.61 (s, 1 H, H-5’), 7.24 (d, 1 H, 3J = 10.7 Hz, H-12), 6.76 (d, 1 H, 3J =
10.7 Hz, H-11), 6.54 (s, 1 H, H-8), 6.44 (s, 1 H, H-4), 5.33 (dd, 1 H, 3J = 11.8 Hz, 3J = 5.2 Hz, H-7), 5.17
(s, 2 H, CH2O), 3.93 (s, 3 H, OMe), 3.89 (s, 3 H, OMe), 3.86 (s, 3 H, OMe), 3.72 (s, 3 H, OMe), 2.84 –
3
2.64 (m, 2 H, H-5), 2.59 – 2.42 (m, 2 H, H-6), 2.26 (t, 2 H, J = 7.6 Hz, C(O)CH2), 1.63 – 1.45 (m, 2 H,
3
13
C(O)CH2CH2), 1.26 – 1.12 (m, 24 H, CH2), 0.82 (t, 3 H, J = 6.6 Hz, CH2CH3). C NMR (75 MHz,
CDCl3): " = 178.72 (s), 173.67 (s), 164.18 (s), 153.87(s), 150.90 (s), 147.38 (s), 143.10 (s), 141.59 (s),
135.32 (d), 134.28 (s), 133.42 (s), 131.74 (d), 124.78 (s), 124.18 (d), 111.67 (d), 107.28 (d), 62.62 (d),
61.19 (q), 61.08 (q), 57.34 (t), 56.32 (q), 56.03 (q), 35.28 (t), 34.01 (t), 31.81 (t), 29.57 (t, 7C), 29.34 (t),
29.24 (t), 29.12 (t), 29.00 (t), 24.69 (t), 22.57 (t), 14.01 (q). MS (EI, 70 eV) m/z (%): 678 (23) [M]+, 562
(6), 394 (10), 341 (29), 312 (100), 297 (52), 282 (58), 267 (29), 251 (23), 239 (26), 224 (16), 211 (16),

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195 (16), 181 (26). HRMS (EI): calcd for [M]+ (C39H55N3O7): 677.4039; found: 677.404. IR (ATR)
# (cm-1): 2921, 2850, 1735, 1617, 1585, 1486, 1460, 1398, 1348, 1321, 1251, 1138, 1095, 1019, 842. Mp
50 °C. [!]D -84.0; [!]546 -119.5 (CHCl3, c 0.535, 20 °C).
Triazole 15 (derived from azide 8 and propargylic alcohol)
1H NMR (300 MHz, CDCl3): " = 7.98 (dd, 1 H, 3J = 8.2 Hz, 4J = 1.6 Hz, H-10), 7.57 (d, 1 H, 3J = 8.2 Hz,
H-11), 7.18 (d, 1 H, 4J = 1.6 Hz, H-8), 6.62 (s, 1 H, s, H-4), 5.49 (dd, 1 H, 3J = 12.6 Hz, 3J = 6.0 Hz, H-7),
4.79 (s, 2 H, CH2OH), 3.89 (s, 6 H, OMe), 3.79 (s, 3 H, OMe), 3.68 (s, 3 H, OMe), 2.94 – 2.87 (m, 1 H,
H-6a), 2.67 – 2.60 (m, 2 H, H-5), 2.44 – 2.37 (m, 1 H, H-6b). 13C NMR (75 MHz, CDCl3): " = 166.95 (s),
154.23 (s), 151.45 (s), 148.20 (s), 141.73 (s), 138.96 (s), 137.69 (s), 134.71 (s), 130.85 (d), 129.57 (s),
128.78 (d), 124.56 (d), 123.49 (s), 122.77 (d), 108.16 (d), 61.55 (d), 61.43 (q), 61.08 (q), 56.93 (t), 56.45
(q), 52.53 (t), 38.20 (q), 30.60 (t). MS (EI, 70 eV) m/z (%): 439 (42) [M]+, 352 (21), 340 (100), 325 (36),
309 (45), 297 (19), 282 (23), 267 (18), 251 (24), 239 (14), 224 (16), 207 (16), 193 (15), 181 (31). HRMS
(EI): calcd for [M]+ (C23H25N3O6): 439.1743; found: 439.173. IR (ATR) # (cm-1): 3355, 2937, 2860, 1717,
1595, 1484, 1455, 1434, 1401, 1348, 1323, 1296, 1237, 1194, 1146, 1106, 1086, 1046, 1006, 823, 749.
Mp 97 °C. [!]D -117.3; [!]546 -156.2 (CHCl3, c 0.4, 20 °C).
Triazole 16 (derived from azide 8 and propargyl oleate)
1H NMR (300 MHz, CDCl3): " = 8.00 (dd, 1 H, 3J = 8.1 Hz, 4J = 1.6 Hz, H-10), 7.66 (s, 1 H, H-5’), 7.57
(d, 1 H, 3J = 8.1 Hz, H-11), 7.19 (d, 1 H, 4J = 1.6 Hz, H-8), 6.62 (s, 1 H, H-4), 5.48 (dd, 1 H, 3J = 12.4 Hz,
3J = 5.9 Hz, H-7), 5.33 – 5.26 (m, 2 H, CH=CH), 5.24 (s, 2 H, CH2O), 3.90 (s, 6 H, OMe), 3.81 (s, 3 H,
OMe), 3.70 (s, 3 H, OMe), 3.01 – 2.90 (m, 1 H, H-6a), 2.69 – 2.55 (m, 2 H, H-5), 2.45 – 2.31 (m, 1 H,
3
H-6b), 2.29 (t, 2 H, J = 7.6 Hz, C(O)CH2), 1.99 – 1.90 (m, 4 H, CH2CH=CH), 1.68 – 1.46 (m, 2 H,
3
13
C(O)CH2CH2), 1.33 – 1.15 (m, 20 H, CH2), 0.84 (t, 3 H, J = 6.7 Hz, CH2CH3). C NMR (75 MHz,
CDCl3): " = 173.65 (s), 166.42 (s), 153.86 (s), 151.07 (s), 143.02 (s), 141.36 (s), 138.51 (s), 137.16 (s),
134.31 (d), 130.46 (d), 129.93 (d), 129.64 (d), 129.29 (s), 128.45 (d), 124.43 (d), 124.19 (d), 123.11 (s),
107.73 (d), 61.17 (q), 61.02 (q), 60.75 (q), 57.50 (t), 56.05 (q), 52.07 (q), 37.81 (t), 34.07 (t), 31.83 (t),
30.21 (t), 29.69 (t), 29.62 (t), 29.45 (t), 29.25 (t), 29.07 (t), 29.03 (t), 27.14 (t), 27.10 (t), 24.74 (t), 22.61
(t), 14.05 (t). MS (EI, 70 eV) m/z (%): 704 (2) [M]+, 617 (1), 394 (5), 362 (17), 341 (100), 313 (15), 309
(27), 297 (7), 282 (15), 266 (12), 251 (15), 235 (7), 224 (6), 208 (6), 193 (5), 181 (8). HRMS (EI): calcd
for [M]+ (C41H57N3O7): 703.4196; found: 703.421. IR (ATR) # (cm-1): 2997, 2922, 2851, 1723, 1595,
1484, 1456, 1434, 1400, 1348, 1324, 1293, 1236, 1194, 1146, 1115, 1087, 1049, 1007, 823, 771. [!]D
-73.4; [!]546 -98.2 (CHCl3, c 0.504, 20 °C).

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Triazole 17 (derived from azide 8 and propargyl palmitate)
1H NMR (300 MHz, CDCl3): " = 8.00 (dd, 1 H, 3J = 8.1 Hz, 4J = 1.6 Hz, H-10), 7.66 (s, 1 H, H-5’), 7.57
(d, 1 H, 3J = 8.1 Hz, H-11), 7.19 (d, 1 H, 4J = 1.6 Hz, H-8), 6.62 (s, 1 H, H-4), 5.48 (dd, 1 H, 3J = 12.4 Hz,
3J = 5.9 Hz, H-7), 5.24 (s, 2 H, CH2O), 3.90 (s, 6 H, OMe), 3.81 (s, 3 H, OMe), 3.71 (s, 3 H, OMe), 3.02
3
– 2.90 (m, 1 H, H-6a), 2.72 – 2.60 (m, 2 H, H-5), 2.48 – 2.34 (m, 1 H, H-6b), 2.29 (t, 2 H, J = 7.6 Hz,
3
C(O)CH2), 1.62 – 1.52 (m, 2 H, C(O)CH2CH2), 1.30 – 1.18 (m, 24 H, CH2), 0.84 (t, 3 H, J = 6.7 Hz,
13
CH2CH3). C NMR (75 MHz, CDCl3): " = 173.68 (s), 166.42 (s), 153.86 (s), 151.08 (s), 143.04 (s),
141.37 (s), 138.51 (s), 137.17 (s), 134.31 (s), 130.46 (d), 129.30 (s) 128.46 (d), 124.42 (d), 124.20 (d),
123.12 (s), 107.73 (d), 61.18 (d), 61.02 (q), 60.75 (q), 57.51 (t), 56.06 (q), 52.08 (q), 37.82 (t), 34.09 (t),
31.86 (t), 30.22 (t), 29.61 (t, 6C), 29.39 (t), 29.30 (t), 29.18 (t), 29.07 (t), 24.76 (t), 22.63 (t), 14.06 (q).
MS (EI, 70 eV) m/z (%): 678 (8) [M]+, 591 (1), 394 (5), 366 (8), 350 (6), 340 (100), 325 (21), 309 (28),
297 (9), 282 (15), 267 (13), 251 (14), 239 (8), 224 (7), 208 (6), 195 (5), 181 (9). HRMS (EI): calcd for
[M]+ (C39H55N3O7): 677.4039; found: 677.404. IR (ATR) # (cm-1): 2920, 2849, 1722, 1595, 1484, 1455,
1434, 1401, 1348, 1324, 1293, 1236, 1194, 1147, 1115, 1088, 1049, 1007, 823, 771. [!!]D -73.3; [!]546
-98.4 (CHCl3, c 0.425, 20 °C).
Triazole 18 (derived from azide 11 and propargyl ferrocenecarboxylate)
1H NMR (300 MHz, CDCl3): " = 1.50-1.86 (m, 1 H, H-5), 2.50-2.64 (m, 3 H, H-5 and H-6), 3.75 (s, 3 H,
OMe), 3.91 (s, 3 H. OMe), 3.93 (s, 3 H, OMe), 4.08 (s, 5 H, H-Cp), 4.38 (s, 2 H, H-4´´), 4.77
(s, 2 H, H-3´´), 5.26 (q, 4J = 15.3 Hz, 2 H, H-3´), 5.37-5.42 (m, 1 H, H-7), 6.16 (d, 4J = 2.2 Hz, 1 H, H-8),
6.62 (s, 1 H, H-4), 6.91 (dd, 4J = 2.2 Hz, 3J = 8.4 Hz, 1 H, H-10), 7.41 (d, 3J = 8.4 Hz, 1 H, H-11), 7.68 (s,
13
1 H, H-1´), 7.97 (s, 1 H, OH). C NMR (75 MHz, CDCl3): " = 30.47 (t), 37.67 (t), 56.06 (q), 56.87 (t),
61.04 (q), 61.53 (q), 69.80 (d), 70.27 (d), 70.29 (d), 71.64 (d), 107.63 (d), 109.98 (d), 114.98 (d), 124.13
(s), 124.89 (s), 125.30 (d), 131.66 (d), 134.30 (s), 137.97 (s), 141.29 (s), 142.75 (s), 151.00 (s), 152.75 (s),
156.56 (s), 171.76 (s). MS (ESI, pos., 70 eV): m/z (%) = 633 (17), 632 (53) [M+Na]+, 610 (61) [M+H]+,
532 (100), 533 (25), 498 (10), 400 (17), 382 (73), 352 (49), 324 (25), 299 (33), 213 (6), 185 (42),
143 (13), 65 (6). HRMS (ESI): calcd for: [M]+ (C32H31FeN3O6): 609.1562, found: 609.156. IR (ATR):
# (cm-1) = 3142, 3052, 2996, 2930, 2850, 2724, 2682, 2592, 2459, 2243, 1902, 1709, 1609, 1594, 1580,
1484, 1456, 1431, 1403, 1372, 1347, 1324, 1234, 1191, 1140, 1125, 1105, 1087, 1049, 1025, 1003, 951,
935, 914, 865, 822, 792, 753, 730, 664, 643, 636. Mp.201 °C. [!]D -51.3; [!]546 -74.7 (CHCl3, c 0.79,
20 °C).
Triazole 19 (derived from azide 11 and propargyl dodecanoate)
3
1H NMR (300 MHz, CDCl3): " = 0.87 (t, J = 6.3 Hz, 3 H, H-12´´), 1.23 (s, 16 H, H-4´´-H-11´´), 1.57

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(t, 3J = 7.1 Hz, 2 H, H-3´´), 2.28 (t, 3J = 7.5 Hz, 2 H, H-2´´), 2.45-2.65 (m, 3 H, H-5 and H-6), 3.08-3.18
(m, 1 H, H-6), 3.76 (s, 3 H, OMe), 3.91 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), 5.12 (q, J = 6,5 Hz, 2 H, H-3´),
5.33-5.39 (m, 1 H, H-7), 6.06 (d, 4J = 2.4 Hz, 1 H, H-8), 6.63 (s, 1 H, H-4), 6.89 (dd, 4J = 2.4 Hz, 3J = 8.4
13
Hz, 1 H, H-10), 7.40 (d, 3J = 8.4 Hz, 1 H, H-11), 7.57 (s, 1 H, H-1´), 7.84 (s, 1 H, NH). C NMR (75
MHz, CDCl3): " = 14.15 (q), 22.71 (t), 24.80 (t), 29.13 (t), 29.26 (t), 29.36 (t), 29.47 (t), 29.62 (t), 30.50
(t), 31.93 (t), 34.05 (t), 37.47 (t), 56.11 (q), 57.15 (t), 61.07 (q), 61.60 (q), 107.67 (d), 109.97 (d), 115.01
(d), 124.15 (s), 124.61 (d), 131.68 (d), 134.41 (s), 138.13 (s), 141.33 (s), 142.69 (s), 151.03 (s), 152.83 (s),
156.61 (s), 173.73 (s). MS (ESI, pos., 70 eV): m/z (%) = 1184 (1), 1183 (2), 1182 (2) [M2+Na]+, 1180 (1),
900 (1), 897 (2), 898 (2), 890 (1), 889 (2), 881 (1), 882 (1), 619 (14), 618 (35) [M+K]+, 603 (37),
602 (100) [M+Na]+, 580 (6) [M+H]+, 449 (6), 346 (7), 244 (1), 243 (7), 241 (4). HRMS (ESI, pos.,
70 eV): calcd for: [M+Na]+ (C33H45N3O6Na): 602.3206, found: 602.320. IR (ATR): # (cm-1) = 3143,
2920, 2849, 2357, 2338, 1735, 1697, 1681, 1648, 1607, 1595, 1579, 1566, 1556, 1537, 1502, 1483, 1454,
1429, 1400, 1371, 1346, 1320, 1292, 1272, 1234, 1193, 1170, 1154, 1142, 1107, 1084, 1049, 1005, 919,
864, 820, 764. Mp 66 °C. [!]D -11.0; [!]546 -16.4; [!]405 -91.7; [!]365 -182.8 (MeOH, c 0.50, 20 °C).
Triazole 20 (derived from azide 11 and propargyl 2-acetoxybenzoate)
1H NMR (300 MHz, CDCl3): " = 2.18 (s, 3 H, H-9´´), 2.47-2.74 (m, 4 H, H-5 and H-6), 3.62 (s, 3 H,
OMe), 3.85 (s, 2 x 3 H, OMe), 5.33 (d, 3J = 12.3 Hz, 1 H, H-7), 5.49-5.57 (m, 2 H, H-3´), 5.65 (d, 4J = 2.4
Hz, 1 H, H-8), 6.56 (s, 1 H, H-4), 6.75 (dd, 4J = 2.4 Hz, 3J = 8.4 Hz, 1 H, H-10), 7.01 (s, 1 H, H-6´´), 7.30
4
4
(t, 3J = 8.4 Hz, 2 H, H-4´´ and H-11), 7.53 (dt, J = 1.6 Hz, J = 7.8 Hz, 1 H, H-5´´), 7.80 (s, 1 H, H-1´),
4
13
8.01 (dd, 4J = 1.6 Hz, J = 7.8 Hz, 1 H, H-3´´). C NMR (75 MHz, CDCl3): " = 21.12 (q), 30.38 (t),
37.80 (t), 56.09 (q), 58.12 (t), 60.99 (q), 61.08 (q), 62.31 (d), 107.59 (d), 109.21 (d), 114.67 (d,), 123.38
(d), 125.10 (d), 126.53 (d), 126.82 (s) 131.86 (d), 132.23 (d), 133.99 (s), 134.32 (d), 137.90 (s), 141.82 (s),
142.32 (s), 151.14 (s), 152.74 (s), 156.30 (s), 164.79 (s), 170.92 (s). MS (ESI, pos., 70 eV): m/z (%) =
599 (16), 598 (39) [M+K]+, 583 (27), 582 (100) [M+Na]+, 560 (35), 299 (10). HRMS (ESI, pos., 70 eV):
calcd for: [M+Na]+ (C30H29N3O8Na): 582.1852, found: 582.185. IR (ATR): # (cm-1) = 3381, 2945, 2915,
2847, 1764, 1705, 1649, 1642, 1633, 1606, 1579, 1537, 1484, 1451, 1429, 1403, 1366, 1324, 1289, 1269,
1247, 1231, 1194, 1154, 1139, 1107, 1086, 1049, 1040, 1007, 950, 931, 917, 861, 820, 791. [!]405 -35.5;
[!]365 -81.7; [!]334 -178.2 (CHCl3, c 1.0, 20 °C).
ACKNOWLEDGEMENTS
This work was supported by the Volkswagen foundation and the DAAD (research fellowship to N.S.) .

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