A highly efficient microwave-assisted solvent-free synthesis of α- and β-2′-deoxy-1,2,3-triazolyl-nucleosides

Article abstract of DOI:10.1016/j.tetlet.2006.05.050

Microwave activation coupled with Cu(I) catalysis, under solvent-free conditions, was found to dramatically enhance the 1,3-dipolar cycloaddition between azido-2′-deoxyribose and terminal alkynes. The process is highly efficient and quantitatively affords

Full text of DOI:10.1016/j.tetlet.2006.05.050

Tetrahedron Letters 47 (2006) 4807–4811
A highly efficient microwave-assisted solvent-free synthesis
of a- and b-20-deoxy-1,2,3-triazolyl-nucleosides
Raja Guezguez,a Khalid Bougrin,b Khalid El Akria,b and Rachid Benhidaa,*
aLaboratoire de Chimie Bioorganique UMR-CNRS 6001, Universite´ de Nice-Sophia Antipolis, Parc Valrose,
06108 Nice Cedex 2, France
b
`
Laboratoire de Chimie des Plantes et de Synthese organique et Bioorganique, Universite Mohammed V-Agdal,
´
Faculte´ des Sciences B.P., 1014 Rabat, Maroc, France
Received 7 April 2006; revised 9 May 2006; accepted 10 May 2006
Abstract—Microwave activation coupled with Cu(I) catalysis, under solvent-free conditions, was found to dramatically enhance the
1,3-dipolar cycloaddition between azido-20-deoxyribose and terminal alkynes. The process is highly efficient and quantitatively
affords, in few minutes, the corresponding 4-substituted 1,2,3-triazolyl-nucleosides.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Apart from being the genomic building blocks, nucleo-
sides interact with nucleic acids, enzymes, and proteins.
Naturally occuring and synthetic analogs of nucleosides
have been the cornerstone of antiviral therapy over the
last decades. The growing interest in such analogs also
rises from their high potential value as therapeutic
Figure 1. Structure of five membered ring nucleosides, Bredinin (1)
and Ribavirin (2).
agents, biochemical probes and as building blocks in
artificial nucleic acid syntheses.1 Among them, nucleo-
sides with five membered ring nucleobase are of great
recently reported and was found to involve polar transi-
interest. Thus, Bredinin (1) is an imidazole nucleoside
tion states, favorable for a microwave activation.4
clinically used as immunosuppressant and Ribavirin
(2), a triazolyl nucleoside, is the unique small molecule
Microwave heating has emerged as a powerful technique
drug currently used for the treatment against hepatitis
to enhance reaction rates of a variety of chemical trans-
C virus, in combination with interferon-a-peg (Fig. 1).
formations.5 Moreover, microwave reactions under sol-
vent-free conditions are attractive in the growing field of
Huisgen azide–alkyne 1,3-dipolar cycloaddition is a ver-
green chemistry.5c Some of us have reported for the first
satile route to 1,2,3-triazoles, and the progress in this
time on the microwave-assisted azide–alkyne cycloaddi-
area has been extensively studied.2 In general, 1,2,3-tri-
tion.6 Recently, an example of microwave-assisted
azole formation requires harsh conditions, that is, high
azide–alkyne cycloaddition was reported by Katritzky
temperature and longer reaction times. Recently, several
et al.7 However, these reactions involved only primary
examples of Cu(I)-catalyzed alkyne–azide 1,3-dipolar
azides and acetylenic amide. Moreover, drastic condi-
cycloaddition under milder conditions have been de-
tions, that is, sealed tube and high reaction temperature
scribed.3 The first mechanistic proposal of the Cu(I)-
and pressure, were necessary for the reaction to proceed.
catalyzed alkyne–azide 1,3-dipolar cycloaddition was
Furthermore, it has been shown that cycloaddition be-
tween primary azide and terminal alkynes gave a mix-
ture of regioisomers.8 Microwave- and Cu(I)-assisted
‘click-chemistry’ has been recently reported. However,
Keywords: 1,3-Dipolar cycloaddition; Microwave activation; Cu(I)/
this method was restricted to primary azides and termi-
nal alkynes using drastic conditions, sealed-vessel under
high pressure and super-heated solvents.9
SiO2; Regiocontrolled process; Nucleoside analogs.
*
Corresponding author. Tel.: +00 33 (0)4 92 07 61 74; fax: +00 33 (0)4
92 07 61 51; e-mail: benhida@unice.fr
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.050

4808
R. Guezguez et al. / Tetrahedron Letters 47 (2006) 4807–4811
the C10 stereocenter.13 Reaction without copper(I)
and/or ligand did not work even at higher temperature
and longer reaction time (entries 1 and 2), and even un-
der microwave activation (entries 8 and 9). The recently
reported conditions for primary azide–alkyne cyclocon-
densation in water also failed to give any product.14 It is
noteworthy that the Sharpless conditions using Cu(II)
and sodium ascorbate as a reducing agent led to moder-
ate yields (40%, entry 6)4a and, stoichiometric amount of
the catalyst was required to achieve the reaction after
24 h (entry 7).
Scheme 1.
As an effort in the development of original nucleoside
chemistry, we report herein on the first example of
Cu(I) promoted regioselective synthesis of functional-
ized a- or b-1,2,3-triazolyl nucleosides through a 1,3-
dipolar cycloaddition between a- or b-azido-2-deoxyri-
bose and different terminal alkynes, by using microwave
activation under atmospheric pressure and solvent-free
conditions. The obtained nucleosides were further
deprotected on their 30- and 50-positions to give the cor-
responding free analogs.
Concerning the stereo- and regio-chemistry of 3ab (b-
configuration and phenyl in position 4), this was unam-
biguously attested by NOESY and HMBC experiments.
Indeed, the 1H 2D NOESY spectrum shows correlations
1
between H1 –H4 and H5–HPh, and the H–13C HMBC
0
0
0
experiment shows C1 –H5 and H5–CPh cross coupling,
in accordance with the proposed structure for 3ab
(Fig. 2).
The starting material, azido-2-deoxyribose 2, was syn-
thesized from protected a-chloro-2-deoxyribose10 under
mild conditions (TMSN3, BF3–Et2O, 0 ꢁC). Compound
2 was obtained in 87% yield as a mixture of separable a/
b anomers (ratio 3/2, Scheme 1).11
The promissing results obtained with CuI/DIEA in tolu-
ene at 110 ꢁC (Table 1, entry 5) prompted us to further
optimize the cycloaddition process by using microwave
activation under solvent-free conditions. Thus, by using
silica gel as a solid support for the bimolecular reaction,
we found that the same reagents and substrates (2b, phen-
ylacetylene and CuI/DIEA) when adsorbed on SiO2
First, we examined the survey of the 1,3-dipolar cyclo-
addition reaction conditions by using azide 2b and phen-
ylacetylene as models. These conditions, which are col-
lected in Table 1, included nature of the solvent, cop-
per(I) source, temperature, and additives (ligand, co-
solvent, etc.).
We found that the reaction performed in toluene in the
presence of diisopropylethylamine (DIEA, entry 5)12
provided the desired cycloadduct 3ab as a single regio-
isomer in 87% yield and without any epimerization of
Figure 2. Significant NOESY and HMBC correlations.
Table 1. Survey of the cycloaddition conditions
Entrya
Catalyst
No
CuI
CuI
CuI
CuI
CuSO4
CuSO4
Ligand/conditions
Solvent/time
T (ꢁC)
Yielde (%)
Conventional heating
1
2
No
No
DIEA
Et3N
DIEA
Sodium ascorbate
Sodium ascorbate
Toluene/24 h
Toluene/24 h
Toluene/72 h
Toluene/24 h
Toluene/24 h
H2O/tBuOH/24 h
H2O/tBuOH/24 h
110
110
rt
110
110
rt
0
<5
10
68
87
40
86
3b
4b
5b
6c
7d
rt
Microwave irradiation
8
No
MW
MW
DIEA, MW
Toluene, 5 min
Toluene/DMF (1/1), 5 min
Adsorbed on SiO2, 3 min
90
140
115
0
<5
95
9
No
CuIa
10
a Azide (1 mmol), alkyne (1.2 equiv).
b CuI (2 equiv), amine (5 equiv).
c Under catalytic conditions (see Ref. 3a).
d Under stoichiometric conditions.
e Yield of the isolated product.

R. Guezguez et al. / Tetrahedron Letters 47 (2006) 4807–4811
Table 2. 1,3-Dipolar cycloaddition under Cu(I) and microwave activation
4809
Entrya
Alkyne:
Azide
Irradiation time (min)
Product
Yieldb (%)
1
2
2a
2b
3
3
3aa
3ab
97
95
3
4
2a
2b
3
3
3ba
3bb
94
96
5
6
2a
2b
3
3
3ca
3cb
98
93
7
8
2a
2b
1.5
1.5
3da
3db
96
95
9
10
2a
2b
1.5
1.5
3ea
3eb
91
95
11
12
2a
2b
1.5
1.5
3fa
3fb
96
97
13
14
2a
2b
3
3
3ga
3gb
0
0
15
16
2a
2b
2
2
3ha
3hb
98
95
17
18
2a
2b
3
3
3ia
3ib
94
96
19
20
2a
2b
2
2
3ja
3jb
93
91
a Conditions: azide (1 mmol), alkyne (2 equiv), CuI (2 equiv) and DIEA (5 equiv) were adsorbed on silica gel (1 g/mmol of azide) and irradiated
(95 ꢁC < T < 115 ꢁC, reaction temperature was digitaly measured).
b Yields based on 1H NMR of the crude products.
(1 g/mmol) and irradiated for 3 min in a simple micro-
wave oven in open vessel afforded 95% of 3ab as the sole
product of the reaction (Table 1, entry 10). The cooper-
ative effect between a microwave heating and Cu(I)
catalysis allowed the dipolar cycloaddition to proceed
cleanly, and the formed cycloadduct was isolated by
simple elution from the silica gel support.
Indeed, the a- and b-1,2,3-triazolyl-nucleosides were iso-
lated in high yields under a short period of microwave
irradiation from their corresponding azide 2a or 2b
and alkynes, excepting in the case of propargylic acid
(entries 13 and 14). It is worth noting that only a single
regioisomer was obtained in each of these reactions.
This regioselectivity is most likely due to the expected
steric factors in the azide–alkyne transition state. Disap-
pointingly, the reaction between propargylic acid and
azido-sugar 2a or 2b did not proceed even with a large
excess of catalyst and increased reaction time. This is
probably due to a strong chelation of Cu(I) with the acid
function, as supported by the formation of a green
gum thus inactivating the catalyst and, consequently,
preventing the reaction to occur. This is further sup-
ported by the formation in high yields of the expected
With this efficient procedure in hand, we investigated its
scope and generalization. Thus, the Cu(I)-assisted sol-
vent-free cycloaddition reaction between a range of
functionalized terminal alkynes and azido-20-deoxy-
ribose 2a or 2b was examined under microwave activa-
tion. The potential and general applicability of this
novel procedure is illustrated by the examples collected
in Table 2.15

4810
R. Guezguez et al. / Tetrahedron Letters 47 (2006) 4807–4811
In Chemistry of Nucleosides and Nucleotides; Townsend, L.
B., Ed.; Plenum Press: New York, 1994; Vol. 3, p 421.
2. (a) Reviews: 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 Press: New York, 1991; Vol. 4, pp 1069–1109;
(c) Fan, W.-Q.; Katritzky, A. R. In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: New York, 1996;
Vol. 4, p 101; (d) Sha, C.-K.; Mohanakrishnan, A. K. In
Comprehensive Heterocyclic Compounds; Padwa, A., Pear-
son, W. H., Eds.; John Wiley: New York, 2002; Vol. 59, p
623; For classical application of the click-chemistry to the
synthesis of nucleoside analogs see: (e) San-Felix, A.;
Alvarez, R.; Velazquez, S.; De Clercq, E.; Balzarini, J.;
Camarasa, M. J. Nucleosides and Nucleotides 1995, 14(3–
5), 595; (f) Joubert, N.; Schinazi, R. F.; Agrofoglio, L. A.
Tetrahedron 2005, 61, 11744.
3. For Cu(I)-catalyzed azide–alkyne cycloadditions, see: (a)
Rostotsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem. Int. Ed. 2002, 41, 2596; (b) Tornøe, C.
W.; Christensen, C.; Medal, M. J. Org. Chem. 2002, 67,
3057; (c) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin,
V. V. Org. Lett. 2004, 6, 2853; (d) Fu, X.; Albermann, C.;
Zhang, C.; Thorson, J. S. Org. Lett. 2005, 7, 1513.
4. (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am.
Chem. Soc. 2005, 127, 210; (b) Rodionov, V. O.; Fokin, V.
V.; Finn, M. G. Angew. Chem. Int. Ed. 2005, 44, 2210.
5. For reviews on microwave-assisted reactions see: (a) De
La Hoz, A.; Diaz-Ortis, A.; Langa, F. In Microwaves in
Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Wein-
heim, 2002; pp 295–343; (b) Kappe, C. O. Angew. Chem.
Int. Ed. 2004, 43, 6250; (c) Bougrin, K.; Loupy, A.;
Soufiaoui, M. J. Photochem. Photobiol. C: Photochem.
Rev. 2005, 6, 139.
Scheme 2. Cleavage of 30- and 50-tolouyl protective group.
cycloadducts 3ha,b from 2a,b and propargylic ethyl-
ester, respectively (entries 15 and 16). In the same way,
with saccharin-substituted alkyne anchoring a sulfon-
amide function, the corresponding triazolyl-nucleosides
3ja and 3ib were obtained in 93% and 90% yield, respec-
tively (entries 19 and 20).
Finally, the obtained a- and b-nucleosides 3a–j were fur-
ther deprotected at their 30- and 50-positions. Typical
examples are shown in Scheme 2. Thus, by simple treat-
ment of 3ha and 3hb with aq NH3 solution, we quanti-
tatively isolated the free nucleosides 4ha and 4hb,
respectively, as close analogs of the potent ribavirin
drug 2. In the same way, methanolysis of 3aa and 3ab
afforded nucleosides 4aa and 4ab in 95% yield (Scheme
2).16
6. Louerat, F.; Bougrin, K.; Loupy, A.; Retana, A. M. O.;
Pagalday, J.; Palacios, F. Heterocycles 1998, 48, 161.
7. Katritzky, A. R.; Singh, S. K. J. Org. Chem. 2002, 67,
9077.
8. Savin, K. A.; Robertson, M.; Gerneret, D.; Green, S.;
Hembre, E. J.; Bishop, J. Mol. Div. 2003, 7, 171.
9. (a) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eycken, E. Org. Lett. 2004, 6, 4223; (b) Ermolat’ev, D.;
Dehaen, W.; Van der Eycken, E. QSAR Combinat. Sci.
2004, 10, 915.
10. a-Chlorosugar 1 was synthesized as described: Hoffer, M.
Chem. Ber. 1960, 93, 2777.
11. The spectral data of compound 2 are in accordance with
the reported ones, see: Stimac, A.; Kobe, J. Carbohydr.
Res. 2000, 329, 317.
In summary, we efficiently synthesized new 20-deoxynu-
cleosides featuring a functionalized 1,2,3-triazolyl ring
as aglycone moiety. Reactions were achieved in high
yields by using a cooperative effect of Cu(I) and micro-
wave activation in the 1,3-dipolar cycloaddition. The
procedure is highly convenient since reactions were car-
ried out in open vessels, without solvent and by using sil-
ica gel as a solid support. Moreover, all reactions were
achieved in fast and clean fashion since, few minutes
are necessary under microwave irradiation and the cyc-
loadducts 3a–j were easily isolated. The scope and limi-
tations of this process together with its generalization to
the ribo series and disubstituted alkynes are underway.
12. The best combination was found to be azide/CuI/
DIEA = 1/2/5.
Acknowledgements
13. Compound 3ab: 1H NMR (200 MHz, CDCl3) d 2.37 (s,
3H, CH3), 2.44 (s, 3H, CH3), 2.90 (m, 1H, H-20), 3.15 (m,
1H, H-20), 4.45–4.80 (m, 3H, H-50 and H-40), 5.80 (m, 1H,
H-30), 6.57 (t, 1H, J = 6.4 Hz, H-10), 7.18 (d, 2H,
J = 8.0 Hz, H-Tol), 7.25–7.45 (m, 5H, 2 · H-Tol and
3 · H-Ph), 7.62 (dd, 2H, J = 7.5 and 1.3 Hz, 2 · H-Ph),
7.87 (d, 2H, J = 8.2 Hz, H-Tol), 7.75 (d, 2H, J = 8.2 Hz,
H-Tol), 7.92 (s, 1H, H-5), 7.95 (d, 2H, J = 8.2 Hz, H-Tol).
13C NMR (CDCl3): d 21.8, 21.9, 31.1, 38.8, 63.9, 74.9,
83.8, 89.2, 118.0, 125.8, 126.5, 126.7, 128.3, 128.8, 129.4,
129.5, 129.8, 129.9, 130.3, 144.4, 144.7, 148.3, 162.8, 166.0,
166.3. MS (ES+): m/z = 520 (M+Na)+.
We gratefully acknowledge the CNRS (convention
´
´
d’echange France-Maroc), Region Provence Alpes
´
Coˆtes d’Azur and Universite de Nice-Sophia Antipolis
for financial support (Med-Accueil Graint to K. El
Akri).
References and notes
1. For reviews on the chemistry, biochemistry, and synthesis
of nucleoside analogs see: (a) Buchanan, J. G. Prog. Chem.
Org. Nat. Prod. 1983, 44, 243; (b) Hacksell, U.; Daves, G.
D., Jr. Prog. Med. Chem. 1985, 22, 1; (c) Watanabe, K. A.
14. Li, Z.; Seo, T. S.; Ju, J. Tetrahedron Lett. 2004, 45, 3143.
15. General procedure for triazolyl-nucleosides synthesis
under microwave irradiation (for general safety and
cautions relating to the use of microwave apparatus see,

R. Guezguez et al. / Tetrahedron Letters 47 (2006) 4807–4811
4811
for example, Refs. 5a,c). Microwave experiments were
carried out in a non-modified domestic oven (BlueSky 900
W). After a careful determination of the higher density
electric spot using an aqueous solution of cobalt chlo-
ride,17 reactions were performed in this point at the
maximum continuous power output of 900 W. To a
solution of azido-sugar 2 (1 mmol) in methylene chloride
or toluene (10 mL) was added: alkyne (1.05–1.5 equiv),
CuI (2 equiv), DIEA (5 equiv) and 1 g of silica gel. The
mixture was stirred for 5 min and the solvent was
evaporated at room temperature. The resulting yellow
powder was placed into a microwave oven and irradiated
for the desired amount of time (the final temperature was
evaluated at the end of the irradiation by digital thermo-
metric probe). The mixture was eluted twice with ethyl
acetate and the solvent evaporated under reduced pressure
to give a crude product with, in general, good purity. The
crude product could be subjected to a simple filtration on
silica gel (cyclohexane/ethyl acetate: 80/20).
H-Tol). 13C NMR (CDCl3): d 14.2, 21.8, 21.9, 22.7, 25. 8,
29.1, 29.3, 31.7, 38.5, 64.1, 75.0, 83.6, 88.9, 119.1,
125.8,129.4,129.8, 129.9,144.3, 144.6, 149.2,166.3. MS
(ES+): m/z = 528 (M+Na)+. Compound 3ca: 1H NMR
(200 MHz, CDCl3): d 0.79 (t, 3H, J = 6.7 Hz, CH3), 1.20–
1.40 (m, 10H, (CH2)5), 1.61 (m, 2H, CH2), 2.32 (s, 3H,
CH3), 2.35 (s, 3H, CH3), 2.63 (t, 2H, J = 7.8 Hz, CH2),
2.8–3.1(m, 2H, H-20), 4.55 (m, 2H, H-50), 4.70 (m, 1H, H-
40), 5.61 (td, 1H, J = 6.5 and 2.0 Hz, H-30); 6.46 (dd, 1H,
J = 5.5 and 1.5 Hz, H-10), 7.12 (d, 2H, J = 8.0 Hz, H-Tol),
7.20 (d, 2H, J = 8.0 Hz, H-Tol), 7.52 (s, 1H, H-5), 7.56 (d,
2H, J = 8.1 Hz, H-Tol), 7.87 (d, 2H, J = 8.1 Hz, H-Tol).
13C NMR (CDCl3): d 14.2 , 21.8, 22.8, 25.9, 29.3, 29.5,
29.6, 32.0, 38.8, 64.1, 74.8, 84.8, 89.9, 126.4, 126.8, 129.3,
129.4, 129.8, 144.4, 144.5, 166.1, 166.3. MS (ES+): m/
z = 534 (M+H)+, 556 (M+Na)+.
1
Compound 3cb: H NMR (200 MHz, CDCl3): d 0.80 (t,
3H, J = 6.7 Hz, CH3), 1.2–1.4 (m, 10H, (CH2)5), 1.6 (m,
2H, CH2), 2.41 (2s, 6H, 2Me), 2.62 (t, 2H, J = 7.8 Hz,
CH2), 2.8–3.1(m, 2H, H-20), 4.5 (m, 2H, H-50), 4.6 (m, 1H,
H-40), 5.7 (m, 1H, H-30), 6.44 (t, 1H, J = 6.4 Hz,H-10),
7.16 (d, 2H,J = 8.0 Hz, H-Tol), 7.20 (d, 2H, J = 8.0 Hz,
H-Tol), 7.37 (s, 1H, H-5), 7.80 (d, 2H, J = 8.2 Hz, H-Tol),
7.87 (d, 2H, J = 8.2 Hz, H-Tol). 13C NMR (CDCl3): d
14.0, 21.8, 21.9, 22.8, 25.8, 29.3, 29.4, 32.0, 38.5, 43.4, 51.9,
64.1, 75.0, 83.6, 88.9, 126.5, 126.8, 129.4, 129.8, 129.9,
144.3, 144.6,166.0, 166.3. MS (ES+): m/z = 556 (M+Na)+.
16. Selected spectral data:
Selected spectral data: Compound 3aa: 1H NMR
(200 MHz, CDCl3): d 2.27 (s, 3H, CH3), 2.36 (s, 3H,
CH3), 2.80–3.20 (m, 2H, H-20), 4.56 (m, 2H, H-50), 4.77
(m, 1H, H-40), 5.61 (td, 1H, J = 6.3 and 1.9 Hz, H-30), 6.51
(dd, 1H, J = 6.4 and 1.5 Hz, H-10), 7.07 (d, 2H,
J = 7.9 Hz, H-Tol), 7.20 (d, 2H, J = 7.9 Hz, H-Tol), 7.31
(m, 3H, H-Ph), 7.59 (d, 2H, J = 8.2 Hz, H-Tol), 7.70 (dd,
2H, J = 7.9 and 1.4 Hz, H-Ph), 7.75 (d, 2H, J = 8.2 Hz, H-
Tol), 8.05 (s, 1H, H-5). 13C NMR (CDCl3): d 21.7, 21.8,
38.9, 64.1, 74.7, 85.1, 90.2, 118.0, 125.8, 126.2, 126.8,
128.3, 128.8, 128.9, 129.3, 129.4, 129.7, 129.9, 129.9, 130.6,
144.4, 144.5, 147.9, 165.9, 166.2. MS (ES+): m/z = 520
(M+Na)+.
Compound 4aa: 1H NMR (200 MHz, CD3OD) d 2.52–
2.60 (m, 1H, H-20), 2.87–2.93 (m, 1H, H-20), 3.62 (dd, 1H,
J = 12.0 and 5.0 Hz, H-50), 3.74 (dd, 1H, J = 12.0 and
4.0 Hz, H-50), 4.31 (q, 1H, J = 4.0 Hz, H-40), 4.49 (m, 1H,
H-30); 6.50 (dd, 1H, J = 7.6 and 2.3 Hz, H-10), 7.37 (t, 1H,
J = 7.4 Hz, H-Ph), 7.46 (t, 2H, J = 7.4 Hz, H-Ph), 7.84 (m,
2H, H-Ph), 8.62 (s, 1H, H-5). 13C NMR (CD3OD): d 41.6
(C-20), 62.8 (C-50), 72.1 (C-30), 90.2 (C-40), 90.9 (C-10),
120.4 (C-5), 126.4 (C-Ph), 129.1 (C-Ph), 129.6 (C-Ph),
131.0 (C-Ph), 148.9 (C-4). MS (ES+): m/z = 284
(M+Na)+.
1
Compound 3ba: H NMR (200 MHz, CDCl3): d 0.82 (t,
3H, J = 6.4 Hz, CH3), 1.20–1.60 (m, 8H, (CH2)4), 2.32 (s,
3H, CH3), 2.35 (s, 3H, CH3), 2.63 (t, 2H, J = 7.9 Hz,
CH2), 2.80–3.20 (m, 2H, H-20), 4.65 (m, 2H, H-50), 4.70
(m, 1H, H-40), 5.55 (td, 1H, J = 4.5 and 2.0 Hz, H-30), 6.41
(dd, 1H, J = 6.3 and 1.5 Hz, H-10), 7.12 (d, 2H,
J = 8.0 Hz, H-Tol), 7.19 (d, 2H, J = 8.0 Hz, H-Tol), 7.52
(br s, 1H, H-5), 7.61 (d, 2H, J = 8.2 Hz, H-Tol), 7.87 (d,
2H, J = 8.2 Hz, H-Tol). 13C NMR (CDCl3): d 14.2, 21.8,
22.7, 25.9, 29.1, 29.6, 31.7, 38.8, 64.1, 74.8, 84.8, 89.9,
118.8, 126.4, 126.9, 129.3, 129.4, 129.8, 144.4, 144.5, 148.8,
166.1, 166.3. MS (ES+): m/z = 528 (M+Na)+.
Compound 4ab: 1H NMR (200 MHz, CD3OD) d 2.31–
2.47 (m, 1H, H-20), 2.69–2.75 (m, 1H, H-20), 3.56 (dd, 1H,
J = 11.9 and 5.0 Hz, H-50), 3.66 (dd, 1H, J = 12.0 and
4.1 Hz, H-50), 3.95 (q, 1H, J = 4.1 Hz, H-40), 4.45 (m, 1H,
H-30); 6.35 (dd, 1H, J = 5.7 and 5.6 Hz, H-10), 7.24 (tt,
1H, J = 7.5 and 1.2 Hz, H-Ph), 7.33 (tt, 2H, J = 7.9 and
1.2 Hz, H-Ph), 7.72 (m, 2H, H-Ph), 8.41 (s, 1H, H-5). 13C
NMR (CD3OD): d 41.7 (C-20), 63.2 (C-50), 72.2 (C-30),
89.7 (C-40), 90.3 (C-10), 120.8 (C-5), 126.7 (C-Ph), 129.4
(C-Ph), 129.9 (C-Ph), 131.6 (C-Ph), 148.9 (C-4). MS
(ES+): m/z = 262 (M+H)+, 284 (M+Na)+.
1
Compound 3bb: H NMR (200 MHz, CDCl3): d 0.80 (t,
3H, J = 6.8 Hz, CH3), 1.20–1.60 (m, 8H, (CH2)4), 2.34 (s,
3H, CH3), 2.36 (s, 3H, CH3), 2.55 (t, 2H, J = 8.0 Hz,
CH2), 2.70 (m, 1H, H-20), 2.70 (m, 1H, H-20), 3.01 (m, 1H,
H-20), 4.40–4.60 (m, 3H, H-50 and H-30), 5.68 (m, 1H, H-
30), 6.41 (t, 1H, J = 6.4 Hz, H-10), 7.16 (d, 2H, J = 8.0 Hz,
H-Tol), 7.20 (d, 2H, J = 8.0 Hz, H-Tol), 7.37 (s, 1H, H-5),
7.61 (d, 2H, J = 8.2 Hz, H-Tol), 7.87 (d, 2H, J = 8.2 Hz,
17. Villemin, D.; Thibault-Starzyk, F. J. Chem. Educ. 1991,
346.