Cu(I)-Catalyzed cycloaddition of constrained azido-alkynes: Access to 12- to 17-membered monomeric triazolophanes incorporating furanoside rings

Article abstract of DOI:10.1016/j.tetlet.2006.02.068

A strained monomeric 12-membered triazolophane was formed by the Cu(I)-catalyzed intramolecular cycloaddition of an azide to an alkyne having a constrained tether incorporating an aromatic ring and a furanoside ring. Similar cycloadditions of azido-alkyne

Full text of DOI:10.1016/j.tetlet.2006.02.068

Tetrahedron Letters 47 (2006) 2775–2778
Cu(I)-Catalyzed cycloaddition of constrained azido-alkynes:
access to 12- to 17-membered monomeric
triazolophanes incorporating furanoside rings
Ankur Ray,a K. Manoj,b Mohan M. Bhadbhade,b Ranjan Mukhopadhyaya
and Anup Bhattacharjyaa,*
aIndian Institute of Chemical Biology, Chemistry Division, 4, Raja S. C. Mullick Road, Kolkata 700032, West Bengal, India
bNational Chemical Laboratory, Pune 411008, India
Received 6 December 2005; revised 7 February 2006; accepted 14 February 2006
Available online 3 March 2006
Abstract—A strained monomeric 12-membered triazolophane was formed by the Cu(I)-catalyzed intramolecular cycloaddition of an
azide to an alkyne having a constrained tether incorporating an aromatic ring and a furanoside ring. Similar cycloadditions of azido-
alkynes having ester, furanoside and peptidic tethers led to the formation of monomeric triazolophanes of higher ring sizes.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The azide–alkyne cycloaddition reaction is one of the
best known of the 1,3-dipolar cycloadditions.1 The
importance of this reaction has been significantly
augmented by the recent upsurge in its application in
‘click’ chemistry.2 A remarkable development in the
azide–alkyne cycloaddition was achieved via the intro-
duction of methods for regioselective formation of
1,4-disubstituted-1,2,3-triazoles,3 and 1,5-disubstituted-
1,2,3-triazoles.4 In particular, the generally efficient
Cu(I)-catalyzed azide–alkyne cycloaddition affording
1,4-disubstituted-1,2,3-triazoles as the exclusive prod-
ucts has made this cycloaddition an invaluable tool in
click chemistry,2 and is currently being applied in the
‘ligation’ of two different molecules of chemical and
biochemical relevance.5 Intramolecular uncatalyzed
cycloaddition of an azido-alkyne resulting in five- to
seven-membered rings fused to a triazole ring is a well-
known process.6 Cyclodimerization of peptides and
glycopeptides involving Cu(I)-catalyzed azide–alkyne
cycloadditions leading to relatively strain-free rings
has been reported.5g,k–n However, monocyclization of
azido-alkynes resulting in strained ring systems using
this cycloaddition remained unknown, and only very
recently Burgess et al. reported the synthesis of some
14-membered monomeric cyclic peptides incorporating
1,4-disubstituted triazole rings.5o This work has
prompted us to describe herein our synthesis of 12- to
17-membered triazolophanes by Cu(I)-catalyzed azide–
alkyne cycloaddition.
A suitably sized azido-alkynes 1 can lead to the bicyclic
triazoles 2 or 3 or both depending on the regioselectivity
of the reaction (Scheme 1). The 1,4-disubstituted triazole
2 is particularly interesting, because relatively small-
sized rings having this structural type would represent
strained triazolophanes. We envisaged that the use of
aromatic rings, furanoside rings and peptides as con-
straints incorporated in the tethered azido-alkynes
would facilitate their monocyclization leading to the
aforementioned triazolophanes. The azido-alkyne 9 hav-
ing a nine-atom tether incorporating two aromatic rings
was prepared from salicylaldehyde 4 and the bromo
compound 6 according to Scheme 2. Other furanoside-
and peptide-appended azido-alkynes were prepared
according to Scheme 3. Results of the cycloaddition of
these substrates are presented in Table 1.
N
N
N
N
N
N
N3
3
1
2
*
Corresponding author. Tel.: +91 33 24728697; fax: +91 33
24735197; e-mail: anupbhattacharjya@iicb.res.in
Scheme 1. Intramolecular azide–alkyne cycloaddition.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.068

2776
A. Ray et al. / Tetrahedron Letters 47 (2006) 2775–2778
strained tether in 9 facilitated cycloaddition to the 11-
membered triazolophane 19. The corresponding 1,4-
disubstituted compound would be more strained and
consequently was not formed. The same product was
obtained in 22% yield under thermal cycloaddition con-
ditions involving refluxing in toluene for 6 h.
OR1
O
4, c
R
O
R2
4: R1 = H, R2 = CHO
5: R1 = propargyl, R2 = CH2OH
6: R1 = propargyl, R2 = CH2Br
a
7: R = CHO
8: R = CH2OH
9: R = CH2N3
d
e
The well-known 1,2-isopropylidenefuranose skeleton
has been previously used as a scaffold for carrying out
intramolecular nitrile oxide cycloaddition for the syn-
thesis of 10- to 12-membered ring compounds.9 The
Cu(I)-catalyzed cycloaddition of 11, which differs from
9 by having a furanoside ring instead of an aromatic
ring as a constraint, led to the formation of a mono-
b
Scheme 2. Synthesis of azido-alkyne 9. Reagents and conditions. (a) (i)
Bu4NBr, 50% aq NaOH, propargyl bromide, CH2Cl2, 12 h, 77%; (ii)
NaBH4, MeOH, 25 ꢁC, 6 h, 95%. (b) PBr3, Et2O, 25 ꢁC, 2 h, 91%. (c)
K2CO3, DMF, 80–100 ꢁC, 12 h, 85%. (d) NaBH4, MeOH, 25 ꢁC, 6 h,
93%. (e) (i) PBr3, Et2O, 25 ꢁC, 2 h; (ii) NaN3, DMF, 60 ꢁC, 24 h, 91%.
1
meric triazole in 35% yield as evidenced by H and 13C
NMR and mass spectroscopic analysis. The liquid nat-
ure of this product precluded X-ray diffraction analysis.
The NOESY spectrum indicated an NOE between the
triazole proton and 12-H as well as between the triazole
proton and 16-H/6-H.10 These NOE characteristics led
to the assignment of structure 20 to this product. To
our knowledge, 20 represents the first example of a
12-membered triazolophane. The Cu(I)-catalyzed cyclo-
addition of the ester-linked azido-alkyne 14 and the
furanoside-peptidic azido-alkynes 15 and 18, all
having longer tethers than 11, furnished the monomeric
triazoles—15-membered 21 (32%), 14-membered 22
(32%) and 17-membered 23 (31%), respectively, as the
exclusive products of cycloaddition (Table 1).
Treatment of a freshly prepared sample of 9 with
1.0 mol % of CuSO4 and 10 mol % sodium ascorbate
in t-butanol–water (1:1) at 25 ꢁC for 15 h gave a com-
plex mixture of products, from which was isolated in
31% yield a triazole having a molecular weight of 293
(positive ion ESI and EI) consistent with the monomeric
triazole structure 19 or its 1,4-regioisomer.7 No dimeric
product could be isolated from the reaction. Although
the NOESY spectrum of the compound hinted at the
1,5-substituted structure 19, confirmation of the struc-
ture came from X-ray diffraction analysis of the product
(Fig. 1).8 The result was rather surprising as 1,4-regio-
selectivity in Cu(I)-catalyzed azide–alkyne cycloadditions
has been observed in all such reported reactions until
now. The triazole 19 was not formed when 9 was sub-
jected to the reaction conditions without the addition
of the copper salt and sodium ascorbate the starting
material 9 being recovered unchanged. So it was evident
that Cu(I) did catalyze the reaction, but led to 1,5-regio-
selectivity. Although the reasons for this result are not
known, it is probable that the presence of the con-
The establishment of the monomeric nature of the tri-
azolophanes 19–23 was based mainly on their mass
spectroscopic molecular weights. The positive ion ESI
mass spectra of these compounds were checked carefully
in order to ascertain that the peaks were due to
(M+Na)+ and not to doubly charged species of the type
(2M+2Na)2+. Formation of dimeric products was not
N3
O
O
N3
O
O
O
H
N
O
O
O
O
N
H
MeO2C
H
O
O
O
18
11
h
N3
O
6, a
O
N3
O
H
N
N3
O
O
RO2C
O
O
O
O
b
f
O
O
HO
O
10
RO2C
16: R = Et
17: R = H
g
12: R = Et
13: R = H
c
N3
N3
e
O
5, d
O
O
O
O
O
H
N
O
O
O
O
O
O
MeO2CH
15
O
14
Scheme 3. Synthesis of azido-alkyne intermediates. Reagents and conditions. (a) NaH, THF, 25 ꢁC, 12 h, 71%; (b) NaH, THF, BrCH2CO2Et, 25 ꢁC,
12 h, 86%; (c) LiOH, MeOH, 25 ꢁC, 6 h, 92%; (d) EDCI, DMAP, CH2Cl2, 25 ꢁC, 12 h, 77%; (e) O-propargylserine methyl ester, EDCI, CH2Cl2,
25 ꢁC, 12 h, 53%; (f) glycine ethyl ester hydrochloride, EDCI, Et3N, CH2Cl2, 25 ꢁC, 12 h, 77%; (g) LiOH, MeOH, 25 ꢁC, 6 h, 87%; (h) O-
propargylserine methyl ester, EDCI, CH2Cl2, 25 ꢁC, 12 h, 54%.

A. Ray et al. / Tetrahedron Letters 47 (2006) 2775–2778
Table 1. Monomeric triazolophanes from furanoside-tethered azido-
2777
alkynes via Cu(I)-catalyzed intramolecular azide–alkyne cyclo-
additiona
Entry Azido- Product
alkyne
Yield (%)b
[%]c
N
N
N
1
9
[31]
O
O
19
N
N
N
16
12
O
O
O
2
11
[35]
6
O
O
O
20
N
N
N
Figure 1. ORTEP view of 19 showing the atom numbering scheme
(ellipsoids drawn at 30% probabilities).
O
O
3
14
[32]
O
O
O
N
Cycloaddition in the presence of CuI and di-i-propyleth-
ylamine led to poorer yields (Table 1). Attempted cyclo-
addition of 9 in a micellar environment containing SDS
and copper salts was unsuccessful leading to the recov-
ery of the starting material. It is possible that polymer-
ization of the alkynes in the presence of copper salts
resulted in the formation of intractable products leading
to poor yields of the reactions. Despite the poor yields,
the aforementioned cycloaddition provided an access to
strained rings.
O
21
N
N
O
O
O
O
4
15
(22)
[32]
O
N
H
MeO2C
O
22
N
In conclusion, the above work has revealed an interest-
ing and useful aspect of the click azide–alkyne cyclo-
addition whereby strained monomeric triazoles including
triazolophanes were synthesized from azido-alkynes
having tethers incorporating aromatic, furanoside and
peptidic moieties. The presence of the furanoside ring
and different peptidic tethers in the azido-alkynes make
this cycloaddition strategy potentially important for the
synthesis of peptidomimetics as well as novel nucleoside
derivatives.
N
N
O
O
MeO2C
5
18
(20)
[31]
NH
O
H
N
O
O
O
O
23
a Azide–alkyne cycloaddition was performed under either one or both
of the following conditions. [A] Stirring a mixture of the azido-alkyne
in THF in the presence of CuI (1.1 equiv) and DIPEA (25 equiv) at
25 ꢁC for 24 h. [B] Stirring a mixture of the azido-alkyne in t-BuOH–
H2O in the presence of CuSO4Æ5H2O (1 mol %) and sodium ascorbate
(10 mol %) at 25 ꢁC for 12–24 h.
Acknowledgements
b Chromatographically isolated yields under conditions [A].
c Chromatographically isolated yields under conditions [B].
A.R. is grateful to CSIR, India, for the award of a
Senior Research Fellowship. Thanks are due to Dr. A.
K. Chakraborty, Dr. P. K. Datta, Mr. A. Bannerjee,
Mr. K. Sarkar, Mr. E. Padmanabhan, Mr. S. Chow-
dhury and Mr. S. Samaddar for spectral analyses.
observed in these reactions, although in some cases
compounds were isolated, the mass, IR and H NMR
1
spectra of which indicated them to be azido-alkynes
derived from the intermolecular cycloaddition of two
azido-alkyne molecules.
References and notes
1. (a) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; pp 1–176; (b)
Padwa, A. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon: Oxford, 1991; Vol. 4, pp 1069–1109.
2. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2004,
8, 1128–1137.
In contrast to the high yields generally reported for
Cu(I)-catalyzed azide–alkyne cycloadditions, yields of
the aforementioned cycloaddition reactions were found
to be low, and could not be improved by changing sol-
vents or using larger quantities of the copper salts.

2778
A. Ray et al. / Tetrahedron Letters 47 (2006) 2775–2778
3. (a) Rostovstev, V. V.; Green, L. G.; Fokin, V. V.;
3H), 1.30 (s, 3H); 13C NMR (75 MHz, CDCl3): d 169.0
(q), 157.1 (q), 144.1(q), 131.7 (CH), 131.0 (CH), 125.5
(CH), 124.4 (q), 121.6 (CH), 113.6 (CH), 112.3 (q), 105.1
(CH), 82.5 (CH), 81.1 (CH), 77.8 (CH), 67.5 (CH2), 63.6
(CH2), 63.0 (CH2), 47.2 (CH2), 27.2 (CH3), 26.6 (CH3)
Calcd. for C20H23N3O7, C, 57.55; H, 5.55; N, 10.07.
Found, C, 57.39; H, 5.33; N, 10.29. Compound 22:
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–
2599; (b) Tornoe, C. W.; Christensen, C.; Meldal, M. J.
Org. Chem. 2002, 67, 3057–3064.
4. Krasinski, A.; Fokin, V. V.; Sharpless, K. B. Org. Lett.
2004, 6, 1237–1240.
5. (a) Perez-Balderas, F.; Ortega-Munoz, M.; Morales-San-
25
´
frutos, J.; Hernandez-Mateo, F.; Calvo-Flores, F. G.;
colourless liquid; ½aꢁD ꢀ63.6 (c 1.01, CHCl3); IR (KBr):
Calvo-Asy´n, J. A.; Isac-Garcy´a, J.; Santoyo-Gonzalez, F.
Org. Lett. 2003, 5, 1951–1954; (b) Speers, A. E.; Adam, G.
C.; Cravatt, B. F. J. Am. Chem. Soc. 2003, 125, 4686–
4687; (c) Suh, B.-C.; Jeon, H. B.; Posner, G. H.;
Silverman, S. M. Tetrahedron Lett. 2004, 45, 4623–4625;
(d) Suarez, P. L.; Gandara, Z.; Gomez, G.; Fall, Y.
Tetrahedron Lett. 2004, 45, 4619–4621; (e) Zhu, L.; Lynch,
V. M.; Anslyn, E. V. Tetrahedron 2004, 60, 7267–7275; (f)
Kuijpers, B. H. M.; Groothuys, S.; Keereweer, A. R.;
Quaedflieg, P. J. L. M.; Blaauw, R. H.; van Delft, F. L.;
Rutjes, F. P. J. T. Org. Lett. 2004, 6, 3123–3126; (g)
Punna, S.; Kuzelka, J.; Wang, Q.; Finn, M. G. Angew.
Chem., Int. Ed. 2005, 44, 2215–2220; (h) Mantovani, G.;
Ladmiral, V.; Tao, L.; Haddleton, D. M. Chem. Commun.
2005, 2089–2091; (i) Rodionov, V. O.; Fokin, V. V.; Finn,
M. G. Angew. Chem., Int. Ed. 2005, 44, 2210–2215; (j)
Lewis, W. G.; Magallon, F. G.; Fokin, V. V.; Finn, M. G.
J. Am. Chem. Soc. 2004, 126, 9152–9153; (k) Weller, R. L.;
Rajski, S. R. Org. Lett. 2005, 7, 2141–2144; (l) Billing, J.
F.; Nilsson, U. J. J. Org. Chem. 2005, 70, 4847–4850; (m)
Bodine, K. D.; Gin, D. Y.; Gin, M. S. Org. Lett. 2005, 7,
4479–4482; (n) van Maarseveen, J. H.; Horne, W. S.;
Ghadiri, M. R. Org. Lett. 2005, 7, 4503–4506; (o) Angell,
Y.; Burgess, K. J. Org. Chem. 2005, 70, 9595–9598.
6. Katritzky, A. R.; Zhang, Y.; Singh, S. K. Heterocycles
2003, 60, 1225–1239.
3411, 3275, 1744, 1676 cmꢀ1; MS (ESI): m/z 413 (M+H),
435 (M+Na), 451 (M+K); 1H NMR (300 MHz, CDCl3): d
7.97 (s, 1H), 6.00 (d, J = 3.7 Hz, 1H), 5.35 (broad
multiplet, 1H), 5.03 (dd, J = 15.0, 2.4 Hz, 1H), 4.79 (dd,
J = 15.0, 5.0 Hz, 1H), 4.65 (s, 2H), 4.59 (d, J = 3.7 Hz,
1H), 4.22–4.11 (m, 3H), 4.04–3.94 (m, 3H), 3.84–3.78 (m,
1H), 3.72 (s, 3H), 1.54 (s, 3H), 1.34 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 169.0 (q), 167.5 (q), 144.7 (q), 125.2
(CH), 112.3 (q), 104.3 (CH), 83.6 (CH), 80.9 (CH), 75.9
(CH), 68.6 (CH2), 67.8 (CH2), 63.9 (CH2), 53.8 (CH), 52.6
(CH3), 48.2 (CH2), 26.6 (CH3), 26.0 (CH3). Compound
´
´
25
23: Yield: white foam; ½aꢁD ꢀ21.4 (c 1.10, CHCl3); IR
(Neat) : 3338, 1744, 1672 cmꢀ1; MS (ESI): m/z 470
(M+H), 492 (M+Na); 1H NMR (300 MHz, CDCl3): d
7.78 (s, 1H), 7.23 (br s, 1H), 6.85 (d, J = 7.1 Hz, 1H), 5.97
(d, J = 3.5 Hz, 1H), 4.87–4.49 (m, 7H), 4.32–4.04 (m, 4H),
3.95–3.72 (m, 6H), 1.51 (s, 3H), 1.33 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 169.9 (q), 169.3 (q), 168.8 (q), 146.2
(q), 123.8 (q), 112.4 (q), 104.8 (CH), 82.8 (CH), 81.4 (CH),
77.4 (CH), 70.1 (CH2), 68.4 (CH2), 65.3 (CH2), 53.2
(CH3), 52.8 (CH), 46.9 (CH2), 43.1 (CH2), 26.7 (CH3),
26.2 (CH3) Calcd. for C19H27N5O9, C, 48.61; H, 5.80; N,
14.92. Found, C, 48.37; H, 5.62; N, 14.71.
8. Crystal data for 19: C17H15N3O2, M = 293.32, crystal
dimensions 0.39 · 0.10 · 0.08 mm, monoclinic space group
˚
P21/c, a = 4.210(2), b = 11.447(6), c = 29.611(16) A, b =
3
˚
7. Spectral and other physical data of the triazoles—Com-
pound 19: white solid, mp 233–235 ꢁC, IR (KBr): 2933,
90.675(11)ꢁ, V = 1427.1(14) A , Z = 4,
qcalcd = 1.365
g cmꢀ3, l (Mo-Ka) = 0.092 mmꢀ1, F(000) = 616, 2hmax
=
1
1603 cmꢀ1; MS (EI): m/z 293 (M); H NMR (300 MHz,
50.00ꢁ, 6938 reflections collected, 2486 unique, 1681
observed (I > 2r (I)) reflections, 199 refined parameters,
R value 0.1228, wR2 = 0.2144 (all data R = 0.1801,
wR2 = 0.2348), S = 1.265, minimum and maximum trans-
mission 0.9650 and 0.9930, respectively, maximum and
minimum residual electron densities +0.241 and
CDCl3): d 7.92 (d, J = 7.5 Hz, 1H), 7.71 (s, 1H), 7.44–7.30
(m, 3H), 7.13–7.03 (m, 4H), 5.58 (s, 2H), 5.21 (s, 2H), 5.08
(s, 2H), 2.17 (s, 1H); 13C NMR (75 MHz, CDCl3): d 157.9
(q), 157.4 (q), 136.6 (CH), 133.9 (CH), 132.3 (CH), 131.8
(q), 130.6 (CH), 130.4 (CH), 130.2 (CH), 126.6 (q), 124.9
(q), 122.5 (CH), 116.1 (CH), 115.1 (CH), 71.6 (CH2), 60.6
(CH2), 45.5 (CH2) Calcd. for C17H15N3O2, C,
69.61; H, 5.15; N, 14.33. Found, C, 69.32; H, 5.29; N,
ꢀ0.188 eAꢀ3, respectively.
˚
X-ray intensity data of 19 was collected on a Bruker
SMART APEX CCD diffractometer with omega and phi
25
˚
14.17. Compound 20: colourless liquid; ½aꢁD ꢀ80.8 (c 0.32,
scan mode, kMoKa = 0.71073 A at T = 297(2) K. All the
CHCl3); IR (Neat): 2980, 2927 cmꢀ1; MS (ESI): m/z 360
(M+H), 382 (M+Na); 1H NMR (300 MHz, CDCl3): d
7.76 (s, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.3 Hz,
1H), 7.06–6.98 (m, 2H), 5.93 (d, J = 3.5 Hz, 1H), 5.46 (d,
J = 12.0 Hz, 1H), 4.94 (dt, J = 10.3, 2.6 Hz, 1H), 4.84 (d,
J = 11.9 Hz, 1H), 4.76–4.68 (m, 3H), 4.52 (dd, J = 12.7,
2.6 Hz, 1H), 4.43 (d, J = 10.6 Hz, 1H), 3.71 (d, J = 2.5 Hz,
1H), 1.53 (s, 3H), 1.35 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 157.4 (q), 134.3 (CH), 132.8 (q), 130.5 (CH),
130.1 (CH), 126.9 (q), 122.3 (CH), 114.6 (CH), 112.4 (q),
104.9 (CH), 81.8 (CH), 80.9 (CH), 79.3 (CH), 70.9 (CH2),
59.2 (CH2), 44.2 (CH2), 26.8 (CH3), 26.3 (CH3) Calcd. for
C18N21N3O5, C, 60.16; H, 5.89; N, 11.69. Found, C, 59.87;
data were corrected for Lorentzian, polarization and
absorption effects using Bruker’s SAINT and SADABS
programs. The crystal structure was solved by direct
method using SHELX-97 and the refinement was performed
by full matrix least squares of F2 using SHELXL-97
(Sheldrick, G. M. SHELX-97 program for crystal structure
solution and refinement, University of Go¨ttingen,
Germany, 1997). Hydrogen atoms were included in the
refinement as per the riding model. Crystallographic data
for 19 reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 297356.
9. (a) Majumdar, S.; Mukhopadhyay, R.; Bhattacharjya, A.
Tetrahedron 2000, 56, 8945–8951; (b) Sengupta, J.;
Mukhopadhyay, R.; Bhattacharjya, A.; Bhadbhade, M.
M.; Bhosekar, G. V. J. Org. Chem. 2005, 70, 8579–8582.
10. The 1H NMR spectrum (500 or 600 MHz) of 20 exhibited
the crucial 16-H and 6-H protons as overlapping signals
with little difference in chemical shifts. The observed NOE
of the triazole proton with any one or both of these
protons can only be explained by the structure 20. In the
alternative 1,5-substituted isomer these protons would be
far apart, and no NOE would be expected.
25
H, 6.01; N, 11.45. Compound 21: white foam; ½aꢁD ꢀ81.1
(c 1.10, CHCl3); IR (KBr): 3169, 1749 cmꢀ1; MS (ESI): m/z
1
418 (M+H), 440 (M+Na); H NMR (300 MHz, CDCl3):
d 7.90 (s, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.1 Hz,
1H), 7.09 (d, J = 8.2 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H),
5.95 (d, J = 3.7 Hz, 1H), 5.83 (d, J = 11.5 Hz, 1H), 5.42
(d, J = 12.6 Hz, 1H), 5.29 (d, J = 12.4 Hz, 1H), 4.85 (d,
J = 11.6 Hz, 1H), 4.81–4.76 (m, 2H), 4.58 (d, J = 11.0 Hz,
1H), 4.53 (d, J = 11.6 Hz, 1H), 4.30 (d, J = 15.5 Hz, 1H),
3.63 (d, J = 15.5 Hz, 1H),3.52 (d, J = 3.1 Hz, 1H), 1.47 (s,