Synthesis of novel 1,2,3-triazolyl derivatives of pregnane, androstane and d-homoandrostane. Tandem "click" reaction/Cu-catalyzed d-homo rearrangement

Article abstract of DOI:10.1039/c4ob00404c

Copper-catalyzed 1,3-dipolar cycloaddition has been employed in the reaction of steroidal azides with various terminal alkynes. A number of novel 1,2,3-triazolyl derivatives of pregnane, androstane and d-homoandrostane were obtained in high yield (70-98%)

Full text of DOI:10.1039/c4ob00404c

Organic &
Biomolecular Chemistry
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Synthesis of novel 1,2,3-triazolyl derivatives of
pregnane, androstane and D-homoandrostane.
Tandem “click” reaction/Cu-catalyzed D-homo
rearrangement†
Cite this: Org. Biomol. Chem., 2014,
12, 3707
Yury N. Kotovshchikov, Gennadij V. Latyshev, Nikolay V. Lukashev* and
Irina P. Beletskaya
Copper-catalyzed 1,3-dipolar cycloaddition has been employed in the reaction of steroidal azides with
various terminal alkynes. A number of novel 1,2,3-triazolyl derivatives of pregnane, androstane and
D-homoandrostane were obtained in high yield (70–98%). The developed synthetic protocols allowed us
to attach the triazolyl moiety to both the side chain and the steroidal backbone directly, despite the steric
hindrance exerted by the polycyclic system. The presence of Cu(II) was shown to evoke D-homo
rearrangement under mild conditions. A rational choice of the copper precatalyst permitted us to carry
out the “click” reaction either along with tandem D-homo rearrangement or in the absence of this
process. The tendency of 16-heterosubstituted steroids to undergo D-homo rearrangement under Cu(II)
catalysis was studied.
Received 21st February 2014,
Accepted 2nd April 2014
DOI: 10.1039/c4ob00404c
www.rsc.org/obc
most prominent inhibitory effect was observed for D-ring-modi-
Introduction
fied steroids with heteroaryl4 or azolyl5 substituents. In 2011
17α-Hydroxylase-C17,20-lyase
(CYP17),
a
cytochrome abiraterone acetate (1) became the first steroidal CYP17 inhibi-
P450 mono-oxygenase, is a key enzyme for androgen biosyn- tor to be approved by the FDA for the treatment of castrate-
thesis. It catalyzes both the hydroxylation of C17 and the clea- resistant prostate cancer,6 while galeterone (2a), another
vage of the C17–C20 bond of pregnanes to produce androst- CYP17 inhibitor with AR antagonistic and ablative activities, is
4-ene-3,17-dione and dehydroepiandrosterone from progester- currently undergoing Phase I/II clinical trials.7
one and pregnenolone. Since the products of these transform-
Unfortunately, the synthesis of such compounds remains
ations are known to stimulate the development of prostate rather expensive and tedious8 despite the great progress
cancer by binding to androgen receptor (AR), selective suppres- in Pd-9,10 and Cu-catalyzed11 cross-coupling with steroids.
sion of androgen biosynthesis became an important thera- 17-(1,2,3-Triazolyl)-substituted steroid 2b5a (Fig. 1) offers another
peutic strategy to inhibit tumor growth.1 The large number of possibility for development of synthetically friendly and cheap
both steroidal and non-steroidal nitrogen-containing hetero- inhibitors of CYP17 since the 1,2,3-triazolyl moiety can be con-
cycles capable of binding to heme iron and blocking the structed through copper-catalyzed 1,3-dipolar azide–alkyne
C17-hydroxylation were found to be potent inhibitors of CYP17.
The use of a lipophilic steroid core with nitrogen-containing
substituents as the basis for the construction of new CYP17
inhibitors has the benefit of both creation of fairly good fitting
to a mostly hydrophobic active site of the enzyme2 and provid-
ing increased cell membrane permeability. Though many
nitrogen-containing steroidal inhibitors3 were proposed, the
Chemistry Department, M. V. Lomonosov Moscow State University, 1/3 Leninskiye
Gory, Moscow 119991, Russia. E-mail: nvluk@org.chem.msu.ru;
Fax: +7 (495) 422-32-97
†Electronic supplementary information (ESI) available: Copies of the 1H and
13C NMR spectra for compounds 4, 6, 8–13, 16, 17a, 17b, 18a, and 19c. See
Fig. 1 Known steroidal CYP17 inhibitors containing the heterocyclic
DOI: 10.1039/c4ob00404c
moiety.
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cycloaddition (CuAAC). This reaction enables an efficient syn-
thesis of 1,4-substituted 1,2,3-triazoles with excellent regios-
electivity and almost complete absence of by-products,
providing a high yield of the desired compound.12 The intro-
duction of a 1,2,3-triazolyl fragment13 into steroid molecules
has led to new biologically active compounds exhibiting anti-
cancer,14 anti-inflammatory,15 antimicrobial,16 and anti-HIV17
effects. Due to the mild conditions of the CuAAC reaction, the
1,2,3-triazole moiety became a convenient linker in bioconju-
gation of steroid-like molecules with various natural com-
pounds such as peptides,18 carbohydrates,14c,19 nucleosides,17
and nucleic acids.20
Scheme 2 Synthesis of 21-azidosteroid 6.
Herein, we report the synthesis of new 1,2,3-triazolylster-
oids bearing a heterocyclic moiety in the side chain as well as
in the 16-C position of the steroidal backbone. The obtained
compounds are of interest to medicinal chemistry as they are
potential CYP17 inhibitors which can be applied for treating
prostate diseases.
Results and discussion
Synthesis of azidosteroids
To prepare substrates for the CuAAC reaction we decided to
introduce the azide moiety into the steroidal framework. This
transformation was accomplished by modifying procedures
presented in the literature. One of the synthetic routes to azi-
dosteroids was nucleophilic ring opening of epoxides by
sodium azide.21 For example, a reaction of epoxide 3 with
sodium azide in a MeCN–H2O (1 : 1) mixture for 16 h at 100 °C
followed by hydrolysis of the enol ether group afforded azidos-
teroid 4 in high yield (Scheme 1).
The introduction of the azide moiety into the 21-C position
of the steroidal framework was performed by a two-step reac-
tion sequence. Mesylation of cortexolone 5 followed by nucleo-
philic substitution of the mesyloxy group by sodium azide gave
21-azidosteroid 6 in good yield (Scheme 2). Although substi-
tution of the 21-mesyloxy group is known to proceed at
ambient temperature,22 in our case the reaction was carried
out under reflux in order to achieve full conversion and reduce
the reaction time without lowering the yield.
Scheme 3 Synthesis of 16β-azidosteroids 8 and 9.
proceed completely.21b Under the conditions employed,
azidosteroid 9 partially transforms to structural isomer 8
undergoing α-ketol rearrangement that leads to the expansion
of 5-membered ring D of the steroidal backbone (so-called D-homo
rearrangement). This process is rather typical for 17α-hydroxy-
20-ketosteroids and can take place under both acid and base
catalysis.23 The mixture of isomers 8 and 9 was obtained in
good yield (71%), and both compounds were isolated in pure
state by column chromatography.
Copper-catalyzed 1,3-dipolar cycloaddition
The reaction of azidosteroid 4 with a number of terminal
alkynes was performed successfully using a standard catalytic
system for CuAAC comprising copper(II) sulfate and sodium
ascorbate (NaAsc) in a mixture of THF and water (Scheme 4).
The conditions used for nucleophilic ring opening of
epoxide 3 appeared to be absolutely ineffective in a reaction of
the more sterically hindered epoxide 7 (Scheme 3). Prolonged
heating for 5.5 days in DMSO in the presence of catalytic
amounts of sulfuric acid was required for the reaction to
Scheme 1 Synthesis of 17α-(azidomethyl)steroid 4.
3708 | Org. Biomol. Chem., 2014, 12, 3707–3720
Scheme 4 Synthesis of 17α-(triazolylmethyl)steroids 10.
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Table 1 Yields of triazolylsteroids in the CuAAC reaction of azidoster-
oids 4 and 6 with terminal alkynesa
Time
(h)
Yieldb
(%)
Entry
1
Substrate
R
Product
4
10a
15
15
81
93
2
4
10b
3
4
5
4
4
4
10c
10d
10e
15
16
14
70
96
93
Scheme 5 Synthesis of 21-triazolylsteroids 11.
chain reacted with terminal alkynes rather easily, and the
steroid fragment did not exert a noticeable steric effect on
their reactivity.
Attachment of the triazolyl moiety to C16 provides another
convenient way to introduce a coordinating N-atom in the
vicinity of the CYP17 active center. Since D-homo rearrange-
ment is the expected metabolic degradation pathway of
17α-hydroxy-20-ketopregnanes 13 and D-homosteroids are
known to exhibit valuable pharmacological properties,25 both
9 and the corresponding D-homoandrostane 8 were studied in
CuAAC. As was expected, the reaction of these more sterically
hindered azidosteroids proceeded more slowly and proved sen-
sitive to the composition of a catalytic system. The use of
CuSO4·5H2O and NaAsc in aqueous THF (method A) allowed
us to obtain product 12c via reaction of azidosteroid 8 with
propargyl alcohol (Scheme 6; Table 2, entry 3), but in the case
of phenylacetylene conversion was only 48% after 14 h. Since
copper carboxylates are known to accelerate the CuAAC reac-
tion,26 we applied presumably more active Cu(OAc)2·H2O as a
catalyst. Triethylamine was added to increase the solubility of
the catalyst in CH2Cl2 and facilitate the formation of copper
acetylide. This catalytic system (method B) appeared to be
effective for both phenylacetylene and 1-hexyne (Table 2,
entries 1 and 2). Alkyne with the diethylamino group also
reacted smoothly (entry 4), though for propargyl alcohol the
conversion was only 51% after 22 h.
Reaction of azidosteroid 9 with phenylacetylene reached
full conversion after 14 h when method A was used (Table 2,
entry 5), while in the case of method B, the result was unex-
pected. Method B led to D-homo rearrangement product
12 instead of 13, whereas this process did not take place in
method A (Scheme 6). Thus, the reaction of azidosteroid
9 with 1-hexyne and propargyl alcohol in method B was com-
plete after 22 h and furnished products 12b and 12c, respect-
ively (Table 2, entries 11 and 12). The yields appeared to be
even slightly better than for the same compounds synthesized
from azidosteroid 8 (cf. entries 2 vs. 11 and 3 vs. 12 in Table 2).
As method A was not applicable for the reaction of azido-
steroid 9 with some alkynes (e.g. the conversion in the case of
propargyl alcohol was only 16%), it was intriguing to find a
more effective catalytic system allowing to avoid D-homo
rearrangement. Apparently, one should prevent the formation
of copper(II) ions which possess higher Lewis acidity than
6
7
4
4
10f
15
16
89
91
10g
8
6
11a
14
86
9
6
6
11b
11c
22
22
98
98
10
a Reaction conditions: CuSO4·5H2O (10 mol%), NaAsc (40 mol%),
1-alkyne (1.2 equiv.), THF–H2O (4 : 1), 50 °C, 14–22 h. b Isolated yield.
All reactions of substrate 4 proceeded under mild con-
ditions affording 1,4-substituted 1,2,3-triazoles 10a–g bearing
both aliphatic (Table 1, entries 1–4) and aromatic (entries 5–7)
fragments in high yield. Hydroxy (entries 1 and 2) and amino
groups (entry 4) were tolerated by the reaction conditions.
4-Nitrophenylacetylene (entry 6), which is known to be a challen-
ging substrate for some reactions due to a tendency to add
nucleophiles, also reacted well. It is worth mentioning that a
high yield (91%) was achieved in the reaction of 4 with ethynyl-
ferrocene (entry 7), though reactivity of azidosteroids is not
always high in the case of alkynes bearing bulky substituents.
For instance, 2-azidosteroid is known to react with ethynylferro-
cene in 64% yield, while the more sterically hindered 6-azi-
dosteroid gives only trace amounts of the corresponding
product.24
The standard catalytic system based on CuSO4·5H2O and
NaAsc also allowed to synthesize 1,2,3-triazoles attached to the
21-C position of the steroidal backbone (Scheme 5). The
corresponding 21-derivatives of 17α-hydroxyprogesterone
11a–c were isolated in excellent yields (Table 1, entries 8–10).
Thus, both substrates 4 and 6 bearing the azide moiety in the side
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Scheme 6 Synthesis of 16β-triazolylsteroids 12 and 13.
Table 2 Yields of triazolylsteroids in the CuAAC reaction of azidosteroids 8 and 9 with terminal alkynesa
Entry
1
Substrate
Product
R
Method
Time (h)
18/14
Isolated yield (%)
79/48b
12a
B/A
2
3
12b
12c
B
22
84
A/B
14/22
84/51b
4
5
12d
13a
B
A
20
14
81
95
6
7
13b
13c
C
19
90
C/A
20/14
94/16b
8
9
13d
13e
C
C
20
20
95
87
10
13f
C
20
73
11
12
12b
12c
B
B
22
22
90
98
a Reaction conditions: A: CuSO4·5H2O (10 mol%), NaAsc (40 mol%), THF–H2O (4 : 1), 50 °C, 14 h; B: Cu(OAc)2·H2O (5 mol%), Et3N (1 equiv.),
CH2Cl2, 50 °C, 18–22 h; C: CuSO4·5H2O (10 mol%), TBTA (10 mol%), NaAsc (40 mol%), THF–H2O (4 : 1), 50 °C, 19–20 h. b 1H NMR yield.
3710 | Org. Biomol. Chem., 2014, 12, 3707–3720
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copper(I) ones, i.e. the reaction should be made in the pres-
Absolute configuration of atoms 17-C and 17a-C in the pro-
ence of the reductant – sodium ascorbate. To increase the con- ducts of tandem CuAAC/D-homo rearrangement reaction was
version of 9 we employed triazole-based chelating ligands that established by 1D NOESY experiments (Scheme 8a). The pres-
are well known to accelerate the CuAAC reaction and stabilize ence of NOEs from the CH3 group in the 17-C position to
copper(I) species.27 Thus,
a catalytic system comprising 15β-H and 18-CH3 in 12c suggests that they are in the same
CuSO4·5H2O, tris(benzyltriazolylmethyl)amine (TBTA) and face. The absence of NOE between the axial proton 16-CH(tria-
NaAsc (method C) allowed us to achieve a full conversion of zole) and the CH3 group in the 17-C position and the presence
azidosteroid 9, suppress the D-homo rearrangement process, of NOE between 16-CH and 17a-CHOH protons confirmed the
and isolate the corresponding products 13b and 13c in high structure of 1,2-diol expressed by formula 16. This configur-
yield (Table 2, entries 6 and 7). Tris(tert-butyltriazolylmethyl) ation is consistent with a bottom face attack of NaBH4 on the
amine (TTTA) while efficiently suppressing D-homo rearrange- carbonyl group as the attack from the top face is less prefer-
ment led to incomplete conversion of azidosteroid 9. Alkyne able due to a significant steric effect of the two methyl groups
containing diethylamino group (entry 8), which could stabilize (Scheme 8b). The regio- and stereochemistry of D-homo
the copper(II) oxidation state and facilitate D-homo rearrange- rearrangement product were also confirmed by X-ray crystallo-
ment, afforded exclusively product 13d in excellent yield. graphic analysis of deacetylated 12a (Fig. 2).
Alkynes bearing acidic phenol and carboxyl moieties (entries 9
and 10) also afforded the corresponding products 13e and 13f Lewis acid catalyzed D-homo rearrangement. Indeed, a com-
in high yield. plete isomerization of 13a to 12a was observed after 18 h not
The structure of rearranged products 12 is consistent with
To confirm the structure of the D-homo rearrangement only under conditions used in method B but also in the pres-
product formed under conditions B, the carbonyl group in the ence of Cu(OAc)2·H2O alone.
D ring was reduced by NaBH4 (Scheme 7). According to the lit-
Although the detailed mechanism of the rearrangement is
erature,23 D-homo rearrangement of 17α-hydroxy-20-keto- not quite clear even for “traditional” Lewis acids, all proposed
steroids can lead to one of the two regioisomers 14a or 14b pathways are very similar. Coordination of the metal ion or
depending on the substrate structure, relative stability of the hydrogen bonding provides the necessary syn alignment of
products and reaction conditions. Since CHOH proton carbonyl and hydroxyl groups and facilitates 1,2-migration of
appears as a singlet at 3.36 ppm in the 1H NMR spectrum
of 1,2-diol 16, the carbonyl group must be in 17a-C position,
i.e. regioisomer 14b formed (Scheme 7).
Scheme 8 (a) 1D NOESY experiments for 12c and 16; (b) assignment of
stereochemistry of the D-homo rearrangement product.
Scheme 7 Assignment of regiochemistry of D-homo rearrangement
product.
Fig. 2 X-ray crystal structure of deacetylated 12a.
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Table 3 Cu-catalyzed D-homo rearrangement of 16-substituted steroids
Conversiona
(%)
Scheme 9 Possible mechanism of Cu-catalyzed D-homo rearrangement.
Parent
structure
Entry
Substrate
R2
R
1
2
3
19a
19b
6
19
19
19
H
OH
N3
H
H
H
0
0
0
16-C via the chair-like transition state, resulting in a more
stable 6-membered ring (Scheme 9).
4
11a
19
H
0
Apart from the “classical” mechanism involving 5-mem-
bered chelate (TS1),28,29 more complex transition states were
proposed. Thus, coordination of 2 BF3 molecules with carbo-
nyl and hydroxyl groups, connected by intramolecular hydro-
gen bond was assumed for BF3-promoted D-homo
5
6
9
18
18
—
—
N3
100
100
rearrangement on the basis of NMR and kinetic data.30
A
13a
7-membered cyclic transition state featuring a hydrogen bond
of the hydroxyl group with an oxygen ligand on the metal was
predicted by DFT calculations for Al-catalyzed 1,2-hydride shift
in hydrated glyoxal.31 Therefore, analogous transition states
TS2 and TS3 can be expected for the Cu-catalyzed D ring
expansion.
The generality of the Cu(II)-catalyzed rearrangement was
studied on various substrates containing a 17α-hydroxy-20-keto
fragment (Table 3). D-Homo rearrangement was not observed
for compounds 6 and 11a (entries 3 and 4) bearing the azide
and 1,2,3-triazolyl moiety in the 21-C position, respectively.
Other 16-unsubstituted steroids 19a and 19b (entries 1 and 2)
were also recovered unchanged after heating with 5 mol%
Cu(OAc)2·H2O at 50 °C for 18 h. Thus, the nature of substituents
on the migrating center was believed to be the main determi-
nant of D-homo rearrangement. In order to understand the
reason for the obtained compounds 13 to transform to 12
7
17a
17
—
Cl
6
23b
0
8
9
18a
17b
18
17
—
—
OAc
SPh
50
66b
19c
0b
10
11
17b
19c
17
19
—
H
SPh
SCN
a By 1H NMR. b The mixture CH2Cl2–DMSO (4 : 1) was used as a solvent
to increase substrate solubility. c 5 mol% Cu(OTf)2 was used as a
catalyst.
We believe that the lone pair of nitrogen atoms can stabilize
under copper(II) catalysis so easily, we investigated steroids the nearby cationoid center; therefore full conversion was
bearing different heteroatoms in the 16-C position.
obtained for 16β-azido and 16β-triazol-1-yl substituted
Regardless of the actual structure of the transition state, a compounds 9 and 13a (Table 3, entries 5 and 6). However
shift of electron density induced by coordination of Lewis acid 16β-acetoxy substituted compound 18a was isolated
to α-ketol increases positive charge on the migrating 16-C unchanged when treated with copper(II) acetate probably due
atom. It is generally accepted that substituents on 16-C, to the combined effect of higher electronegativity of oxygen
capable of stabilizing partial positive charge in the transition and the electron-withdrawing property of the acetyl group
state, facilitate D-homoannulation.32 Thus, 16β-methyl-33 and (entry 8). The phenylthio group produces a significant amount
16β-phenylsteroids25b rearrange under milder conditions than of rearranged product but the replacement of the almost
the corresponding unsubstituted derivatives. The same ten- electron-neutral phenyl group at sulfur (entry 9) with a
dency was observed for the rearrangement of p-substituted strong electron-withdrawing cyano-group (entry 11) led to
16α-benzoyloxysteroids.33b
complete suppression of the rearrangement. Therefore copper
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(II) acetate can be regarded as a rather weak Lewis acid capable with an Elementar Vario MICRO cube apparatus. Column
of inducing D-homo rearrangement only with “activated” chromatography was carried out on Macherey–Nagel silica gel
substrates.
60 (0.040–0.063 mm). Compounds 17a,34 17b,35 18a36 and
The rearrangement of 17b was attempted with more electro- 19c37 were prepared according to literature procedures.
philic copper(II) triflate (entry 10) but only 19% of the product
was obtained. Since the increased electrophilicity of copper
Synthesis of azidosteroids
should favor the rearrangement via TS2 (Scheme 9), this
17α-(Azidomethyl)-17β-hydroxyandrost-4-en-3-one (4). In a
pathway is doubtful. Under the same conditions anhydrous vial with a screw cap, a mixture of 3 (1.572 g, 5.00 mmol),
CuCl2 afforded only traces of D-homosteroid, whereas 47% con- NaN3 (1.30 g, 20.0 mmol), acetonitrile (5.0 mL), and water
version of 17b was observed for hydrate CuCl2·2H2O. In con- (5.0 mL) was stirred at 100 °C for 16 h. The solution was
trast, anhydrous Cu(OAc)2 afforded even slightly higher diluted with CH2Cl2 (50 mL), washed with water (2 × 50 mL),
conversion than Cu(OAc)2·H2O (58% vs. 50%). Thus, oxygen dried with anhydrous Na2SO4, and evaporated under vacuum.
ligands on copper play a significant role in modulating the The residue was mixed with 95% ethanol (20 mL) and conc.
catalyst activity. These data are more consistent with transition HCl (1.0 mL) and stirred under reflux for 30 min. The solution
state TS3 where the hydrogen bond of α-ketol with a ligand was diluted with CH2Cl2 (100 mL), washed with satd. Na2CO3
bound to copper(II) is a distinct feature of the mechanism, (100 mL), water (2 × 100 mL), dried with anhydrous Na2SO4,
though the pathway via “classical” transition state TS1 cannot and evaporated under vacuum. The residue was purified by
be definitely ruled out.
column chromatography (eluent: CH2Cl2–MeOH = 50 : 1). Yield
1.551
g
(90%). White solid; mp 154–156 °C (lit.,21a
1
153–155 °C); H NMR (400 MHz, CDCl3) δ 5.72 (s, 1H, 4-CH),
3.52 (d, J = 12.1 Hz, 1H, CH2N3), 3.23 (d, J = 12.1 Hz, 1H,
CH2N3), 2.47–2.30 (m, 3H), 2.26 (ddd, J = 14.7, 4.5, 2.5 Hz, 1H),
Conclusions
New types of 1,2,3-triazolyl steroids were prepared by the 2.05–1.94 (m, 3H), 1.84 (m, 1H), 1.76–1.56 (m, 6H), 1.45 (qd,
CuAAC reaction. Primary azides 4 and 6 were transformed to J = 12.6, 3.8 Hz, 1H), 1.36 (qd, J = 12.3, 7.1 Hz, 1H), 1.25–1.08
the corresponding products in high yields (70–98%) using (m, 2H), 1.18 (s, 3H, 19-CH3), 1.05–0.85 (m, 2H), 0.93 (s, 3H,
standard conditions (CuSO4·5H2O, NaAsc, THF–H2O), while 18-CH3); 13C NMR (100.6 MHz, CDCl3) δ 199.4 [C(3)vO], 170.8
the reaction of more sterically hindered secondary azides (5-C), 123.9 (4-CH), 83.2 (17-COH), 58.2 (CH2N3), 53.6, 50.7,
8 and 9 proved sensitive to the composition of the catalytic 45.7 (quat.), 38.6 (quat.), 36.3, 35.7, 34.7, 33.9, 32.7, 31.7,
system. The use of Cu(OAc)2·H2O generally afforded more 31.6, 23.5, 20.6, 17.3, 14.1; IR (KBr) ν = 3414 (OH), 2094 (N3),
reliable results in these cases. Cu(II)-catalyzed α-ketol 1657 (CvO) cm−1; HRMS (MALDI-TOF) calcd for C20H30NO2
rearrangement was found to interfere in the coupling of 9 with [M + H − N2]+ 316.2277; found 316.2273.
1-alkynes leading to exclusive formation of D-homoandrostanes
21-Methanesulfonyloxy-17α-hydroxypregn-4-ene-3,20-dione
12 instead of 13 by a tandem CuAAC/rearrangement sequence. (5a). A solution of 5 (1.386 g, 4.00 mmol) in a mixture of
Prevention of Cu(I) oxidation and addition of TBTA led to CH2Cl2 (40 mL) and triethylamine (1.23 mL, 8.80 mmol) was
acceleration of the CuAAC reaction and suppression of isomer- cooled to 0 °C in an ice bath. Then methanesulfonyl chloride
ization. Cu(II) appeared to be a rather weak Lewis acid that (0.341 mL, 4.40 mmol) was added dropwise, and the solution
could facilitate D-homo rearrangement only of “activated” sub- was stirred at rt for 1 h. The mixture was diluted with CH2Cl2
strates. The compounds synthesized will be evaluated for their (50 mL) and subsequently washed with HCl (10%, 100 mL),
potential CYP17 inhibitory effect.
satd. Na2CO3 (100 mL), and water (100 mL). The organic layer
was dried with anhydrous Na2SO4, and the solvents were evap-
orated under vacuum. The product was used in the synthesis
of 6 without further purification. Yield 1.645 g (97%). White
solid; 1H NMR (400 MHz, CDCl3–DMSO-d6) δ 5.70 (s, 1H,
4-CH), 5.39 (d, J = 18.1 Hz, 1H, 21-CH2OMs), 5.36 (d, J = 18.1 Hz,
Experimental
General information
NMR spectra were recorded with a Bruker Avance 400 and an 1H, 21-CH2OMs), 3.18 (s, 3H, SO2CH3), 2.63 (m, 1H), 2.47–2.21
Agilent 400MR spectrometer (1H 400 MHz, 13C 100.6 MHz) (m, 4H), 2.03 (m, 1H), 1.94–1.24 (m, 12H), 1.18 (s, 3H, 19-CH3),
at ambient temperature in CDCl3 or in CDCl3–DMSO-d6, 1.08 (qd, J = 13.0, 4.0 Hz, 1H), 0.97 (m, 1H), 0.66 (s, 3H,
CCl4–DMSO-d6 and CDCl3–CD3OD mixtures for compounds 18-CH3); 13C NMR (100.6 MHz, CDCl3–DMSO-d6) δ 204.9 [C(20)vO],
with low solubility in CDCl3. Chemical shifts are presented in 199.1 [C(3)vO], 170.9 (5-C), 123.3 (4-CH), 89.0 (17-COH), 72.8
ppm (δ scale) and referenced to hexamethyldisiloxane (δ = (21-CH2OMs), 52.8, 49.9, 47.7 (quat.), 38.6 (SO2CH3), 38.1
1
0.05 ppm) in the H NMR spectra and to the solvent signal in (quat.), 35.2 (2C), 33.9, 33.5, 32.4, 31.6, 29.8, 23.2, 20.3, 16.9,
the 13C NMR spectra. IR spectra were recorded with a Thermo 14.2.
Nicolet 200 FT-IR instrument in KBr pellets. MALDI-TOF
21-Azido-17α-hydroxypregn-4-ene-3,20-dione (6). A suspen-
spectra were recorded with a Bruker Daltonics UltraFlex instru- sion of 5a (1.645 g, 3.87 mmol) and NaN3 (1.040 g, 16.0 mmol)
ment in a dithranol matrix using PEG 400 or PEG 600 as in acetone (50 mL) was heated for 6 h under reflux with stir-
the internal standard. Elemental analyses were performed ring. The mixture was diluted with CH2Cl2 (100 mL), washed
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with water (2 × 100 mL), dried with anhydrous Na2SO4, and General procedure for copper-catalyzed 1,3-dipolar
evaporated under vacuum. The residue was purified by column cycloaddition
chromatography (eluent: CH2Cl2–MeOH = 20 : 1). Yield 1.071 g
Method A: In
a vial with a screw cap, azidosteroid
1
(74%). White solid; mp 201–203 °C (dec.); H NMR (400 MHz,
(0.200 mmol), CuSO4·5H2O (5.0 mg, 20 μmol, 10 mol%), and
water (0.2 mL) were mixed. Then THF (0.8 mL), terminal
alkyne (0.240 mmol), and sodium ascorbate (16.7 mg,
80 μmol, 40 mol%) were subsequently added. The reaction
mixture was stirred at 50 °C for 12–24 h, diluted with CH2Cl2
(25 mL), and washed with water (2 × 25 mL). The organic layer
was dried with anhydrous Na2SO4, and the solvents were evap-
orated under vacuum. The residue was purified by column
chromatography.
Method B: In a vial with a screw cap, azidosteroid
(0.200 mmol), terminal alkyne (0.240 mmol), Cu(OAc)2·H2O
(2.0 mg, 10 μmol, 5 mol%), and triethylamine (27.8 μL,
0.200 mmol) were mixed under an Ar atmosphere in CH2Cl2
(1.0 mL). The reaction mixture was stirred at 50 °C for 12–24 h,
diluted with CH2Cl2 (25 mL), and washed with water
(2 × 25 mL). The organic layer was dried with anhydrous
Na2SO4, and the solvents were evaporated under vacuum. The
residue was purified by column chromatography.
CDCl3–DMSO-d6) δ 5.69 (s, 1H, 4-CH), 4.48 (d, J = 18.7 Hz,
1H, 21-CH2N3), 3.95 (d, J = 18.7 Hz, 1H, 21-CH2N3), 2.67 (ddd,
J = 14.7, 11.6, 3.2 Hz, 1H), 2.49–2.22 (m, 4H), 2.03 (dt, J = 13.4,
4.0 Hz, 1H), 1.94–1.22 (m, 12H), 1.18 (s, 3H, 19-CH3), 1.08 (qd,
J = 13.0, 4.0 Hz, 1H), 0.97 (td, J = 11.4, 4.2 Hz, 1H), 0.65 (s, 3H,
18-CH3); 13C NMR (100.6 MHz, CDCl3–DMSO-d6) δ 206.9
[C(20)vO], 198.8 [C(3)vO], 170.7 (5-C), 123.1 (4-CH), 88.8
(17-COH), 55.5 (21-CH2N3), 52.6, 49.7, 47.1 (quat.), 38.0 (quat.),
35.0 (2C), 33.5, 33.3, 32.2, 31.4, 29.9, 23.0, 20.1, 16.8, 14.3;
IR (KBr) ν = 3506 (OH), 2109 (N3), 1718 [C(20)vO], 1654
[C(3)vO] cm−1; HRMS (MALDI-TOF) calcd for C21H30N3O3
[M
+
H]+ 372.2282; found 372.2287; Anal. calcd for
C21H29N3O3: C, 67.90; H, 7.87; N, 11.31; found C, 67.92; H,
7.79; N, 11.52.
3β-Acetoxy-16β-azido-17α-hydroxy-17β-methyl-D-homo-
androst-5-en-17a-one (8) and 3β-acetoxy-16β-azido-
17α-hydroxypregn-5-en-20-one (9). A mixture of 7 (1.128 g,
3.00 mmol), NaN3 (3.942 g, 60.6 mmol), and H2SO4 (98%,
186 μL) in DMSO (36 mL) was stirred at 100 °C for 132 h. The
mixture was diluted with CH2Cl2 (100 mL), washed with satd.
Na2CO3 (100 mL), water (3 × 100 mL), dried with anhydrous
Na2SO4, and evaporated under vacuum. The residue was sub-
jected to column chromatography (eluent: hexanes–EtOAc =
4 : 1) to afford pure products 8 and 9.
Method C: Synthesis was performed as described for
method A with the addition of 10 mol% of tris[(1-benzyl-1H-
1,2,3-triazol-4-yl)methyl]amine (TBTA).
17β-Hydroxy-17α-{[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]-
methyl}androst-4-en-3-one (10a). Synthesized according to
method A from 4 (68.7 mg, 0.200 mmol) and propargyl alcohol
(14.0 μL, 0.240 mmol); heating 15 h; eluent: CH2Cl2–MeOH =
3β-Acetoxy-16β-azido-17α-hydroxy-17β-methyl-D-homoan-
drost-5-en-17a-one (8). Yield 571.2 mg (46%). White solid; mp
208–210 °C (lit.,21b 209–210 °C); 1H NMR (400 MHz, CDCl3)
δ 5.36 (d, J = 4.4 Hz, 1H, 6-CH), 4.58 (tt, J = 11.4, 4.7 Hz, 1H,
3-CHOAc), 4.18 (s, 1H, OH), 3.52 (dd, J = 12.5, 4.6 Hz, 1H,
16-CHN3), 2.39–2.13 (m, 3H), 2.02 [s, 3H, OC(O)CH3],
2.01–1.82 (m, 3H), 1.72–0.93 (m, 11H), 1.40 (s, 3H, 17-CCH3),
1.10 (s, 3H, 18-CH3), 1.01 (s, 3H, 19-CH3); 13C NMR
(100.6 MHz, CDCl3) δ 215.3 [C(17a)vO], 170.4 [OC(O)CH3],
139.6 (5-C), 121.4 (6-CH), 79.7 (17-COH), 73.5 (3-CHOAc),
69.6 (16-CHN3), 48.8, 47.2, 46.3 (quat.), 37.7, 36.8 (quat.),
36.5, 32.6, 31.5, 30.6, 27.5, 27.1, 22.7, 21.4, 19.2 (2C), 15.8;
IR (KBr) ν = 3505 (OH), 2130 (N3), 1730 (CvO, ester),
1
10 : 1. Yield 65.0 mg (81%). White solid; mp 236 °C; H NMR
(400 MHz, CDCl3–DMSO-d6) δ 7.87 [s, 1H, CH(triazole)], 5.66
(s, 1H, 4-CH), 5.00 (br t,
J = 5.8 Hz, 1H, OH), 4.64
(m, 3H, CH2OH, OH), 4.44 (d, J = 13.7 Hz, 1H, CH2N), 4.25 (d, J =
13.7 Hz, 1H, CH2N), 2.48–2.22 (m, 4H), 2.04 (ddd, J = 13.5, 5.0,
3.2 Hz, 1H), 1.88 (m, 1H), 1.76–1.17 (m, 11H), 1.21 (s, 3H,
19-CH3), 1.09 (td, J = 12.5, 4.4 Hz, 1H), 1.01–0.96 (m, 1H), 0.94
(s, 3H, 18-CH3); 13C NMR (100.6 MHz, CDCl3–DMSO-d6)
δ
197.4 [C(3)vO], 169.6 (5-C), 146.6 [C(triazole)], 122.9
[CH(triazole)], 122.3 (4-CH), 80.7 (17-COH), 54.9, 54.6, 52.1,
49.0, 44.8 (quat.), 37.2 (quat.), 35.0, 34.2, 32.6, 31.3, 30.3 (2C),
29.5, 22.1, 19.2, 16.0, 13.1; HRMS (MALDI-TOF) calcd for
C23H34N3O3 [M + H]+ 400.2595; found 400.2598; Anal. calcd
for C23H33N3O3: C, 69.14; H, 8.33; N, 10.52; found C, 69.00;
H, 8.38; N, 10.37.
1700 (CvO, ketone) cm−1
.
3β-Acetoxy-16β-azido-17α-hydroxypregn-5-en-20-one (9). Yield
310 mg (25%). White solid; mp 141–143 °C (lit.,21b
142.5–144.5 °C); 1H NMR (400 MHz, CDCl3) δ 5.37 (d, J =
4.0 Hz, 1H, 6-CH), 4.58 (tt, J = 11.5, 5.4 Hz, 1H, 3-CHOAc), 3.95
(dd, J = 8.0, 6.2 Hz, 1H, 16-CHN3), 3.62 (s, 1H, OH), 2.44–2.25
(m, 3H), 2.38 (s, 3H, 21-CH3), 2.06–1.94 (m, 1H), 2.02 [s, 3H,
OC(O)CH3], 1.90–1.80 (m, 2H), 1.72–1.36 (m, 9H), 1.11 (td, J =
14.0, 4.5 Hz, 1H), 1.05–0.93 (m, 1H), 1.02 (br s, 6H, 18-CH3,
19-CH3); 13C NMR (100.6 MHz, CDCl3) δ 208.3 [C(20)vO],
170.5 [OC(O)CH3], 139.7 (5-C), 122.0 (6-CH), 89.1 (17-COH),
73.7 (3-CHOAc), 69.5 (16-CHN3), 49.4, 48.6, 47.6 (quat.), 38.0,
36.9, 36.6 (quat.), 33.1, 31.7, 31.1, 30.5, 29.5, 27.6, 21.4, 19.9,
17β-Hydroxy-17α-{[4-(1-hydroxy-1-methylethyl)-1H-1,2,3-triazol-
1-yl]methyl}androst-4-en-3-one (10b). Synthesized according
to method A from 4 (68.7 mg, 0.200 mmol) and 2-methylbut-
3-yn-2-ol (23.3 μL, 0.240 mmol); heating 15 h; eluent: CH2Cl2–
MeOH = 10 : 1. Yield 79.4 mg (93%). White solid; mp 129 °C;
1H NMR (400 MHz, CCl4–DMSO-d6) δ 7.70 [s, 1H, CH(triazole)],
5.58 (s, 1H, 4-CH), 4.80 (s, 1H, OH), 4.62 (s, 1H, OH), 4.36 (d,
J = 13.7 Hz, 1H, CH2N), 4.14 (d, J = 13.7 Hz, 1H, CH2N),
2.45–2.13 (m, 4H), 2.00 (m, 1H), 1.85 (m, 1H), 1.73–0.81
(m, 13H), 1.46 [s, 3H, C(CH3)2OH], 1.44 [s, 3H, C(CH3)2OH],
19.3, 15.3; IR (KBr) ν = 3330–3490 (OH), 2125 (N3), 1740 (CvO, 1.19 (s, 3H, 19-CH3), 0.88 (s, 3H, 18-CH3); 13C NMR (100.6 MHz,
ester), 1715 (CvO, ketone) cm−1
.
CCl4–DMSO-d6) δ 196.8 [C(3)vO], 169.5 (5-C), 155.2 [C(triazole)],
3714 | Org. Biomol. Chem., 2014, 12, 3707–3720
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123.2 (4-CH), 121.4 [CH(triazole)], 81.4 (17-COH), 67.1 130.1 [1-C(Ph)], 127.9 [2C, 3,5-CH(Ph)], 126.9 [4-CH(Ph)], 124.5
[C(CH3)2OH], 55.5, 52.9, 49.6, 45.7 (quat.), 38.0 (quat.), 36.0, [2C, 2,6-CH(Ph)], 122.8 (4-CH), 121.4 [CH(triazole)], 81.3
(17-COH), 55.6, 52.7, 49.5, 45.4 (quat.), 37.7 (quat.), 35.5, 34.7,
33.0, 31.8, 31.0, 30.7, 30.1, 22.6, 19.7, 16.5, 13.5; IR (KBr) ν =
3630–3200 (OH), 1676 (CvO), 771 (Ar) cm−1; HRMS (MALDI-
TOF) calcd for C28H36N3O2 [M + H]+ 446.2802; found 446.2798;
Anal. calcd for C28H35N3O2: C, 75.47; H, 7.92; N, 9.43; found C,
75.62; H, 7.63; N, 9.22.
35.1, 33.4, 32.1, 31.2, 30.9, 30.7, 30.4, 30.3, 23.0, 20.1, 16.9,
14.0; HRMS (MALDI-TOF) calcd for C25H37N3NaO3 [M + Na]+
450.2733; found 450.2732; Anal. calcd for C25H37N3O3: C,
70.22; H, 8.72; N, 9.83; found C, 69.88; H, 8.65; N, 9.62.
17β-Hydroxy-17α-[(4-butyl-1H-1,2,3-triazol-1-yl)methyl]androst-
4-en-3-one (10c). Synthesized according to method A from 4
(68.7 mg, 0.200 mmol) and hex-1-yne (27.6 μL, 0.240 mmol);
heating 15 h; eluent: CH2Cl2–Et2O = 4 : 1. Yield 59.8 mg (70%).
White solid; mp 95–96 °C; 1H NMR (400 MHz, CDCl3) δ 7.58 [s,
1H, CH(triazole)], 5.72 (s, 1H, 4-CH), 4.42 (d, J = 13.7 Hz, 1H,
CH2N), 4.32 (d, J = 13.7 Hz, 1H, CH2N), 2.69 (t, J = 7.7 Hz, 2H,
CH2Pr), 2.47–2.28 (m, 3H), 2.27 (ddd, J = 15.1, 4.7, 3.1 Hz, 1H),
2.02 (ddd, J = 13.4, 5.0, 3.2 Hz, 1H), 1.86 (m, 1H), 1.76–1.12 (m,
17β-Hydroxy-17α-{[4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl]-
methyl}androst-4-en-3-one (10f). Synthesized according to
method A from 4 (68.7 mg, 0.200 mmol) and (4-nitrophenyl)
acetylene (35.3 mg, 0.240 mmol); heating 15 h; eluent:
CH2Cl2–MeOH = 50 : 1. Yield 87.7 mg (89%). White solid; mp
1
249 °C; H NMR (400 MHz, CDCl3) δ 8.26 [d, J = 8.7 Hz, 2H,
3,5-CH(Ar)], 8.22 [s, 1H, CH(triazole)], 7.99 [d, J = 8.7 Hz, 2H,
14H), 1.20 (s, 3H, 19-CH3), 1.10–0.86 (m, 2H), 1.11–0.89 (m, 2,6-CH(Ar)], 5.72 (s, 1H, 4-CH), 4.56 (d, J = 13.7 Hz, 1H, CH2N),
2H), 0.94 (s, 3H, 18-CH3), 0.91 (t, J = 7.4 Hz, 3H, CH3); 13C 4.39 (d, J = 13.7 Hz, 1H, CH2N), 2.60 (m, 1H), 2.47–2.24 (m,
NMR (100.6 MHz, CDCl3) δ 199.3 [C(3)vO], 170.9 (5-C), 147.8 4H), 2.03 (ddd, J = 13.3, 4.9, 3.3 Hz, 1H), 1.87 (m, 1H),
[C(triazole)], 123.8 (4-CH), 122.9 [CH(triazole)], 82.6 (17-COH), 1.82–1.61 (m, 6H), 1.51 (qd, J = 12.9, 3.8 Hz, 1H), 1.57–1.17 (m,
56.2, 53.5, 50.2, 46.0 (quat.), 38.5 (quat.), 36.2, 35.5, 33.7, 32.6 4H), 1.20 (s, 3H, 19-CH3), 1.10–0.91 (m, 2H), 1.01 (s, 3H,
18-CH3); 13C NMR (100.6 MHz, CDCl3) δ 199.4 [C(3)vO], 170.7
(5-C), 147.1 [C(triazole) or 4-C(Ar)], 145.2 [C(triazole) or 4-C(Ar)],
(2C), 31.4, 31.3, 30.8, 25.2, 23.4, 22.1, 20.4, 17.2, 14.0, 13.7; IR
(KBr) ν = 3311 (OH), 1660 (CvO) cm−1; HRMS (MALDI-TOF)
calcd for C26H40N3O2 [M + H]+ 426.3115; found 426.3110; Anal.
137.0 [1-C(Ar)], 126.0 [2C, CH(Ar)], 124.2 [2C, CH(Ar)], 124.0
calcd for C26H39N3O2: C, 73.37; H, 9.24; N, 9.87; found C,
73.32; H, 9.10; N, 9.72.
[CH(triazole) or 4-CH], 123.5 [CH(triazole) or 4-CH], 82.9
(17-COH), 56.5, 53.6, 50.3, 46.1 (quat.), 38.5 (quat.), 36.4, 35.6,
33.8, 33.3, 32.6, 31.5, 30.9, 23.5, 20.5, 17.3, 14.0; IR (KBr)
ν = 3400 (OH), 1654 (CvO), 1517 (NO2), 1334 (NO2), 852 (C–N)
cm−1; HRMS (MALDI-TOF) calcd for C28H34N4NaO4 [M + Na]+
513.2478; found 513.2473; Anal. calcd for C28H34N4O4: C,
68.55; H, 6.99; N, 11.42; found C, 68.26; H, 6.93; N, 11.41.
17β-Hydroxy-17α-[(4-ferrocenyl-1H-1,2,3-triazol-1-yl)methyl]-
androst-4-en-3-one (10g). Synthesized according to method A
from 4 (68.7 mg, 0.200 mmol) and ethynylferrocene (50.4 mg,
0.240 mmol); heating 16 h; eluent: CH2Cl2–MeOH = 50 : 1.
Yield 101.2 mg (91%). Orange solid; mp 235 °C (dec.); 1H NMR
(400 MHz, CDCl3) δ 7.68 [s, 1H, CH(triazole)], 5.73 (s, 1H,
4-CH), 4.77 (br s, 1H, C5H4), 4.73 (br s, 1H, C5H4), 4.42 (d, J =
13.8 Hz, 1H, CH2N), 4.32 (m, 3H, 1H, CH2N + 2H, C5H4), 4.07
(s, 5H, C5H5), 2.91 (s, 1H, 17-COH), 2.48–2.24 (m, 4H), 2.01
(ddd, J = 13.5, 4.6, 3.8 Hz, 1H), 1.90–0.87 (m, 14H), 1.19 (s, 3H,
19-CH3), 1.00 (s, 3H, 18-CH3); 13C NMR (100.6 MHz, CDCl3) δ
199.4 [C(3)vO], 170.7 (5-C), 146.4 [C(triazole)], 124.0 (4-CH),
121.2 [CH(triazole)], 83.0 (17-COH), 75.9 (quat., C5H4), 69.8
(5C, C5H5), 68.9 (2C, C5H4), 66.74 (1C, C5H4), 66.69 (1C, C5H4),
56.3, 53.6, 50.3, 46.1 (quat.), 38.6 (quat.), 36.4, 35.7, 33.9, 33.3,
32.7, 31.5, 31.0, 23.5, 20.5, 17.3, 14.1; HRMS (MALDI-TOF)
calcd for C32H39FeN3NaO2 [M
576.2292; Anal. calcd for C32H39FeN3O2: C, 69.44; H, 7.10; N,
7.59; found C, 69.61; H, 7.21; N, 7.57.
21-(4-Phenyl-1H-1,2,3-triazol-1-yl)-17α-hydroxypregn-4-ene-3,
20-dione (11a). Synthesized according to method A from 6
(74.3 mg, 0.200 mmol) and phenylacetylene (26.4 μL,
0.240 mmol); heating 14 h; eluent: CH2Cl2–MeOH = 20 : 1.
Yield 81.2 mg (86%). White solid; mp 254–255 °C; 1H NMR
(400 MHz, CDCl3–DMSO-d6) δ 7.89 [s, 1H, CH(triazole)], 7.83
[d, J = 7.2 Hz, 2H, 2,6-CH(Ph)], 7.41 [t, J = 7.2 Hz, 2H, 3,5-CH
17β-Hydroxy-17α-({4-[(diethylamino)methyl]-1H-1,2,3-triazol-
1-yl}methyl)androst-4-en-3-one (10d). Synthesized according
to method A from 4 (68.7 mg, 0.200 mmol) and N,N-diethylpro-
pargylamine (33.3 μL, 0.240 mmol); heating 16 h; eluent:
CH2Cl2–MeOH = 10 : 1. Yield 87.3 mg (96%). Light-yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.80 [s, 1H, CH(triazole)], 5.73 (s,
1H, 4-CH), 4.43 [d, J = 13.8 Hz, 1H, CH2N(triazole)], 4.33 [d, J =
13.8 Hz, 1H, CH2N(triazole)], 3.84 (s, 2H, CH2NEt2), 3.20 (br s,
1H, OH), 2.59 [q, J = 7.0 Hz, 4H, N(CH2CH3)2], 2.47–2.24 (m,
4H), 2.02 (ddd, J = 13.5, 4.9, 3.4 Hz, 1H), 1.86 (m, 1H),
1.76–0.77 (m, 14H), 1.20 (s, 3H, 19-CH3), 1.10 [t, J = 7.0 Hz, 6H,
N(CH2CH3)2], 0.98 (s, 3H, 18-CH3); 13C NMR (100.6 MHz,
CDCl3) δ 199.3 [C(3)vO], 170.7 (5-C), 143.6 [C(triazole)], 125.2
[4-CH or CH(triazole)], 123.9 [4-CH or CH(triazole)], 82.7 (17-
COH), 56.4, 53.6, 50.3, 47.4 (CH2NEt2), 46.6 [2C, N(CH2CH3)2],
46.1 (quat.), 38.5 (quat.), 36.3, 35.6, 33.8, 33.0, 32.6, 31.5, 30.9,
23.5, 20.5, 17.3, 14.1 [2C, N(CH2CH3)2], 11.4; HRMS (MALDI-
TOF) calcd for C27H43N4O2 [M + H]+ 455.3381; found 455.3387.
17β-Hydroxy-17α-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]androst-
4-en-3-one (10e). Synthesized according to method A from 4
(68.7 mg. 0.200 mmol) and phenylacetylene (26.4 μL,
0.240 mmol); heating 14 h; eluent: CH2Cl2–MeOH = 50 : 1.
+
Na]+ 576.2289; found
1
Yield 82.9 mg (93%). White solid; mp 282 °C (dec.); H NMR
(400 MHz, CDCl3–DMSO-d6) δ 8.19 [s, 1H, CH(triazole)], 7.81
[d, J = 7.8 Hz, 2H, 2,6-CH(Ph)], 7.40 [t, J = 7.8 Hz, 2H, 3,5-CH
(Ph)], 7.29 [t, J = 7.6 Hz, 1H, 4-CH(Ph)], 5.69 (s, 1H, 4-CH), 4.56
(s, 1H, OH), 4.51 (d, J = 13.7 Hz, 1H, CH2N), 4.32 (d, J = 13.7
Hz, 1H, CH2N), 2.48–2.24 (m, 4H), 2.04 (ddd, J = 13.4, 5.0, 3.1
Hz, 1H), 1.88 (m, 1H), 1.78–0.92 (m, 13H), 1.21 (s, 3H,
19-CH3), 0.97 (s, 3H, 18-CH3); 13C NMR (100.6 MHz,
CDCl3–DMSO-d6) δ 198.1 [C(3)vO], 170.1 (5-C), 145.9 [C(triazole)],
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(Ph)], 7.32 [t, J = 6.9 Hz, 1H, 4-CH(Ph)], 5.74 (d, J = 18.4 Hz, 1H, 2H, 3,5-CH(Ph)], 7.31 [t, J = 7.2 Hz, 1H, 4-CH(Ph)], 5.36 (m, 1H,
21-CH2N), 5.71 (s, 1H, 4-CH), 5.38 (d, J = 18.4 Hz, 1H, 6-CH), 4.59 (tt, J = 11.7, 4.5 Hz, 1H, 3-CHOAc), 4.41 (dd, J =
21-CH2N), 4.57 (br s, 1H, OH), 2.68 (t, J = 12.9 Hz, 1H), 2.49–2.20 12.6, 3.8 Hz, 1H, 16-CH), 4.31 (br s, 1H, OH), 2.65 (q, J = 12.9
(m, 4H), 2.11–1.97 (m, 2H), 1.94–0.79 (m, 12H), 1.18 (s, 3H, Hz, 1H, 15β-CH), 2.51 (m, 1H, 15α-CH), 2.40–2.23 (m, 3H), 2.04
19-CH3), 0.66 (s, 3H, 18-CH3); 13C NMR (100.6 MHz, CDCl3– (m, 1H), 2.02 [s, 3H, OC(O)CH3], 1.92–1.83 (m, 2H), 1.80–1.42
DMSO-d6) δ 204.0 [C(20)vO], 199.2 [C(3)vO], 170.9 (5-C), (m, 6H), 1.37–0.98 (m, 3H), 1.23 (s, 3H, 17-CCH3), 1.08 (s, 3H,
147.1 [C(triazole)], 130.1 [1-C(Ph)], 128.5 [2C, 3,5-CH(Ph)], 18-CH3), 1.05 (s, 3H, 19-CH3); 13C NMR (100.6 MHz, CDCl3) δ
127.8 [4-CH(Ph)], 125.4 [2C, 2,6-CH(Ph)], 123.4 (4-CH), 121.4 215.1 [C(17a)vO], 170.5 [OC(O)CH3], 147.2 [C(triazole)], 139.5
[CH(triazole)], 89.3 (17-COH), 56.6 (21-CH2N), 52.8, 50.1, 47.6 (5-C), 130.6 [1-C(Ph)], 128.8 [2C, CH(Ph)], 128.1 [4-CH(Ph)],
(quat.), 38.2 (quat.), 35.3 (2C), 33.9, 33.6, 32.4, 31.7, 30.3, 23.3, 125.7 [2C, CH(Ph)], 121.5 [2C, 6-CH, CH(triazole)], 78.6
20.4, 17.0, 14.6; HRMS (MALDI-TOF) calcd for C29H36N3O3 (17-COH), 73.5 (3-CHOAc), 68.9 (16-CH), 48.9, 48.0, 46.7 (quat.),
[M + H]+ 474.2751; found 474.2748; Anal. calcd for C29H35N3O3: 37.7, 36.8 (quat.), 36.6, 32.7, 31.6, 30.8, 27.6, 25.6, 22.9, 21.4,
C, 73.54; H, 7.45; N, 8.87; found C, 73.36; H, 7.31; N, 8.71.
19.3 (2C), 15.9; HRMS (MALDI-TOF) calcd for C31H40N3O4
21-(4-Butyl-1H-1,2,3-triazol-1-yl)-17α-hydroxypregn-4-ene-3, [M + H]+ 518.3013; found 518.3018; Anal. calcd for C31H39N3O4:
20-dione (11b). Synthesized according to method A from 6 C, 71.93; H, 7.59; N, 8.12; found C, 71.71; H, 7.57; N, 7.74.
(74.3 mg, 0.200 mmol) and hex-1-yne (27.6 μL, 0.240 mmol);
heating 22 h; eluent CH2Cl2–MeOH = 20 : 1. Yield 88.8 mg 17β-methyl-D-homoandrost-5-en-17a-one
3β-Acetoxy-16β-(4-butyl-1H-1,2,3-triazol-1-yl)-17α-hydroxy-
(12b). Synthesized
(98%). White solid; mp 115–117 °C; 1H NMR (400 MHz, according to method B from 8 (83.1 mg, 0.200 mmol) and
CDCl3) δ 7.32 [s, 1H, CH(triazole)], 5.72 (s, 1H, 4-CH), 5.71 (d, hex-1-yne (27.6 μL, 0.240 mmol); heating 22 h. Yield 83.5 mg
J = 18.4 Hz, 1H, 21-CH2N), 5.30 (d, J = 18.4 Hz, 1H, 21-CH2N), (84%). Synthesized according to method B from 9 (83.1 mg,
4.62 (br s, 1H, OH), 2.70 [t, J = 7.6 Hz, 2H, CH2Pr], 2.67 0.200 mmol) and hex-1-yne (27.6 μL, 0.240 mmol); heating
(m, 1H), 2.48–2.23 (m, 4H), 2.09–1.97 (m, 2H), 1.92–1.56 (m, 9H), 22 h; eluent: CH2Cl2–MeOH = 100 : 1. Yield 89.2 mg (90%).
1.51–0.80 (m, 7H), 1.18 (s, 3H, 19-CH3), 0.91 (t, J = 7.3 Hz, 3H, White solid; mp 234–236 °C; 1H NMR (400 MHz, CDCl3) δ 7.48
CH2CH3), 0.66 (s, 3H, 18-CH3); 13C NMR (100.6 MHz, CDCl3) δ [s, 1H, CH(triazole)], 5.35 (m, 1H, 6-CH), 4.58 (m, 1H,
204.1 [C(20)vO], 199.8 [C(3)vO], 171.5 (5-C), 148.1 [C(tria- 3-CHOAc), 4.32 (dd, J = 12.9, 4.3 Hz, 1H, 16-CH), 4.29 (s, 1H,
zole)], 123.7 (4-CH), 122.6 [CH(triazole)], 89.8 (17-COH), 56.8 OH), 2.72 [m, 2H, CH2Pr], 2.61 (q, J = 13.5 Hz, 1H, 15β-CH),
(21-CH2N), 53.2, 50.4, 48.1 (quat.), 38.5 (quat.), 35.6 (2C), 34.4, 2.45 (m, 1H, 15α-CH), 2.38–2.22 (m, 3H), 2.05–1.97 (m, 1H),
33.8, 32.7, 31.9, 31.3, 30.6, 25.1, 23.5, 22.2, 20.6, 17.3, 14.9, 2.02 [s, 3H, OC(O)CH3], 1.93–1.83 (m, 2H), 1.79–1.43 (m, 8H),
13.7; HRMS (MALDI-TOF) calcd for C27H39N3NaO3 [M + Na]+ 1.37 (sextet, J = 7.5 Hz, 2H, CH2CH3), 1.32–0.98 (m, 3H), 1.22
476.2889; found 476.2888; Anal. calcd for C27H39N3O3: C, (s, 3H, 17-CCH3), 1.04 (s, 3H, 18-CH3), 1.03 (s, 3H, 19-CH3),
71.49; H, 8.67; N, 9.26; found C, 71.70; H, 8.86; N, 8.70.
0.92 (t, J = 7.4 Hz, 3H, CH2CH3); 13C NMR (100.6 MHz, CDCl3)
21-[4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl]-17α-hydroxy- δ 215.2 [C(17a)vO], 170.4 [OC(O)CH3], 147.8 [C(triazole)],
pregn-4-ene-3,20-dione (11c). Synthesized according to 139.5 (5-C), 122.4 [CH(triazole)], 121.4 (6-CH), 78.6 (17-COH),
method A from 6 (74.3 mg, 0.200 mmol) and propargyl alcohol 73.5 (3-CHOAc), 68.5 (16-CH), 48.9, 47.9, 46.7 (quat.), 37.7,
(14.0 μL, 0.240 mmol); heating 22 h; eluent: CH2Cl2–MeOH = 36.8 (quat.), 36.5, 32.7, 31.6, 31.5, 30.7, 27.5, 25.5, 25.3, 22.8,
10 : 1. Yield 84.2 mg (98%). White solid; mp 248–251 °C; 1H 22.2, 21.3, 19.23, 19.18, 15.8, 13.8; HRMS (MALDI-TOF) calcd
NMR (400 MHz, CDCl3–DMSO-d6) δ 7.65 [s, 1H, CH(triazole)], for C29H43N3NaO4 [M + Na]+ 520.3151; found 520.3153; Anal.
5.68 (s, 1H, 4-CH), 5.66 (d, J = 18.6 Hz, 1H, 21-CH2N), 5.30 (d, J calcd for C29H43N3O4: C, 69.99; H, 8.71; N, 8.44; found C,
= 18.6 Hz, 1H, 21-CH2N), 4.70 (s, 2H, CH2OH), 4.22 (br s, 2H, 70.12; H, 8.94; N, 8.27.
OH), 2.63 (m, 1H), 2.49–2.22 (m, 4H), 2.11–1.95 (m, 2H),
1.93–0.78 (m, 12H), 1.19 (s, 3H, 19-CH3), 0.63 (s, 3H, 18-CH3); 17α-hydroxy-17β-methyl-D-homoandrost-5-en-17a-one (12c).
13C NMR (100.6 MHz, CDCl3–DMSO-d6) δ 203.5 [C(20)vO], Synthesized according to method
from (83.1 mg,
3β-Acetoxy-16β-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]-
A
8
198.1 [C(3)vO], 170.2 (5-C), 147.4 [C(triazole)], 122.9 [4-CH or 0.200 mmol) and propargyl alcohol (14.0 μL, 0.240 mmol);
CH(triazole)], 122.7 [4-CH or CH(triazole)], 88.4 (17-COH), 55.7 heating 14 h. Yield 79.0 mg (84%). Synthesized according to
(21-CH2N), 55.0 (CH2OH), 52.2, 49.3, 46.8 (quat.), 37.5 (quat.), method B from 9 (83.1 mg, 0.200 mmol) and propargyl alcohol
34.6 (2C), 33.0, 32.9, 31.7, 31.0, 29.6, 22.6, 19.7, 16.4, 13.9; (14.0 μL, 0.240 mmol); heating 22 h; eluent: CH2Cl2–MeOH =
HRMS (MALDI-TOF) calcd for C24H34N3O4 [M + H]+ 428.2544; 20 : 1. Yield 92.1 mg (98%). White solid; mp 274–275 °C; 1H
found 428.2544; Anal. calcd for C24H33N3O4: C, 67.42; H, 7.78; NMR (400 MHz, CDCl3) δ 7.76 [s, 1H, CH(triazole)], 5.35 (m,
N, 9.83; found C, 67.33; H, 7.77; N, 9.77.
1H, 6-CH), 4.80 (br s, 2H, CH2OH), 4.58 (tt, J = 12.1, 4.8 Hz,
3β-Acetoxy-16β-(4-phenyl-1H-1,2,3-triazol-1-yl)-17α-hydroxy- 1H, 3-CHOAc), 4.38 (s, 1H, OH), 4.37 (dd, J = 12.6, 4.2 Hz, 1H,
17β-methyl-D-homoandrost-5-en-17a-one (12a). Synthesized 16-CH), 3.03 (s, 1H, OH), 2.60 (q, J = 13.4 Hz, 1H, 15β-CH),
according to method B from 8 (41.6 mg, 0.100 mmol) and 2.44 (m, 1H, 15α-CH), 2.38–2.21 (m, 3H), 2.05–1.98 (m, 1H),
phenylacetylene (13.2 μL, 0.120 mmol); heating 18 h; eluent: 2.02 [s, 3H, OC(O)CH3], 1.95–1.83 (m, 2H), 1.77–1.41 (m, 6H),
CH2Cl2–Et2O = 20 : 1. Yield 40.7 mg (79%). White solid; mp 1.34–0.98 (m, 3H), 1.22 (s, 3H, 17-CCH3), 1.04 (br s, 6H, 18-
>300 °C; 1H NMR (400 MHz, CDCl3) δ 7.99 [s, 1H, CH(tri- CH3, 19-CH3); 13C NMR (100.6 MHz, CDCl3) δ 214.9 [C(17a)vO],
azole)], 7.85 [d, J = 7.8 Hz, 2H, 2,6-CH(Ph)], 7.41 [t, J = 7.6 Hz, 170.5 [OC(O)CH3], 147.0 [C(triazole)], 139.6 (5-C), 123.5
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[CH(triazole)], 121.4 (6-CH), 78.5 (17-COH), 73.5 (3-CHOAc), 1.06 (s, 3H, 19-CH3); 13C NMR (100.6 MHz, CDCl3) δ 208.8
68.8 (16-CH), 56.4 (CH2OH), 48.9, 47.9, 46.7 (quat.), 37.7, 36.8 [C(20)vO], 170.5 [OC(O)CH3], 147.9 [C(triazole)], 139.8 (5-C),
(quat.), 36.5, 32.7, 31.6, 30.7, 27.6, 25.6, 22.8, 21.3, 19.2 (2C), 130.2 [1-C(Ph)], 128.8 [2C, CH(Ph)], 128.3 [4-CH(Ph)], 125.7
15.9; 1H NMR (400 MHz, CDCl3–CD3OD) δ 7.79 [s, 1H, CH(tria- [2C, CH(Ph)], 121.9 (6-CH), 120.9 [CH(triazole)], 90.4 (17-COH),
zole)], 5.35 (m, 1H, 6-CH), 4.73 (s, 2H, CH2OH), 4.57 (tt, J = 73.7 (3-CHOAc), 71.3 (16-CH), 49.3, 49.2 (quat.), 48.7, 38.0,
11.1, 4.9 Hz, 1H, 3-CHOAc), 4.38 (s, 1H, OH), 4.43 (dd, J = 12.9, 36.9, 36.6 (quat.), 31.9, 31.7, 30.9, 30.6, 27.9, 27.6, 21.4, 20.1,
4.1 Hz, 1H, 16-CH), 3.08 (br s, 2H, OH), 2.57 (q, J = 13.4 Hz, 19.3, 15.9; HRMS (MALDI-TOF) calcd for C31H40N3O4 [M + H]+
1H, 15β-CH), 2.40 (m, 1H, 15α-CH), 2.37–2.20 (m, 3H), 518.3013; found 518.3020; Anal. calcd for C31H39N3O4:
2.04–1.98 (m, 1H), 2.02 [s, 3H, OC(O)CH3], 1.93–1.83 (m, 2H), C, 71.93; H, 7.59; N, 8.12; found C, 72.02; H, 7.78; N, 8.12.
1.78–1.40 (m, 6H), 1.32 (ddd, J = 12.9, 10.3, 2.7 Hz, 1H, 14-CH),
3β-Acetoxy-16β-(4-butyl-1H-1,2,3-triazol-1-yl)-17α-hydroxy-
1.26–0.98 (m, 2H), 1.21 (s, 3H, 17-CCH3), 1.04 (s, 3H, 19-CH3), pregn-5-en-20-one (13b). Synthesized according to method C
1.03 (s, 3H, 18-CH3); 13C NMR (100.6 MHz, CDCl3–CD3OD) δ from 9 (58.2 mg, 0.140 mmol) and hex-1-yne (19.3 μL,
214.8 [C(17a)vO], 170.6 [OC(O)CH3], 147.0 [C(triazole)], 139.3 0.168 mmol); heating 19 h; eluent: CH2Cl2–MeOH = 50 : 1.
(5-C), 123.7 [CH(triazole)], 121.3 (6-CH), 78.3 (17-COH), 73.5 Yield 62.4 mg (90%). White solid; mp 164–166 °C; 1H NMR
(3-CHOAc), 68.5 (16-CH), 55.7 (CH2OH), 48.7 (9-CH), 47.6 (400 MHz, CDCl3) δ 7.42 [s, 1H, CH(triazole)], 5.38 (d, J = 3.9
(14-CH), 46.6 (13-C), 37.5, 36.6 (10-C), 36.3, 32.5, 31.4, 30.5, 27.4, Hz, 1H, 6-CH), 4.92 (t, J = 8.7 Hz, 1H, 16-CH), 4.60 (tt, J = 11.7,
25.5 (15-CH or 17-CCH3), 22.6 (15-CH or 17-CCH3), 21.2, 19.1, 4.6 Hz, 1H, 3-CHOAc), 2.71 [t, J = 7.6 Hz, 2H, CH2Pr], 2.60 (td, J
19.0, 15.8 (18-CH3); HRMS (MALDI-TOF) calcd for = 12.8, 9.3 Hz, 1H, 15β-CH), 2.43 (ddd, J = 12.8, 8.6, 5.2 Hz, 1H,
C26H37N3NaO5 [M + Na]+ 494.2631; found 494.2614; Anal. 15α-CH), 2.38–2.25 (m, 2H), 2.07 (m, 1H), 2.03 [s, 3H, OC(O)
calcd for C26H37N3O5: C, 66.22; H, 7.91; N, 8.91; found C, CH3], 1.91–1.54 (m, 10H), 1.62 (s, 3H, 21-CH3), 1.48 (qd, J =
66.10; H, 8.12; N, 8.79.
13.0, 4.5 Hz, 1H), 1.36 (sextet, J = 7.3 Hz, 2H, CH2CH2CH3),
3β-Acetoxy-16β-{4-[(diethylamino)methyl]-1H-1,2,3-triazol- 1.29–1.13 (m, 4H), 1.10 (s, 3H, 18-CH3), 1.05 (s, 3H, 19-CH3),
1-yl}-17α-hydroxy-17β-methyl-D-homoandrost-5-en-17a-one 0.91 (t, J = 7.3 Hz, 3H, CH2CH3); 13C NMR (100.6 MHz, CDCl3)
(12d). Synthesized according to method B from 8 (62.3 mg, δ 209.0 [C(20)vO], 170.5 [OC(O)CH3], 148.1 [C(triazole)], 139.7
0.150 mmol) and N,N-diethylpropargylamine (24.7 μL, (5-C), 122.3 [CH(triazole)], 121.8 (6-CH), 89.7 (17-COH), 73.6 (3-
0.180 mmol); heating 20 h; eluent: CH2Cl2–MeOH = 10 : 1. CHOAc), 71.0 (16-CH), 49.2, 48.7 (quat.), 48.4, 37.9, 36.8, 36.5
Yield 63.7 mg (81%). White solid; mp 249–250 °C; 1H NMR (quat.), 31.9, 31.6, 31.4, 30.9, 30.7, 28.1, 27.6, 25.1, 22.2, 21.3,
(400 MHz, CDCl3) δ 7.85 [s, 1H, CH(triazole)], 5.35 (m, 1H, 20.1, 19.2, 15.6, 13.7; HRMS (MALDI-TOF) calcd for
6-CH), 4.58 (tt, J = 11.5, 4.8 Hz, 1H, 3-CHOAc), 4.38 (dd, J = 12.9, C29H43N3NaO4 [M + Na]+ 520.3151; found 520.3147; Anal.
4.0 Hz, 1H, 16-CH), 3.98 (d, J = 14.2 Hz, 1H, CH2NEt2), 3.92 (d, calcd for C29H43N3O4: C, 69.99; H, 8.71; N, 8.44; found C,
J = 14.2 Hz, 1H, CH2NEt2), 2.74–2.62 [m, 4H, N(CH2CH3)2], 69.84; H, 8.79; N, 8.19.
2.58 (q, J = 13.2 Hz, 1H, 15β-CH), 2.44 (m, 1H, 15α-CH),
3β-Acetoxy-16β-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]-
2.39–2.21 (m, 3H), 2.06–1.97 (m, 1H), 2.02 [s, 3H, OC(O)CH3], 17α-hydroxypregn-5-en-20-one (13c). Synthesized according to
1.92–1.83 (m, 2H), 1.78–1.42 (m, 6H), 1.34–0.98 (m, 4H), 1.22 method C from 9 (58.2 mg, 0.140 mmol) and propargyl alcohol
(s, 3H, 17-CCH3), 1.10 [t, J = 7.1 Hz, 6H, N(CH2CH3)2], 1.04 (s, (9.8 μL, 0.168 mmol); heating 20 h; eluent: CH2Cl2–MeOH =
3H, 18-CH3), 1.03 (s, 3H, 19-CH3); 13C NMR (100.6 MHz, 20 : 1. Yield 62.0 mg (94%). White solid; mp 219–221 °C; 1H
CDCl3) δ 214.9 [C(17a)vO], 170.4 [OC(O)CH3], 142.2 [C(tria- NMR (400 MHz, CDCl3) δ 7.73 [br s, 1H, CH(triazole)], 5.37 (m,
zole)], 139.5 (5-C), 125.2 [CH(triazole)], 121.4 (6-CH), 78.4 1H, 6-CH), 4.98 (m, 1H, 16-CH), 4.74 (br s, 2H, CH2OH), 4.60
(17-COH), 73.4 (3-CHOAc), 68.7 (16-CH), 48.8, 47.9, 47.0, 46.7 (tt, J = 11.3, 4.9 Hz, 1H, 3-CHOAc), 3.86 (br s, 2H, OH),
(quat.), 46.5 [2C, N(CH2CH3)2], 37.7, 36.8 (quat.), 36.5, 32.7, 2.54–2.24 (m, 4H), 2.05 (m, 1H), 2.03 [s, 3H, OC(O)CH3],
31.5, 30.7, 27.5, 25.5, 22.8, 21.3, 19.2 (2C), 15.9, 11.1 [2C, N 1.92–1.40 (m, 8H), 1.82 (s, 3H, 21-CH3), 1.38–0.78 (m, 4H), 1.04
(CH2CH3)2]; HRMS (MALDI-TOF) calcd for C30H46N4NaO4 (s, 3H, 19-CH3), 0.98 (s, 3H, 18-CH3); 13C NMR (100.6 MHz,
[M + Na]+ 549.3417; found 549.3425.
CDCl3) δ 209.9 [C(20)vO], 170.6 [OC(O)CH3], 147.7 [C(tria-
3β-Acetoxy-16β-(4-phenyl-1H-1,2,3-triazol-1-yl)-17α-hydroxy- zole)], 139.7 (5-C), 129.1 [CH(triazole)], 121.8 (6-CH), 89.1
pregn-5-en-20-one (13a). Synthesized according to method A (17-COH), 73.7 (3-CHOAc), 71.5 (16-CH), 55.8 (CH2OH), 49.2,
from 9 (83.1 mg, 0.200 mmol) and phenylacetylene (26.4 μL, 48.4 (quat.), 48.2, 37.9, 36.8, 36.5 (quat.), 31.9, 31.7, 31.1 (2C),
0.240 mmol); heating 14 h; eluent: CH2Cl2–MeOH = 50 : 1. 28.8, 27.6, 21.4, 20.3, 19.2, 15.4; HRMS (MALDI-TOF) calcd for
Yield 98.1 mg (95%). White solid; mp >300 °C; 1H NMR C26H38N3O5 [M + H]+ 472.2806; found 472.2802; Anal. calcd for
(400 MHz, CDCl3) δ 7.81 [d, J = 7.3 Hz, 2H, 2,6-CH(Ph)], 7.79 C26H37N3O5: C, 66.22; H, 7.91; N, 8.91; found C, 66.18; H, 8.06;
[s, 1H, CH(triazole)], 7.41 [t, J = 7.5 Hz, 2H, 3,5-CH(Ph)], 7.32 N, 8.74.
[t, J = 7.4 Hz, 1H, 4-CH(Ph)], 5.39 (d, J = 4.7 Hz, 1H, 6-CH), 4.97
3β-Acetoxy-16β-{4-[(diethylamino)methyl]-1H-1,2,3-triazol-
(t, J = 9.0 Hz, 1H, 16-CH), 4.61 (m, 1H, 3-CHOAc), 4.50 (s, 1H, 1-yl}-17α-hydroxypregn-5-en-20-one (13d). Synthesized accord-
OH), 2.61 (td, J = 12.5, 9.7 Hz, 1H, 15β-CH), 2.48 (ddd, J = 12.5, ing to method C from 9 (62.3 mg, 0.150 mmol) and
8.4, 5.2 Hz, 1H, 15α-CH), 2.39–2.26 (m, 2H), 2.08 (m, 1H), 2.03 N,N-diethylpropargylamine (24.7 μL, 0.180 mmol); heating 20 h;
[s, 3H, OC(O)CH3], 1.92–1.55 (m, 8H), 1.59 (qd, J = 13.4, 4.3 Hz, eluent: CH2Cl2–MeOH = 10 : 1. Yield 74.9 mg (95%). White
1H), 1.67 (s, 3H, 21-CH3), 1.33–1.01 (m, 3H), 1.14 (s, 3H, 18-CH3), solid; mp 163–166 °C; 1H NMR (400 MHz, CDCl3) δ 7.93 [s, 1H,
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CH(triazole)], 5.38 (m, 1H, 6-CH), 5.12 (br s, 1H, OH), 4.97 (t, J 20.3, 19.2, 15.5; HRMS (MALDI-TOF) calcd for C33H42N3O7 [M
= 9.0 Hz, 1H, 16-CH), 4.60 (m, 1H, 3-CHOAc), 4.02 (d, J = 14.1 + H]+ 592.3017; found 592.3021; Anal. calcd for C33H41N3O7: C,
Hz, 1H, CH2NEt2), 3.96 (d, J = 14.1 Hz, 1H, CH2NEt2), 2.78 [q, J 66.99; H, 6.98; N, 7.10; found C, 67.31; H, 6.88; N, 6.83.
= 7.0 Hz, 4H, N(CH2CH3)2], 2.59–2.26 (m, 4H), 2.12–1.98 (m,
3β-Acetoxy-16β-(4-butyl-1H-1,2,3-triazol-1-yl)-17β-methyl-
1H), 2.03 [s, 3H, OC(O)CH3], 1.93–1.53 (m, 7H), 1.52 (qd, J = D-homoandrost-5-ene-17α,17aβ-diol (16). NaBH4 (104 mg,
13.2, 8.8 Hz, 1H), 1.85 (s, 3H, 21-CH3), 1.38–0.79 (m, 4H), 1.21 2.79 mmol) was gradually added to a suspension of 12b
[t, J = 7.0 Hz, 6H, N(CH2CH3)2], 1.04 (s, 3H, 19-CH3), 0.98 (s, (104.3 mg, 0.210 mmol) in anhydrous methanol (5.0 mL). The
3H, 18-CH3); 13C NMR (100.6 MHz, CDCl3) δ 209.3 [C(20)vO], mixture was stirred for 30 min at rt, diluted with CH2Cl2
170.4 [OC(O)CH3], 141.4 [C(triazole)], 139.7 (5-C), 125.7 [CH (25 mL), washed with water (2 × 25 mL), dried with anhydrous
(triazole)], 121.9 (6-CH), 89.3 (17-COH), 73.7 (3-CHOAc), 71.2 Na2SO4, and evaporated under vacuum. The residue was sub-
(16-CH), 49.2, 48.4 (quat.), 48.2, 47.1 (CH2NEt2), 46.5 [2C, N jected to column chromatography (eluent: CH2Cl2–MeOH =
(CH2CH3)2], 38.0, 36.8, 36.5 (quat.), 31.9, 31.4, 31.10, 31.05, 20 : 1) to afford the pure product. Yield 75.5 mg (72%). White
28.8, 27.6, 21.3, 20.3, 19.2, 15.3, 10.6 [2C, N(CH2CH3)2]; HRMS solid; mp >250 °C; 1H NMR (400 MHz, CDCl3) δ 7.44 [s, 1H,
(MALDI-TOF) calcd for C30H46N4NaO4 [M + Na]+ 549.3417; CH(triazole)], 5.34 (m, 1H, 6-CH), 4.58 (tt, J = 11.1, 4.7 Hz,
found 549.3423.
1H, 3-CHOAc), 4.34 (dd, J = 12.8, 3.5 Hz, 1H, 16-CH), 3.36 (s, 1H,
3β-Acetoxy-16β-[4-(5-chloro-2-hydroxyphenyl)-1H-1,2,3-triazol- 17a-CHOH), 3.06 (br s, 2H, OH), 2.71 [t, J = 7.6 Hz, 2H, CH2Pr],
1-yl]-17α-hydroxypregn-5-en-20-one (13e). Synthesized accord- 2.37–2.24 (m, 2H), 2.21–2.09 (m, 2H), 2.07–1.82 (m, 4H), 2.02
ing to method C from 9 (62.3 mg, 0.150 mmol) and 4-chloro-2- [s, 3H, OC(O)CH3], 1.69–1.44 (m, 6H), 1.36 (sextet, J = 7.5 Hz,
ethynylphenol (27.5 mg, 0.180 mmol); heating 20 h; eluent: 2H, CH2CH2CH3), 1.30–1.20 (m, 1H), 1.17–0.96 (m, 4H), 1.02
CH2Cl2–MeOH = 50 : 1. Yield 74.5 mg (87%). White solid; mp (s, 3H, 19-CH3), 0.92 (t, J = 7.3 Hz, 3H, CH3), 0.889 (s, 3H,
157–159 °C; 1H NMR (400 MHz, CDCl3) δ 10.70 [br s, 1H, 17-CCH3 or 18-CH3), 0.886 (s, 3H, 17-CCH3 or 18-CH3); 13C NMR
2-COH(Ar)], 7.88 [s, 1H, CH(triazole)], 7.37 [d, J = 2.3 Hz, 1H, (100.6 MHz, CDCl3) δ 170.6 [OC(O)CH3], 147.3 [C(triazole)],
6-CH(Ar)], 7.37 [dd, J = 8.7, 2.3 Hz, 1H, 4-CH(Ar)], 7.37 [d, J = 8.7 139.6 (5-C), 121.64 (6-CH), 121.56 [CH(triazole)], 84.0
Hz, 1H, 3-CH(Ar)], 5.38 (m, 1H, 6-CH), 5.00 (t, J = 8.9 Hz, 1H, (17a-CHOH), 76.2 (17-COH), 73.7 (3-CHOAc), 67.5 (16-CH), 49.3,
16-CH), 4.61 (tt, J = 11.6, 4.7 Hz, 1H, 3-CHOAc), 4.24 (br s, 1H, 48.6, 38.2 (quat.), 37.8, 37.2, 36.8 (quat.), 36.6, 31.8, 31.5, 30.2,
17-COH), 2.56–2.45 (m, 2H), 2.40–2.27 (m, 2H), 2.13–1.99 27.6, 26.5, 25.2, 22.3, 21.4, 19.2 (2C), 17.4, 13.8, 11.3; HRMS
(m, 1H), 2.04 [s, 3H, OC(O)CH3], 1.93–1.56 (m, 7H), 1.51 (qd, J = (MALDI-TOF) calcd for C29H46N3O4 [M + H]+ 500.3483; found
13.1, 4.3 Hz, 1H), 1.76 (s, 3H, 21-CH3), 1.34 (m, 1H), 1.26–0.98 500.3476; Anal. calcd for C29H45N3O4: C, 69.71; H, 9.08; N,
(m, 3H), 1.08 (s, 3H, 18-CH3 or 19-CH3), 1.06 (s, 3H, 18-CH3 or 8.41; found C, 70.09; H, 9.25; N, 8.19.
19-CH3); 13C NMR (100.6 MHz, CDCl3) δ 208.3 [C(20)vO],
170.7 [OC(O)CH3], 154.3 [2-COH(Ar)], 146.3 [C(triazole)], 139.7
(5-C), 129.4, 125.4, 124.1 (quat.), 121.7 (6-CH), 120.5, 119.0,
115.0 (quat.), 89.9 (17-COH), 73.7 (3-CHOAc), 71.7 (16-CH),
Acknowledgements
49.2, 48.8 (quat.), 48.5, 37.9, 36.8, 36.6 (quat.), 31.9, 31.8, 30.9,
This work was supported by the Russian Foundation for Basic
30.8, 28.3, 27.6, 21.4, 20.2, 19.2, 15.7; HRMS (MALDI-TOF)
Research (grant number 11-03-00265-a) and M. V. Lomonosov
calcd for C31H39ClN3O5 [M + H]+ 568.2573; found 568.2588.
Moscow State University Program of Development. We are
3β-Acetoxy-16β-{4-[(4-carboxyphenoxy)methyl]-1H-1,2,3-
grateful to D. Sc. Yu. K. Grishin for carrying out NOE and
triazol-1-yl}-17α-hydroxypregn-5-en-20-one (13f). Synthesized
HMBC experiments and to Dr V. B. Rybakov for X-ray analysis.
according to method C from 9 (62.3 mg, 0.150 mmol) and
4-(prop-2-yn-1-yloxy)benzoic acid (31.7 mg, 0.180 mmol);
heating 20 h; eluent: CH2Cl2–MeOH = 50 : 1. Yield 64.8 mg
(73%). White solid; mp 247–248 °C; 1H NMR (400 MHz,
CDCl3–CD3OD) δ 8.00 [d, J = 8.9 Hz, 2H, 3,5-CH(Ar)], 7.75
Notes and references
[s, 1H, CH(triazole)], 7.00 [d, J = 8.9 Hz, 2H, 2,6-CH(Ar)], 5.38
(m, 1H, 6-CH), 5.25 (s, 2H, CH2O), 4.96 (t, J = 9.1 Hz, 1H, 16-CH),
4.60 (m, 1H, 3-CHOAc), 2.91 (br s, 2H, OH), 2.47–2.26 (m, 3H),
2.17 (td, J = 13.1, 9.9 Hz, 1H, 15β-CH), 2.08–1.99 (m, 1H), 2.03
[s, 3H, OC(O)CH3], 1.93–1.54 (m, 7H), 1.48 (qd, J = 13.1, 4.7
Hz, 1H), 1.42–1.36 (m, 1H), 1.93 (s, 3H, 21-CH3), 1.27–0.99
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37.8, 36.7, 36.5 (quat.), 31.9, 31.8, 31.0, 30.9, 28.6, 27.5, 21.3,
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