Synthesis of triazole analogues of the nanaomycin antibiotics using 'click chemistry'

Article abstract of DOI:10.1016/j.tet.2010.04.048

A series of triazole analogues of the nanaomycin family of antibiotics have been prepared using a 'click' dipolar cycloaddition of a naphthalene azide to various alkynes, followed by oxidation to the desired pyranonaphthoquinones.

Full text of DOI:10.1016/j.tet.2010.04.048

Tetrahedron 66 (2010) 4002e4009
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of triazole analogues of the nanaomycin antibiotics
using ‘click chemistry’
,
,
,b,
*
Kris Rathwell a b, Jonathan Sperry a b, Margaret A. Brimble a
a Department of Chemistry, University of Auckland, 23 Symonds Street, Auckland, New Zealand
b Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of triazole analogues of the nanaomycin family of antibiotics have been prepared using a ‘click’
dipolar cycloaddition of a naphthalene azide to various alkynes, followed by oxidation to the desired
pyranonaphthoquinones.
Received 4 February 2010
Received in revised form 26 March 2010
Accepted 12 April 2010
Available online xxx
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyranonaphthoquinone
‘Click chemistry’
Triazole
Nanaomycin
1. Introduction
For all the biomedical promise of genetic engineering and
combinatorial chemistry, nature continues to remain the key
source of current pharmaceuticals and future drug candidates. By
modification of a biologically active natural product, often libraries
of simplified, non-natural compounds can be synthesised in order
to improve the desired pharmacological activity.1,2
The pyranonaphthoquinone family of antibiotics display a wide
range biological activity with medicinal potential.3 One subclass
within this family, the nanaomycins 1e6 are of particular interest
due to their relatively simple, unique structure and biological ac-
tivity thus rendering them attractive lead compounds (Fig. 1).
As part of an on-going screening program for anti-mycoplasmal
antibiotics, Omura et al. isolated nanaomycins A 14e6 B 2,4,5 C 3,7 D
48 and E 59 from Streptomyces rosa. Nanaomycins 1e5 possess
a broad range of biological properties, including varying levels of
inhibition against mycoplasma, fungi and Gram-positive
bacteria.4e9 In addition, nanaomycin A 1 has been shown to inhibit
the platelet aggregation agent, adenosine diphosphate (ADP).10
Furthermore, fermentation of
a Nocardia species produced
YS-02931K- 6, the enantiomer of nanaomycin A 1. Compound 6
b
exhibited strong antimicrobial activity against Gram-positive bac-
teria as well as dermaphytes and fungi.11e13 Some simplified
Figure 1. Nanaomycin family of pyranonaphthoquinone antibiotics.
* Corresponding author. E-mail address: m.brimble@auckland.ac.nz (M.A.
Brimble).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.048

K. Rathwell et al. / Tetrahedron 66 (2010) 4002e4009
4003
Scheme 1. Retrosynthesis of triazole analogues of the nanaomycins.
synthetic analogues of nanaomycins A 1 and D 4 were subsequently
tested against various microorganisms for antibacterial properties,
the results showing that the naphthoquinone and lactone moieties
are the key pharmacophores.14 Furthermore, the significantly re-
duced antimicrobial activity of the five nanaomycins isolated from
a different strain of S. rosa var. notoensis (strain OM-173), namely
previously.21 Base-mediated epoxide formation followed by treat-
ment with EOMCl gave protected epoxide 20. Successful opening of
epoxide 20 with the alkoxide of benzyl alcohol delivered secondary
alcohol 21, which underwent smooth silylation furnishing 22.
Deprotection gave alcohol 23, which underwent oxidation to the
corresponding aldehyde followed by HornereWadsworthe
Emmons olefination delivering the desired (ꢀ)-enone 17 in good
overall yield (Scheme 2).
OM-173 aA 7, aB 8, aE 9, bA 10 and bE 11, in which the carboxyl
group is methylated or reduced to the corresponding hydroxy-
methyl moiety, established that the carboxyl group (or the cyclised
Next, the key annulation could be attempted. The Hau-
sereKraus annulation between cyanophthalide 18 and (ꢀ)-enone
17 initially proved problematic, but it was found that isolating the
g
-lactone) is indeed vital for the bioactivity to be maintained.15
Guided by this bioactivity data, the synthesis of several 1,2,3-
triazole mimics of the amide containing nanaomycin C 3 was
initiated. Being a rigid linker, the triazole ring system holds the
substituents in a similar geometry and distance to that of an amide,
as well as providing a comparable dipole moment. However, unlike
the amide counterpart, triazoles are stable towards hydrolytic
cleavage (especially under enzymatic conditions), oxidation and
reduction and thus display ideal characteristics to be successful
therapeutic candidates in vivo.16
crude annulation product after a very short reaction time
(10 min) and immediately subjecting it to reductive methylation
conditions furnished naphthalene 16 in modest overall yield.
Treatment of 16 with excess TBAF for three days effected silyl
group removal with concomitant cyclisation and the resulting
crude lactol 24 was stereoselectively reduced with trifluoroacetic
acid and triethylsilane delivering the cis-1,3-dimethylpyran 25 as
a single diastereomer as determined by 1H and 13C NMR spec-
troscopy. Debenzylation under an atmosphere of hydrogen over
Pearlman’s catalyst followed by tosylation of the resulting crude
alcohol gave tosylate 15. At this stage, the 1,3-cis stereochemistry
in 15 was confirmed by the NOE correlation between the axial
protons at C1 and C3 on the pyran ring (see Supplementary data).
Finally, displacement with sodium azide gave the key azide in-
termediate 13 (Scheme 3). With a scalable route to azide 13 in
hand, attention turned to the key ‘click’ cycloadditions using
a variety of alkynes (Scheme 4, Table 1). Gratifyingly, azide 13
underwent smooth cycloaddition with an excess of phenyl-
acetylene and CuI[P(OEt)3] (20 mol %)22 in toluene upon heating
to 85 ꢁC, affording an excellent yield of the desired 1,4-di-
substituted triazole 26 (entry 1). Several other substituted phe-
nylacetylenes reacted smoothly under the same conditions
(entries 2e5) affording 27e30, as did benzylacetylene (entry 6)
giving 31. The cycloaddition of dimethyl acetylenedicarboxylate
required forcing thermal conditions to proceed, delivering the
1,4,5-trisubstituted triazole 32 (entry 7). Reaction of azide 13
2. Results and discussion
The retrosynthesis of various triazole analogues 12 is shown in
Scheme 1 and centred on the enantioselective synthesis of cis-1,3-
dimethylpyran-containing natural products developed in our lab-
oratory.17 Thus, azide 13 was envisaged to be a key intermediate
upon which various dipolar cycloadditions could be conducted.
Thus, the [3þ2]-cycloaddition of azide 13 to various alkynes 14 in
a ‘click’-type process18 delivers triazoles 12. The azide itself is ac-
cessible by displacement of tosylate 15, formed via intramolecular
pyran formation and subsequent stereocontrolled lactol re-
duction.19 A HausereKraus annulation20 between enone 17 and
cyanophthalide 18 is initially used to construct naphthalene 16
(Scheme 1).
With cyanophthalide 18 already readily available in our labo-
ratory,17a the synthesis of enone 17 was instigated. Bromodiol 19 was
prepared from (S)-aspartic acid in two steps as described

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K. Rathwell et al. / Tetrahedron 66 (2010) 4002e4009
Scheme 2. Synthesis of (ꢀ)-enone 17.
Scheme 3. Synthesis of azide 13.
most synthetically complex azides to access benzotriazoles using
this method to date. Cycloadditions using long chain alkynes
(entries 10d35 and 11d36) and a bis-alkyne (entry 12d37) were
also successful.
As seen in Scheme 5 and Table 2, all of the triazole cycloadducts
underwent smooth oxidation with either silver(II) oxide (Method A)
or CAN (Method B) affording a series of nanaomycin triazole ana-
25
logues 38e50. The MOM-deprotection of 42 with NaHSO4eSiO2
also provided phenol-substituted analogue 43 (entry 6).
Scheme 4. Summary of ‘click’ cycloadditions between azide 13 and various alkynes.
It was subsequently shown that the triazole analogue cis-26 was
compatible with the conditions required to effect epimerization to
the more stable trans-isomer. Thus, triazole cis-38 was treated with
concentrated sulfuric acid in toluene at room temperature for
30 min, effecting epimerization and delivering trans-38 possessing
with trimethylsilyl acetylene followed by cleavage with TBAF
afforded the 1-substituted triazole 33 (entry 8). Azide 13 was also
found to be compatible with the recently reported ‘click’ benzyne
cycloaddition23,24 (entry 9) giving 34, representing one of the

K. Rathwell et al. / Tetrahedron 66 (2010) 4002e4009
4005
Table 1
Summary of ‘click’ cycloadditions between azide 13 and various alkynes
Entry
Alkyne
Reagents and conditionsa
Product
Yield (%)
A
1 h
1
94
A
48 h
2
74
A
5 h
3
80
A
6.5 h
4
88
A
48 h
5
70
(continued on next page)

4006
K. Rathwell et al. / Tetrahedron 66 (2010) 4002e4009
Table 1 (continued)
Entry
Alkyne
Reagents and conditionsa
Product
Yield (%)
A
4.5 h
6
71
100 ꢁ
Neat
C
7
86
1.25 h
A, 48 h then
TBAFeAcOH
THF
8
60 (two steps)
CsF, 18-Crown-6,
MeCN, 1 h
9
74
OMe OMe
O
A
1.5 h
10
93
OMe
N
N
35
N

K. Rathwell et al. / Tetrahedron 66 (2010) 4002e4009
4007
Table 1 (continued)
Entry
Alkyne
Reagents and conditionsa
Product
Yield (%)
A
11
81
2.25 h
A (0.5 equiv bis-alkyne)
23 h
12
87
a
Conditions AdAzide 13, CuI[P(OEt)3] (10e20 mol %), alkyne (1.2e5 equiv), toluene, 85 ꢁC (See Supplementary data for full details).
Scheme 5. Oxidation to ‘click’ analogues of the nanaomycins.
the natural, C1eC3-trans stereochemistry present in the nanao-
mycins (Scheme 6).
4. Experimental
4.1. General
Full experimental details are provided in the Supplementary
data. Details of a representative ‘click’ cycloaddition and oxida-
tion steps are described herein.
4.1.1. 4-Phenyl-1-(((1R,3R)-5,9,10-trimethoxy-1-methyl-3,4-dihydro-
1H-benzo[g]isochromen-3-yl)methyl)-1H-1,2,3-triazole
(26). To
a solution of azide 13 (27.3 mg, 0.08 mmol) in toluene (0.8 mL) was
added phenylacetylene (25.1 mg, 0.24 mmol) and CuI[P(OEt)3]
(4.9 mg, 0.014 mmol). The reaction was stirred in a sealed vial at
85 ꢁC for 1 h, concentrated in vacuo and purified by flash chroma-
tography eluting with hexanes/ethyl acetate (2:1) to afford the title
compound as a colourless solid (33.3 mg, 0.075 mmol, 94%); mp
Scheme 6. Epimerization of a triazole pyranonaphthoquinone.
68e72 ꢁC; TLC (hexanes/ethyl acetate 2:1) Rf¼0.17; [
a]
20 þ130.2 (c
D
3. Conclusions
0.05, CH2Cl2); nmax (neat)/cmꢀ1 2931, 2837, 1733, 1594, 1570, 1499,
1462, 1444, 1371, 1339, 1263, 1223, 1179, 1136, 1109, 1061, 1008; dH
(400 MHz, CDCl3) 1.66 (3H, d, J 6.3, CHCH3), 2.59 (1H, dd, J 15.8 and
11.5, CHaxH), 3.17 (1H, dd, J 15.8 and 1.6, CHHeq), 3.74 (3H, s, OCH3),
3.85 (3H, s, OCH3), 3.99 (4H, s, OCH3þH-3), 4.58 (1H, dd, J 14.2 and
7.0, CHHN), 4.78 (1H, dd, J 14.2 and 2.9, CHHN), 5.24 (1H, q, J 6.3,
CHCH3), 6.84 (1H, d, J 7.7, PhH), 7.34e7.46 (4H, m, PhH), 7.66 (1H, d, J
8.5, PhH), 7.87e7.89 (2H, m, PhH), 8.07 (1H, s, triazole); dC
(100 MHz, CDCl3) 23.2 (CH3), 27.0 (CH2), 54.6 (CH2), 56.1 (CH3), 61.3
(CH3), 61.7 (CH3), 71.5 (CH), 72.0 (CH), 105.7 (CH), 114.5 (CH), 119.5
In conclusion, we have prepared a series of triazole analogues of
the nanaomycin family of antibiotics via a ‘click’ dipolar cycload-
dition of a cis-1,3-disubstituted pyranonaphthalene azide to various
alkynes, followed by oxidation to the desired pyranonaph-
thoquinones. Epimerization of cis-38, delivered triazole nanaomy-
cin analogue trans-38 possessing the natural 1,3-trans-pyran
stereochemistry. Biological evaluation of these analogues is cur-
rently in progress.

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K. Rathwell et al. / Tetrahedron 66 (2010) 4002e4009
Table 2
Table 2 (continued)
Oxidation to ‘click’ analogues of the nanaomycins
Starting
Entry
Starting
material/
Methoda
Product
Yield (%)
Entry
material/
Product
Yield (%)
Methoda
42
26
B
6
66
1
72
NaHSO4eSiO2
27
A
2
83
31
A
7
75
28
A
3
82
32
B
8
50
29
A
4
90
33
A
9
71
30
A
5
90
34
A
10
82

K. Rathwell et al. / Tetrahedron 66 (2010) 4002e4009
4009
Table 2 (continued)
70.6 (CH), 71.3 (CH), 117.9 (CH), 119.1 (CH), 120.0 (C), 121.0 (CH),
125.7 (2ꢂCH), 128.1 (CH), 128.8 (2ꢂCH), 130.6 (C), 133.8 (C), 134.8
(CH), 138.5 (C), 147.8 (C), 148.0 (C), 159.5 (C), 183.1 (C), 183.5 (C); m/z
(EIþ) 415 (3%, Mþ), 270 (4), 255 (5), 241 (6), 229 (13), 213 (5),197 (6),
171 (6),152 (7),145 (10),128 (15),116 (51),103 (38), 89 (48), 77 (49),
63 (45), 55 (52), 41 (100); HRMS (FABþ, Mþ) found 415.1528, calcd
for C24H21N3O4 415.1532.
Starting
Entry
material/
Product
Yield (%)
Methoda
35
B
Acknowledgements
11
73
The authors thank the Royal Society of New Zealand Marsden
fund for financial support.
Supplementary data
Full experimental details, NOE data, 1H and 13C NMR spectra of
all new compounds. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tet.2010.04.048.
36
B
12
69
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(2ꢂCH), 129.1 (C), 129.9 (C), 130.8 (C), 147.7 (C), 148.9 (C), 149.1 (C),
156.0 (C); m/z (EIþ): 445 (100%, Mþ), 414 (1), 402 (2), 386 (2), 370
(4), 342 (3), 300 (5), 285 (15), 271 (7), 243 (8), 229 (11), 213 (7), 159
(9), 130 (10), 116 (10), 102 (13), 89 (5), 77 (8), 57 (12), 43 (13); HRMS
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4.1.2. (1R,3R)-9-Methoxy-1-methyl-3-((4-phenyl-1H-1,2,3-triazol-1-
yl)methyl)-3,4-dihydro-1H-benzo[g]isochromene-5,10-dione
(cis-
38). To a solution of the triazole 26 in acetonitrile (1.5 mL) was
added a solution of cerium(IV) ammonium nitrate (70.6 mg,
0.13 mmol) in water (0.8 mL). The reaction was stirred for 50 min at
room temperature, then partitioned between ethyl acetate and
water. The aqueous layer was extracted with ethyl acetate, dried
over magnesium sulfate and the solvent removed in vacuo. The
crude oil was purified by column chromatography to afford the title
compound as a yellow solid (18.6 mg, 0.045 mmol, 72%); mp
19
109e111 ꢁC; TLC (hexanes/ethyl acetate 1:2) Rf¼0.33; [
a
]
D
þ154.4
(c 0.06, CH2Cl2); nmax (neat)/cmꢀ1 2937,1767,1653,1584,1470,1444,
1365, 1332, 1273, 1254, 1205, 1188, 1105, 1059; dH (300 MHz, CDCl3)
1.55 (3H, d, J 6.6, CHCH3), 2.25 (1H, ddd, J 18.2, 10.7 and 3.7, CHaxH),
2.85 (1H, ddd, J 18.2, 2.6 and 2.6, CHHeq), 3.88e3.98 (1H, m, H-3),
3.98 (3H, s, OCH3), 4.52 (1H, dd, J 14.2 and 7.2, CHHN), 4.73 (1H, dd, J
14.2 and 3.1, CHHN), 4.83e4.87 (1H, m, CHCH3), 7.29e7.36 (2H, m,
PhH), 7.40e7.45 (2H, m, PhH), 7.64 (1H, t, J 7.8, PhH), 7.72 (1H, dd, J
7.7 and 1.1, PhH), 7.83e7.86 (2H, m, PhH), 7.96 (1H, s, triazole); dC
(75 MHz, CDCl3) 20.8 (CH3), 25.3 (CH2), 53.9 (CH2), 56.5 (OCH3),
25. For the preparation of NaHSO4eSiO2 see: Khalili, M. S.; Ghafuri, H.; Mojahedi-
Jahromi, S.; Hashemi, M. H. Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 175.