Synthesis of triazole-epothilones by using Cu2O nanoparticles to catalyze 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/ejoc.201101306

We report the total synthesis of a triazole-epothilone analogue 1. The key step to generate the macrocyclic ring and the triazole ring was to apply Cu ₂O nanoparticles (Cu₂O-NPs) to catalyze the 1,3-dipolar cycloaddition. The conform

Full text of DOI:10.1002/ejoc.201101306

FULL PAPER
DOI: 10.1002/ejoc.201101306
Synthesis of Triazole-Epothilones by Using Cu2O Nanoparticles to Catalyze
1,3-Dipolar Cycloaddition
Xiyan Duan,[a] Yan Zhang,[a] Yahui Ding,[a] Jianping Lin,[a] Xianglei Kong,[a] Quan Zhang,[a]
Changming Dong,[a] Guoan Luo,*[a] and Yue Chen*[a]
Keywords: Natural products / Nanoparticles / Total synthesis / Cycloaddition / Click reaction
We report the total synthesis of a triazole-epothilone ana-
logue 1. The key step to generate the macrocyclic ring and
the triazole ring was to apply Cu2O nanoparticles (Cu2O-
NPs) to catalyze the 1,3-dipolar cycloaddition. The conforma-
tion of 1 and its bioactivity in MCF cancer cell lines were
investigated.
ine[7g] moieties shows a slight improvement in biological ac-
tivity against cancer cell lines. These results suggest that the
type of replacement is largely conformational. On the other
hand, the CuAAC product, 1,5-triazole or 1,4-triazole, was
reported to be isostatic to amides and olefins in drugs with
linear structure, and the resulting analogues maintain sig-
nificant biological activity.[9]
Here we report the first synthesis of a triazole-epothilone
analogue through a Cu2O-NP catalyzed CuAAC reaction
to simultaneously generate the macrocyclic ring and the tri-
azole ring. The resulting triazole analogue (Scheme 1) may
be suitable for exploring the conformational and biological
effects in more complex polyketide macrolide systems.
Inspection of the structure of triazole-epothilone ana-
logue 1 reveals the possibility of applying the click reaction
with precursor 2 (Scheme 1). The aldol moiety in 2 allows
the indicated disconnection of the reported aldehyde 3[10]
and ester 4 as potential intermediates. An esterification re-
action was identified to disconnect 4 from its components:
the known carboxylic acid 6[11] and secondary alcohol 5.
The latter may be derived from the ketone alcohol 7 and
known thiazole fragment derivative 8.[12]
Introduction
The copper-catalyzed azide–alkyne cycloaddition
(CuAAC) reaction is increasingly being used to generate
vast libraries of materials, new applications, and chemical
modifications.[1,2] In particular, the click reaction provides
a facial approach for construction of macrocyclic molecules
through intramolecular cycloaddition. The catalyst systems
that are employed in this type of ring formation includes:
CuSO4/NaAsc,[2c] CuI/DIEA,[3] Cu(CN)4PF6,[4] and CuBr/
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).[5] Chen and
Kong[6] recently reported the use of Cu2O nanoparticles
(Cu2O-NPs) to catalyze this reaction either under physio-
logical conditions or in acetonitrile. This Cu2O-NP catalyst
demonstrates less cytotoxicity and superior efficiency than
traditional CuSO4/NaAsc systems.
Epothilones, which were isolated in 1993 from myxobac-
teria by Höfle et al., are polyketide macrolides.[7] Compared
to paclitaxel, the epothilones possess improved water solu-
bility and activity against various human cancer cells. These
advantages have evoked large-scale research efforts within
both academic and pharmaceutical research groups and
this has resulted in numerous total syntheses, structure ac-
The key step in the synthesis of target compound 1 is the
tivity relationship (SAR) studies, and computational mod- utilization of intramolecular 1,3-dipolar cycloaddition to
eling.[8] For example, epothilone D (Scheme 1), in which the construct the sixteen-membered macrocycle. A model reac-
C12–C13 olefin is replaced by cyclopropane[7b–7f] or azirid- tion to form a fourteen-membered heterocycle 10 was ap-
plied to explore the best conditions for the intramolecular
CuAAC reaction (Scheme 2). Exposure of the key interme-
diate 9 to CuI/DIEA[3] or [Cu(CN)4PF6][4] either provided
the cyclization product in only trace amounts or no reaction
[a] College of Pharmacy and The State Key Laboratory of
was observed. However, compound 10 was successfully ob-
Elemento-organic Chemistry, Nankai University,
tained in 64% yield when the reaction was catalyzed by
Cu2O-NPs. The success of the study with the model system
demonstrates that the use of Cu2O-NPs is feasible for intra-
molecular CuAAC reactions.
Tianjin 300071, P. R. China
E-mail: yuechen@nankai.edu.cn
luoga@nankai.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101306.
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Synthesis of Triazole-Epothilones
Scheme 1. Retrosynthetic analysis.
Addition of MeMgBr to 12 afforded keto alcohol 7 in
87% yield (Scheme 4), and subsequent Horner–Wads-
worth–Emmons reaction with tributyl[(2-methylthiazol-4-
yl)methyl]phosphonium chloride (8) to provide (E)-olefin
13 in 97% yield.[16] Desilylation of the latter using tetrabut-
ylammonium fluoride (TBAF) furnished alcohol 5 (95%).
Thus, the coupling reaction between fragments 5 and 6 led
to the formation of ester 4 in 85% yield.[17] Aldol condensa-
tion of the Ti enolate of keto 4 (generated by TiCl4 under
basic conditions) and aldehyde 3 provided adduct 14 (73%,
dr = 8:1).[18] Desilylation of 14 with trifluoroacetic acid at
0 °C furnished the intermediate 15, which was treated with
NaHCO3 in CH2Cl2/MeOH to afford triol 16 (80% for two
steps).
Scheme 2. Model system used to study the conditions for the intra-
molecular CuAAC reaction.
Results and Discussion
The preparation of fragment 12 started with the Weinreb
After protection of triol 16 with a combination of
amide 11 (Scheme 3), which was synthesized according to TESOTf and 2,6-lutidine to obtain compound 17
Chen and Li.[13] The nucleophile (trimethylsilyl)ethyn-1-ide (Scheme 5), the less sterically hindered TES group in 17 was
was generated using (trimethylsilyl)acetylene and nBuLi, selectively removed with pyridinium p-toluenesulfonate
and the following alkynylation of epoxide 11 was tested un- (PPTS) to provide primary alcohol 18 in 80% yield for two
der various reaction conditions. However, the expected ep- steps.[19] Treatment of 18 with p-toluenesulfonyl chloride
oxide product was either not formed or generated in trace (TsCl) to generate a TsO leaving group, followed by NaN3
amounts with BF3·OEt[14] or Me3Al[15] as the catalyst. Fi- replacement, afforded 2 in 87% yield for two steps.[20]
nally, an organo-aluminum species, which was prepared
Exposure of the key intermediate 2 to conventional cata-
with iBu2AlCl and (trimethylsilyl)ethyn-1-ide, provided the lyst systems (Scheme 6, entries 1–3), CuI/DIEA,[3] CuSO4/
desired alcohol 12 in 75% yield.
NaAsc,[2c] or CuBr/DBU,[5] either provided the cyclization
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Scheme 3. Preparation of 12 from the Weinreb amide 11.
Scheme 4. Preparation of 16 from 12.
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Synthesis of Triazole-Epothilones
Scheme 5. Preparation of 2 from 16.
product in only trace amounts or no reaction was observed. (IC50 Ͼ 50 μm). However, it was interesting to find that the
The best approach was to apply [Cu(CN)4PF6] (Scheme 6, dimer 21 is active against MCF-7 (IC50 = 10 μm, which is
entry 4), which provided the product 19 in 36% yield.[4] about 200 times less potent than Epothilone D in the same
Interestingly, for the first time, we applied this Cu2O-NP assay).
catalyst in a ring-closure click reaction (Scheme 6, entry 5),
and found the result to be satisfactory: using acetonitrile as
solvent, the desired monomer 19 was isolated in 74% yield
and dimer 20 was isolated in 6% yield. Both compounds
were treated with trifluoroacetic acid at 0 °C to furnish the
target molecule 1 in 92% yield and compound 21 in 87%
yield.
The absolute structure of 1 was confirmed by X-ray
analysis (Figure 1). Computational modeling (see Figure S2
in the Supporting Information) suggests that the conforma-
tion of compound 1 in solution is similar to that in the
solid-state, and this conformation is significantly different
from the solid-state structure of epothilones[21] and the sug-
Figure 1. X-ray ORTEP illustration of compound 1.
gested bioactive conformations.[22] This comparison is fur-
ther confirmed by the NMR analysis of compound 1 in
solution. The main feature of 1 is a rigid and planar confor-
mation of the C10–C14 region, which contrasts with the
same region in natural epothilones which is flexible and has
at least two conformers.[22] Furthermore, there is also a con-
formational change in the C1–C7 region, which is probably
vital to the biological activity of epothilone.[23] The best
docking of 1 to the structure of α,β-tubulin (PDB ID:
1TVK) using the software AutoDock v.4.2 (http://auto-
dock.scripps.edu) (Figure 2) requires a reversal of confor-
mation compared to natural epothilones (for the docking
procedure, see the Supporting Information). Moreover, the
binding energy of 1 to the structure of α,β-tubulin is
2.7 kcal/mol higher than that of natural epothilones.[24] It is
therefore not surprising to find that compound 1 had re-
duced biological activity against MCF-7 cancer cell lines and natural Epothilone A (yellow) to α,β-tubulin.
Figure 2. Superposition of best docking position of 1 (light purple)
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Scheme 6. Preparation of 1 and the dimer 21.
Conclusions
Cu2O-NPs has been evaluated in the cyclization of large
ring systems. The superior yield of this reaction demon-
strates that Cu2O-NPs are a feasible catalyst for intramolec-
ular macrocyclic ring formation.
A novel type of triazole-epothilone analogue was synthe-
sized through Cu2O-NP catalyzed 1,3-dipolar cycloaddition
as the key step. This is the first time that the efficiency of
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Synthesis of Triazole-Epothilones
9 (170 mg, 0.71 mmol) in CH3CN (5 mL) at 37 °C in 24 h. The
mixture was stirred at 37 °C for 48 h (TLC indicated the disappear-
ance of 9). The mixture was filtered through Celite and concen-
trated under reduced pressure. The residue was purified by column
chromatograph (silica gel; EtOAc/hexanes, 30%) to give 10
(108 mg, 64%) as a white solid. Rf = 0.4 (EtOAc/hexanes, 50%).
1H NMR (400 MHz, CDCl3): δ = 7.24 (s, 1 H), 4.34–4.31 (m, 2
H), 3.99–3.96 (m, 2 H), 2.84–2.81 (m, 2 H), 2.28–2.26 (m, 2 H),
2.14–2.08 (m, 2 H), 1.96–1.89 (m, 2 H), 1.49–1.44 (m, 2 H), 1.28–
1.21 (m, 2 H), 0.94–0.89 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 173.8, 145.8, 122.8, 63.7, 50.1, 32.6, 28.1, 27.6, 25.2,
25.0, 24.7, 22.2 ppm. HRMS (ESI): calcd. for C12H19N3O2 [M +
H+] 238.1550; found 238.1552.
Experimental Section
General: All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous conditions, un-
less otherwise noted. Yields refer to chromatographically and spec-
troscopically (1H NMR) homogeneous materials, unless otherwise
stated. The used solvents were purified and dried according to com-
mon procedures. Polyvinylpyrrolidone (PVP) coated copper(I) ox-
ide nanoparticle (Cu2O-NPs) were synthesized according to Chen
and Kong’s procedures.[6] Other chemicals and solvents are com-
mercially available. The phosphate buffer solution (pH 7.2, 0.1 m)
was prepared by dissolving disodium hydrogen phosphate
(Na2HPO4·12H2O, 25.79 g) and sodium dihydrogen phosphate
(NaH2PO4·2H2O, 4.37 g) in distilled, deionized water (1000 mL).
High-resolution mass spectra (HRMS) were obtained with a
FTICR-MS (Ionspec 7.0T) spectrometer. 1H NMR spectra were
obtained with a Bruker AC-P 300, AV 400, AV 600, or a Varian
Mercury Plus 400 spectrometer. Chemical shifts are reported in
parts per million (ppm) relative to either a tetramethylsilane in-
ternal standard or solvent signals. Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, br. = broad, m = multiplet), coupling constants, and
integration. 13C NMR spectra were recorded with a Bruker AC-P
300 (75 MHz) or AV 400 spectrometer (100 MHz) using CDCl3
or MeOD as the solvent. Chemical shifts (δ) are reported in ppm
measured relative to the solvent peak. IR spectra were recorded
with a Bio-Rad FTS 6000 Fourier infrared spectrometer.
Synthesis of 12: To a solution of (trimethylsilyl)acetylene (6.8 mL,
48 mmol) in toluene (150 mL) at 0 °C, was added nBuLi (17.6 mL,
44 mmol) by using a syringe over 30 min under Ar. The resulting
mixture was stirred for 30 min then iso-Bu2AlCl (60 mL, 48 mmol)
was added. The resulting solution was stirred at room temperature
for 2 h, then recooled to 0 °C and epoxy amide 9 (5.24 g, 40 mmol)
was added. The solution was stirred at 0 °C for 2 h, then the mix-
ture was diluted with diethyl ether (200 mL) and acidified with 1 m
HCl (pH 4). The aqueous layer was extracted with Et2O
(3ϫ100 mL) and the combined organic layer was dried with
Na2SO4, filtered through Celite, and the solvents were removed un-
der reduced pressure. The residue was purified by a flash column
chromatography (silica gel; EtOAc/hexanes, 20%) to give 12
(6.89 g, 75%) as a yellow oil. Rf = 0.24 (EtOAc/hexanes, 20%). [α]
Synthesis of 9
20 = –67.4 (c = 1.1, CHCl ). IR (KBr): ν = 3429, 2959, 2901, 2822,
˜
D
3
2177, 1658, 1443, 1370, 1249, 1179, 1077, 1046, 983, 839, 759 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.51 (s, 1 H), 3.72 (s, 3 H), 3.59–
3.58 (m, 1 H), 3.25 (s, 3 H), 2.66 (q, J = 16.9 Hz, 2 H), 0.13 (s, 9
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.67, 101.69, 87.40,
67.18, 61.52, 32.46, 26.37, 0.07 ppm. HRMS (ESI): calcd. for
C10H19NO3Si [M + H+] 230.1207; found 230.1214.
Synthesis of 7: To a solution of amide 12 (6 g, 26.1 mmol) in THF
(200 mL) under N2 was added methylmagnesium bromide
(1.53 mL, 1.96 mmol) at –20 °C. The reaction mixture was warmed
to room temperature and stirred for 8 h. EtOAc (100 mL) was
added slowly, followed by saturated aqueous oxalic acid (100 mL).
The aqueous layer was extracted with EtOAc (3ϫ50 mL), and the
combined organic layer was washed with brine (120 mL), dried
with Na2SO4, filtered through Celite, and the solvents were re-
moved under reduced pressure. The residue was purified by flash
column chromatography (silica gel; EtOAc/hexanes, 10%) to give 7
(4.2 g, 87%) as a yellow oil. Rf = 0.83 (EtOAc/hexanes, 50%)
To a solution of acid 22 (391 mg, 3.49 mmol) at 0 °C, was added a
solution of 4-(dimethylamino)pyridine (4-DMAP; 641 mg,
5.24 mmol) and alcohol 23 (500 mg, 3.49 mmol) in CH2Cl2
(20 mL), and the mixture was treated with 1-ethyl-3-[(dimeth-
ylamino)propyl]carbodiimide
hydrochloride
(EDC;
1.3 g,
6.98 mmol). The reaction mixture was stirred at 0 °C for 2 h and
then at 25 °C for 12 h. The solution was concentrated under re-
duced pressure and the residue was taken up in EtOAc (20 mL)
and water (100 mL). The organic layer was sequentially washed
with saturated NH4Cl (10 mL) and water (10 mL), and dried with
MgSO4. The solvent was removed under vacuum and the residue
was purified by flash column chromatography (silica gel; EtOAc/
hexanes, 7%) to give ester 9 (700 mg, 84%) as a yellow oil. Rf =
[α]2D0 = +39.0 (c = 0.8, CHCl ). IR (KBr): ν = 3445, 2959, 2900,
˜
3
2177, 1717, 1411, 1358, 1249, 1181, 1095, 1046, 948, 840, 760 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.28 (q, J = 5.4 Hz, 1 H), 3.67
(d, J = 5.5 Hz, 1 H), 2.63–2.49 (m, 2 H), 2.29 (s, 3 H), 0.13 (s, 9
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 207.9, 101.1, 87.6, 74.7,
25.6, 25.0, –0.4 ppm. HRMS (ESI): calcd. for C9H16O2Si [M +
Na+] 207.0812; found 207.0816.
1
0.67 (hexanes/EtOAc, 5:1). H NMR (400 MHz, CDCl3): δ = 3.96
Synthesis of 13: To a solution of Wittig reagent 8 (22 g, 65.2 mmol)
in THF (100 mL), was added KHMDS (65.2 mL, 65.2 mmol) at
0 °C. After stirring for 0.5 h, the reaction mixture was cooled to
–78 °C and a solution of ketone 7 (3 g, 16.3 mmol) in THF (40 mL)
was added. The reaction mixture was warmed to –20 °C, and, after
1 h, TLC indicated the disappearance of keto 7. The reaction mix-
ture was quenched with saturated aqueous NH4Cl (50 mL), the
aqueous layer was extracted with EtOAc (100 mL), and the com-
bined organic layer was washed with brine (120 mL), and dried
(t, J = 6.6 Hz, 2 H), 3.16 (t, J = 6.8 Hz, 2 H), 2.33 (t, J = 7.4 Hz,
2 H), 2.16–2.13 (m, 2 H), 1.89 (s, 1 H), 1.76–1.69 (m, 2 H), 1.55–
1.48 (m, 4 H), 1.29–1.28 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.8, 83.1, 69.0, 64.0, 51.1, 32.7, 28.5, 28.3, 26.2,
25.3, 23.5, 17.6 ppm. HRMS (ESI): calcd. for C12H19N3O2 [M +
H+] 238.1550; found 238.1552.
Synthesis of 10: To a solution of freshly prepared polyvinylpyr-
rolidone (PVP) coated copper(I) oxide nanoparticle (Cu2O-NP;
75 mg, 0.71 mmol) in CH3CN (355 mL, c = 211 μg/mL), was added with Na2SO4. The solvent was removed under vacuum and the resi-
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due was purified by a flash column chromatography (silica gel; hex-
CHCl ). IR (KBr): ν = 3506, 3310, 3071, 2957, 2932, 2857, 1740,
˜
3
ane/EtOAc, 3:1) to give 13 (4.82 g, 97%) as a yellow oil. Rf = 0.21
1686, 1505, 1470, 1428, 1386, 1293, 1255, 1177, 1106, 1089, 996,
834, 777, 738, 703 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.68–
7.66 (m, 4 H), 7.39–7.37 (m, 6 H), 6.98 (s, 1 H), 6.57 (s, 1 H), 5.39
(t, J = 6.5 Hz, 1 H), 4.42 (m, 1 H), 3.72 (dd, J = 6.3, 12.7 Hz, 2
(EtOAc/hexanes, 30%). [α]2D0 = –1.0 (c = 1.0, CHCl ). IR (KBr): ν
˜
3
= 3290, 3118, 2957, 2902, 2175, 1654, 1506, 1438, 1422, 1248, 1030,
999, 837, 758 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.85 (s, 1 H),
6.53 (s, 1 H), 4.27–4.24 (m, 1 H), 3.95–3.92 (m, 1 H), 2.63 (s, 3 H), H), 3.38 (s, 1 H), 3.31–3.26 (m, 2 H), 2.68 (s, 3 H), 2.64 (s, 2 H),
2.51–2.49 (m, 2 H), 1.94 (s, 3 H), 0.06 (s, 9 H) ppm. 13C NMR
2.50 (dd, J = 3.5, 17.3 Hz, 1 H), 2.37 (dd, J = 5.8, 17.2 Hz, 1 H),
(100 MHz, CDCl3): δ = 164.8, 152.4, 140.7, 119.3, 115.5, 103.6, 2.10 (s, 3 H), 1.98 (s, 1 H), 1.70 (m, 2 H), 1.20 (s, 3 H), 1.09 (s, 3
87.0, 75.2, 27.5, 18.9, 14.2, 0.04 ppm. HRMS (ESI): calcd. for
H), 1.04 (m, 12 H), 0.88 (m, 12 H), 0.80 (d, J = 6.8 Hz, 3 H), 0.11
(s, 3 H), 0.08 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
221.5, 170.9, 164.8, 162.4, 152.4, 135.7, 135.6, 134.2, 134.1, 129.6,
127.8, 127.7, 121.9, 117.0, 79.5, 77.3, 74.9, 73.6, 70.9, 62.4, 53.9,
41.7, 40.3, 35.6, 32.9, 29.8, 26.9, 26.1, 23.6, 22.3, 20.0, 19.4, 19.3,
18.3, 15.9, 14.7, 10.0, –4.1, –4.7 ppm. HRMS (ESI): calcd. for
C47H69NO6SSi2 [M + H+] 832.4457; found 832.4450.
C14H21NOSSi [M + H+] 280.1186; found 280.1189.
Synthesis of 5: To a solution of TBAF (92 g, 294 mmol) in THF
(200 mL), was added a solution of alcohol 13 (27 g, 98 mmol) in
THF (3 mL) at 30 °C, and the reaction mixture was stirred for 2 h.
The reaction was quenched by addition of water (50 mL) and the
aqueous layer was extracted with Et2O (3ϫ60 mL). The combined
organic layer was dried with Na2SO4 and the solvent was removed
under vacuum to give a residue that was purified by flash
chromatography on silica gel (hexane/EtOAc, 10:1) to give product
5 (19 g, 95%) as a yellow oil. Rf = 0.19 (EtOAc/hexanes, 30%).
Synthesis of 16: To a solution of 14 (228 mg, 0.274 mmol) was
added a freshly prepared 20% CF3COOH solution in CH2Cl2
(8 mL) at –20 °C. The reaction mixture was allowed to reach 0 °C
and stirred for 1 h. The reaction mixture was diluted with EtOAc
and quenched with saturated aqueous NaHCO3 to adjust the pH
to 7. The aqueous layer was extracted with EtOAc (3ϫ10 mL) and
the combined organic layer was washed with brine, dried with
MgSO4, filtered through Celite and the solvents removed under
reduced pressure to give the crude product 15. To a solution of
crude 15 in a mixture of CH2Cl2 (8 mL) and MeOH (2 mL) was
added NaHCO3 (500 mg) at 0 °C. The mixture was stirred until the
starting martial was completely converted. The solvent was re-
moved under reduced pressure and the residue was dissolved in
CH2Cl2 (20 mL) and washed with brine, dried with Na2SO4, and
the solvent was removed under reduced pressure. The residue was
purified by column chromatograph on silica gel (hexanes/EtOAc,
1:2) to obtain 16 (104 mg, 80% for two steps) as a colorless oil. Rf
= 0.23 (hexanes/EtOAc, 1:2). [α]2D0 = –43.6 (c = 1.0, CHCl3) IR
[α]2D0 = –2.1 (c = 1, CHCl ). IR (KBr): ν = 3296, 2917, 2118, 1655,
˜
3
1508, 1441, 1377, 1270, 1191, 1036 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 6.97 (s, 1 H), 6.61 (s, 1 H), 4.36 (t, J = 6.2 Hz, 1 H),
2.71 (s, 3 H), 2.57–2.54 (m, 2 H), 2.42 (s, 1 H), 2.07–2.06 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.9, 152.3, 140.4,
119.7, 115.8, 81.0, 75.4, 70.6, 25.9, 19.0, 14.1 ppm. HRMS (ESI):
calcd. for C11H13NOS [M + H+] 208.0791; found 208.0794.
Synthesis of 4: To a solution of acid 6 (8.88 g, 29.4 mmol) at 0 °C,
was added a solution of DMAP (5.4 g, 44.1 mmol) and alcohol 5
(7.3 g, 35.2 mmol) in CH2Cl2 (40 mL), and then treated with EDC
(11.3 g, 58.8 mmol). The reaction mixture was stirred at 0 °C for
2 h and then at 25 °C for 12 h. The solution was concentrated to
dryness in vacuo and the residue was taken up in EtOAc (100 mL)
and water (100 mL). The organic layer was sequentially washed
with saturated NH4Cl (50 mL) and water (50 mL), and dried with
MgSO4. The solvent was removed under vacuum and the residue
was purified by flash column chromatography (silica gel; EtOAc/
hexanes, 7%) to give 4 (12 g, 85%) as a yellow oil. Rf = 0.74 (hex-
(KBr): ν = 3299, 2956, 2918, 2849, 1784, 1736, 1697, 14723, 1463,
˜
1
1378, 1295, 1261, 1220, 1169, 1018, 801, 719, 728 cm–1. H NMR
(400 MHz, CDCl3): δ = 6.99 (s, 1 H), 6.58 (s, 1 H), 5.46 (t, J =
6.6 Hz, 1 H), 4.27 (d, J = 8.7 Hz, 1 H), 3.76–3.71 (m, 1 H), 3.64–
3.60 (m, 1 H), 3.49–3.45 (m, 2 H), 3.40 (s, 1 H), 3.27 (dd, J = 6.3,
13.0 Hz, 1 H), 2.70 (s, 3 H), 2.66–2.63 (m, 2 H), 2.54–2.42 (m, 2
H), 2.10 (s, 3 H), 2.01 (m, 1 H), 1.79–1.73 (m, 2 H), 1.58–1.53 (m,
1 H), 1.22–1.20 (m, 3 H), 1.13 (s, 3 H), 1.09 (d, J = 6.9 Hz, 3 H),
0.90 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
221.9, 171.8, 164.9, 151.9, 135.5, 121.7, 116.9, 79.3, 77.2, 75.4, 72.3,
70.9, 60.8, 52.2, 41.4, 37.0, 36.8, 33.6, 23.6, 21.6, 19.2, 18.6, 17.2,
14.7, 10.5 ppm. HRMS (ESI): calcd. for C25H37NO6S [M + H+]
480.2414; found 480.2412.
anes/EtOAc, 5:1). [α]2D0 = –15.6 (c = 0.23, CHCl ). IR (KBr): ν =
˜
3
3506, 3310, 3071, 2957, 2932, 2857, 1740, 1686, 1505, 1470, 1428,
1386, 1293, 1255, 1177, 1106, 1089, 996, 834, 777, 703, 738 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.96 (s, 1 H), 6.54 (s, 1 H), 5.35
(t, J = 6.6 Hz, 1 H), 4.46 (dd, J = 4.0, 5.8 Hz, 1 H), 2.67 (s, 3 H),
2.61 (t, J = 5.8 Hz, 2 H), 2.57–2.30 (m, 3 H), 2.33 (dd, J = 6.3,
16.8 Hz, 1 H), 2.08 (s, 3 H), 1.96 (s, 1 H), 1.08 (s, 3 H), 1.04 (s, 3
H), 0.97–0.94 (t, J = 7.1 Hz, 3 H), 0.82 (s, 9 H), 0.03 (d, J = 7.8 Hz,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 214.4, 170.7, 164.4,
152.2, 135.3, 121.7, 116.8, 79.2, 77.0, 73.3, 70.8, 52.4, 39.3, 31.6,
25.8, 23.3, 20.7, 20.6, 19.1, 17.9, 14.3, 7.6, –4.4, –5.2 ppm. HRMS
(ESI): calcd. for C9H16O2Si [M + H+] 492. 2598; found 492.2601.
Synthesis of 18: To a solution of 16 (930 mg, 1.94 mmol) in CH2Cl2
(50 mL) was added 2,6-lutidine (2.7 mL, 23.3 mmol), followed by
TESOTf (4 mL, 17.5 mmol) at –78 °C. The resulting solution was
stirred at –78 °C for 5 h before being quenched by addition of satu-
rated aqueous NaHCO3 (30 mL). The aqueous layer was extracted
Synthesis of 14: To a solution of 4 (5.37 g, 11 mmol) in CH2Cl2
(250 mL), was added TiCl4 (13.2 mL, 13.2 mmol, 1 mmol/mL) at with EtOAc (3ϫ50 mL) and the combined organic layer was
–78 °C, followed by addition of DIEA (2.2 mL, 13.2 mmol). After
stirring for 1.5 h at –78 °C, a solution of aldehyde 3 (3.71 g,
11 mmol) in CH2Cl2 (5 mL) was added. The mixture was warmed
slowly to room temperature and then diluted with Et2O (100 mL)
and quenched with phosphoric buffer solution (30 mL). The aque-
ous layer was extracted with diethyl ether, and the combined or-
ganic layers were dried with MgSO4. The solvent was removed un-
der vacuum and the residue was purified by flash column
chromatography (silica gel; EtOAc/hexanes, 5%) to afford 14 (6.6 g,
73%) as a yellow oil and 14a (822 mg, 9%) as a yellow oil. Com-
pound 14: Rf = 0.68 (hexanes/EtOAc, 5:1). [α]2D0 = –44.8 (c = 1.0,
washed with brine, dried with MgSO4, filtered through Celite, and
the solvent removed under reduced pressure to obtain crude prod-
uct 17 as a yellow oil, which was used immediately in the next step
without further purification. To a solution of crude 17 in a mixture
of MeOH/CH2Cl2 (4 mL/12 mL) was added pyridinium 4-toluene-
sulfonate (137 mg, 0.54 mmol) at –10 °C. The mixture was stirred
until the starting martial was completely converted. The mixture
was quenched with saturated aqueous NH4Cl (16 mL) and the
aqueous phase was extracted with Et2O (3ϫ16 mL). The combined
organic layer was washed with brine, dried with Na2SO4, and the
solvent was removed under vacuum. The residue was purified by
506
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 500–508

Synthesis of Triazole-Epothilones
column chromatograph on silica gel (EtOAc/hexanes, 20%) to ob-
(d, J = 2.9 Hz, 1 H), 3.19–3.07 (m, 2 H), 2.73–2.71 (m, 1 H), 2.67
(s, 3 H), 2.45–2.36 (m, 2 H), 2.19 (s, 3 H), 1.71–1.61 (m, 2 H), 1.53–
1.50 (m, 1 H), 1.03–1.01 (m, 6 H), 0.96–0.90 (m, 21 H), 0.81 (s, 3
H), 0.65–0.59 (m, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
216.3, 169.7, 164.7, 152.7, 144.1, 137.8, 122.2, 120.3, 116.5, 79.1,
77.1, 72.8, 53.5, 47.6, 45.9, 42.0, 32.3, 31.2, 30.5, 20.3, 19.3, 18.9,
18.3, 16.7, 14.8, 7.1, 7.0, 5.4, 5.1 ppm. HRMS (ESI): calcd. for
C37H64N4O5SSi2 [M + H+] 733.4209; found 733.4191.
tain 18 (1.1 g, 80% for two steps) as a colorless oil. Rf = 0.27
(EtOAc/hexanes, 20%) [α]2D0 = –33 (c = 1.0, CHCl ) IR (KBr): ν =
˜
3
3314, 2956, 2917, 2877, 1737, 1690, 1458, 1379, 1293, 1238, 1096,
988, 733 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.97 (s, 1 H), 6.56
(s, 1 H), 5.38 (t, J = 6.4 Hz, 1 H), 4.36 (dd, J = 1.4, 4.4 Hz, 1 H),
3.81 (d, J = 7.7 Hz, 1 H), 3.66 (br., 1 H), 3.52–3.51 (m, 1 H), 3.20–
3.17 (m, 1 H), 2.69 (s, 3 H), 2.64–2.60 (m, 2 H), 2.48 (dd, J = 2.7,
17.1 Hz, 1 H), 2.34 (dd, J = 7.3, 17.0 Hz, 1 H), 2.09 (s, 3 H), 1.96
(t, J = 2.5 Hz, 1 H), 1.63–1.60 (m, 1 H), 1.52–1.49 (m, 2 H), 1.21
(s, 3 H), 1.08 (s, 3 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.94 (m, 21 H),
0.66–0.58 (m, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 218.4,
171.2, 164.8, 152.4, 135.7, 122.1, 116.9, 79.4, 78.7, 77.1, 73.6, 70.8,
60.1, 53.5, 45.7, 39.9, 34.8, 33.6, 29.8, 23.5, 19.8, 19.3, 18.2, 15.6,
14.6, 7.2, 7.1, 5.5, 5.2 ppm. HRMS (ESI): calcd. for
C37H65NO6SSi2 [M + H+] 708.4144; found 708.4147.
Synthesis of 19 with Cu(CN)4PF6: To a solution of [Cu(CN)4PF6]
(15 mg, 0.04 mmol) in toluene (14 mL), was added 2 (28 mg,
0.04 mmol) in toluene (3 mL) at 80 °C in 12 h. The mixture was
stirred at 37 °C for 48 h, when TLC indicated the disappearance
of 2. The mixture was filtered through Celite, concentrated under
reduced pressure, and the residue was purified by column chroma-
tograph (silica gel; EtOAc/hexanes, 30%) to give 19 (10 mg, 36%).
Synthesis of 2: To a solution of 18 (323 mg, 0.45 mmol) in CH2Cl2
(10 mL), was added Et3N (0.39 mL, 2.7 mmol) and DMAP
(5.5 mL, 0.045 mmol) at 0 °C, followed by addition of TsCl
Synthesis of 1: To a solution of 19 (164 mg, 0.22 mmol), was added
a freshly prepared 20% CF3COOH solution in CH2Cl2 (8 mL) at
–20 °C. The reaction mixture was allowed to reach 0 °C and stirred
(435 mg, 2.3 mmol) in CH2Cl2 (1 mL). The reaction mixture was overnight. The reaction mixture was diluted with CH2Cl2 and
stirred at room temperature for 6 h, then the reaction was quenched
with water (10 mL). The aqueous phase was extracted with CH2Cl2
(3ϫ10 mL) and the extracts were washed with brine, dried with
Na2SO4, and the solvent was removed under vacuum to give the
crude product. To a solution of the 4-methylbenzenesulfonyl crude
product in DMF (16 mL) was added NaN3 (87.7 mg, 1.35 mmol)
under Ar, and the mixture was heated to 80 °C and stirred for 5 h.
The reaction mixture was diluted with Et2O and quenched with
saturated aqueous NaCl, the aqueous layer was extracted with
Et2O (3 ϫ5 mL) and the combined organic layer was washed with
H2O (2ϫ10 mL), dried with MgSO4, filtered through Celite, and
the solvent was removed under reduced pressure. The residue was
purified by column chromatograph (silica gel; EtOAc/hexanes, 1:30
Ǟ 1:10) to obtain 2 (288 mg, 87% for two steps) as a colorless oil.
Rf = 0.64 (EtOAc/hexanes, 15%). [α]2D0 = –45.2 (c = 1.0, CHCl3)
quenched with saturated aqueous NaHCO3 to adjust the pH to 7.
The aqueous phase was extracted with CH2Cl2 (3ϫ 5 mL), and the
combined organic layer was washed with brine, dried with MgSO4,
filtered through Celite, and the solvent was concentrated under re-
duced pressure. The residue was purified by column chromatograph
(silica gel; EtOAc/hexanes, 50%) to provide 1 (101 mg, 92%) as a
white solid. Rf = 0.24 (EtOAc/hexanes, 80%). [α]2D0 = –26.7 (c =
1.0, CHCl ). M.p. 198–199 °C. IR (KBr): ν = 3577, 3335, 3138,
˜
3
2958, 2920, 1742, 1690, 1432, 1365, 1292, 1175, 1145, 1012, 982,
1
938 cm–1. H NMR (400 MHz, CDCl3): δ = 7.42 (s, 1 H), 6.99 (s,
1 H), 6.59 (s, 1 H), 5.61 (dd, J = 3.6, 10.0 Hz, 1 H), 4.46–4.43 (m,
2 H), 3.62 (br., 2 H), 3.18–3.06 (m, 3 H), 2.71 (s, 3 H), 2.37 (m, 2
H), 2.17 (s, 3 H), 2.00 (br., 2 H), 1.70–1.64 (m, 1 H), 1.25 (s, 3 H),
1.07–1.04 (m, 6 H), 1.00 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 219.7, 170.7, 164.9, 152.1, 143.2, 137.0, 123.4, 120.2,
IR (KBr): ν = 3401, 3314, 2962, 2918, 2849, 2663, 2096, 1945, 116.7, 78.4, 75.3, 74.4, 51.3, 47.3, 44.4, 38.1, 32.1, 30.1, 29.6, 22.3,
˜
1739, 1691, 1621, 1472, 1462, 1415, 1379, 1337, 1260, 872, 743,
722, 730 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.97 (s, 1 H), 6.56
(s, 1 H), 5.39 (t, J = 6.6 Hz, 1 H), 4.34 (dd, J = 3.0, 7.1 Hz, 1 H),
3.78 (d, J = 7.6 Hz, 1 H), 3.36–3.30 (m, 1 H), 3.22–3.17 (m, 1 H),
3.13–3.06 (m, 1 H), 2.70 (s, 3 H), 2.65–2.60 (m, 2 H), 2.51 (dd, J
= 2.9, 17.0 Hz, 1 H), 2.33 (dd, J = 7.2, 17.0 Hz, 1 H), 2.10 (s, 3
H), 1.97 (t, J = 2.6 Hz, 1 H), 1.74–1.67 (m, 1 H), 1.39 (br., 2 H),
1.24 (s, 3 H), 1.06–1.03 (m, 6 H), 0.97–0.90 (m, 21 H), 0.65–0.69
(m, 12 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 218.1, 171.1,
164.8, 152.5, 135.7, 122.1, 117.0, 79.5, 78.6, 77.1, 73.9, 70.8, 53.3,
50.0, 45.8, 39.9, 35.3, 29.8, 23.5, 23.3, 20.1, 19.3, 17.9, 15.3, 14.5,
7.2, 7.1, 5.6, 5.2 ppm. HRMS (ESI): calcd. for C37H64N4O5SSi2 [M
+ H+] 733.4209; found 733.4206.
19.2, 18.9, 16.7, 15.1, 13.9 ppm. HRMS (ESI): calcd. for
C25H36N4O5S [M + H+] 505.2479; found 505.2480.
Synthesis of 21: To a solution of 20 (14 mg, 0.009 mmol), was
added a freshly prepared 20% CF3COOH solution in CH2Cl2
(1 mL) at –20 °C. The reaction mixture was allowed to reach 0 °C
and stirred overnight. The reaction mixture was diluted with
CH2Cl2 and quenched with saturated aqueous NaHCO3 to adjust
the pH to 7. The aqueous phase was extracted with CH2Cl2 (3 mL),
and the combined organic layer was washed with brine, dried with
MgSO4, filtered through Celite, and the solvent was concentrated
under reduced pressure. The residue was purified by column chro-
matograph (silica gel; EtOAc/hexanes, 50%) to provide 21 (8 mg,
87%) as a white solid. 1H NMR (400 MHz, MeOD): δ = 7.89 (s, 2
H), 7.21 (s, 2 H), 6.49 (s, 2 H), 5.51 (t, J = 5.8 Hz, 2 H), 4.47–4.35
(m, 4 H), 4.30 (dd, J = 2.5, 9.7 Hz, 2 H), 3.57 (t, J = 5.5 Hz, 2 H),
3.28–3.27 (m, 4 H), 3.16 (d, J = 5.9 Hz, 4 H), 2.68 (s, 6 H), 2.49–
2.37 (m, 4 H), 2.20–2.13 (m, 4 H), 2.10 (s, 6 H), 1.74–1.65 (m, 2
H), 1.53–1.50 (m, 2 H), 1.18 (s, 6 H), 1.09 (s, 6 H),1.06 (d, J =
6.8 Hz, 6 H), 0.96 (d, J = 6.7 Hz, 6 H) ppm. 13C NMR(100 MHz,
MeOD): δ = 221.6, 172.9, 166.9, 153.1, 138.5, 124.7, 120.1, 117.9,
78.9, 76.7, 73.9, 53.8, 48.8, 44.2, 34.7, 33.7, 30.8, 21.5, 20.0, 18.7,
17.1, 15.5, 12.8 ppm. HRMS (ESI): calcd. for C50H72N8O10S2 [M
+ H+] 1009.4886; found 1009.4908.
Synthesis of 19 with Cu2O-NP: To a solution of freshly prepared
polyvinylpyrrolidone (PVP) coated copper(I) oxide nanoparticle
(Cu2O-NP, 48 mg) in CH3CN (160 mL, c = 300 μg/mL), was added
2 (238 mg, 0.32 mmol) in CH3CN (20 mL) at 37 °C in 24 h. The
mixture was stirred at 37 °C for 48 h, when TLC indicated the dis-
appearance of 2. The mixture was filtered through Celite and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatograph (silica gel; EtOAc/hexanes, 30%) to give 19
(174 mg, 74%) as a white solid and 20 as a white solid. Compound
19: Rf = 0.15 (EtOAc/hexanes, 30%). [α]2D0 = –14.7 (c = 2.0, CHCl3).
IR (KBr): ν = 2961, 2917, 2873, 2849, 1728, 1600, 1580, 1462, 1380,
˜
1261, 1074, 1020, 865, 799, 745, 724 cm–1. 1H NMR (400 MHz,
Supporting Information (see footnote on the first page of this arti-
CDCl3): δ = 7.44 (s, 1 H), 6.92 (s, 1 H), 6.58 (s, 1 H), 5.53 (d, J = cle): Experimental procedure, 1H and 13C NMR spectra, X-ray
9.6 Hz, 1 H), 4.42 (t, J = 12.2 Hz, 1 H), 4.30–4.28 (m, 2 H), 3.58
data, molecular modeling methods, and data for compound 1.
Eur. J. Org. Chem. 2012, 500–508
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
507

G. Luo, Y. Chen et al.
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Received: September 8, 2011
Published Online: December 2, 2011
508
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 500–508