Synthesis of unexpected six-membered imides by free-radical carbocyclisation on carbohydrate templates

Article abstract of DOI:10.1016/j.tet.2004.08.039

Free-radical reactions of amido-esters anchored to a carbohydrate derived from methyl α-d-glucopyranoside afforded unexpected six-membered cyclic imides. Their structures were elucidated by ESI-MS/MS and NMR spectral analyses, and a mechanism for the formation of these imides is proposed. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.08.039

Tetrahedron 60 (2004) 9901–9908
Synthesis of unexpected six-membered imides by free-radical
carbocyclisation on carbohydrate templates
a
a
b
´
Renata B. de Oliveira, Jose D. de Souza Filho, Maria Auxiliadora F. Prado,
Marcos N. Eberlin,c Eduardo C. Meurer,c Leonardo S. Santosc and Ricardo J. Alvesb,
*
a
´ ˆ ˆ
Departamento de Quımica, Instituto de Ciencias Exatas, Universidade Federal de Minas Gerais (UFMG), Avenida Antonio Carlos 6627,
Belo Horizonte, MG 31.270-901, Brazil
´
Departamento de Produtos Farmaceuticos, Faculdade de Farmacia, Universidade Federal de Minas Gerais (UFMG),
b
ˆ
ˆ
Avenida Antonio Carlos, 6627, Belo Horizonte, MG 31.270-901, Brazil
´ ´
Laboratorio Thomson de Espectrometria de Massas, Instituto de Quımica, Universidade Estadual de Campinas (UNICAMP),
c
Campinas, SP 13083-970, Brazil
Received 9 April 2004; revised 13 August 2004; accepted 16 August 2004
Available online 11 September 2004
Abstract—Free-radical reactions of amido-esters anchored to a carbohydrate derived from methyl a-D-glucopyranoside afforded unexpected
six-membered cyclic imides. Their structures were elucidated by ESI-MS/MS and NMR spectral analyses, and a mechanism for the
formation of these imides is proposed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
a-D-glucopyranoside in seven steps using classical carbo-
hydrate chemistry. The C-6 and C-4 hydroxy groups of the
starting material were protected as a benzylidene acetal and
the C-2 and C-3 hydroxyl groups were O-methylated.8
Hannesian reaction followed by treatment of the 6-bromo
derivative9 with sodium azide gave the 6-azido derivative,
which was treated with MeONa in MeOH to give methyl
6-azido-6-deoxy-2,3-di-O-methyl-a-D-glucopyranoside 5.10
Compound 5 was treated with either crotonic or cinnamic
acid, N,N0-dicyclohexylcarbodiimide (DCC) in CH2Cl2 in
the presence of catalytic amount of 4-dimethylamino-
pyridine (DMAP), furnishing the ester derivatives 6 or 7,
respectively. The amido-esters 1–4 were finally prepared
from the corresponding azido-esters through a two-step one-
pot reaction sequence: selective reduction of the azido group
with PPh3 in THF or ethyl ether and subsequent treatment of
the resulting 6-amino derivative with 2-iodobenzoic acid,
DCC and DMAP or with 3-iodopropanoyl chloride
(Scheme 2).
The use of carbohydrate derivatives in the synthesis of
carbocycles via free-radical cyclisation reaction has been a
theme of interest in our laboratory.1–5 Encouraged by our
previous studies on tri-n-butyltin-mediated radical carbo-
cyclisation reaction of o-iodobenzamides, we decided to test
this methodology for the synthesis of chiral polysubstituted
macrocycles exploring the stereocontrolling properties of
carbohydrates to create chirality at a ‘site’ outside the
carbohydrate ring.
Thus, we report herein the results of our recent studies on
free-radical cyclisation reactions of the amido-esters (1–4)
anchored to a carbohydrate derived from methyl a-D-
glucopyranoside. We expected that free-radical cyclisations
of these precursors could lead to the macrocycles A/C and/
or B/D by 11-endo or 10-exo cyclisations, respectively.
Although the construction of ten- and eleven-membered
ring carbocycles are very difficult,6,7 we expected that
cyclisation could be favored by the conformational
restraints imposed by the sugar unit (Scheme 1).
Free-radical reaction of 1 and 3 in boiling benzene
(0.01 mol LK1) with Bu3SnH (1.1 equiv) in the presence
of AIBN (catalytic amount) afforded only the hydro-
genolysed products 8 (72%) and 11 (62%), respectively.
When compounds 2 and 4 were treated under the same
conditions, the unexpected six-membered imides 10 and 13
were obtained in 11 and 22% yield, respectively, with none
of the anticipates macrocycles A/C and/or B/D. The
Precursors 1–4 were prepared from readily available methyl
Keywords: Radical cyclisation; Carbohydrate; Imides.
* Corresponding author. Tel.: C55-31-3339-7676; fax: C55-31-3339-
7663; e-mail: rickydylan@ig.com.br
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.039

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R. B. de Oliveira et al. / Tetrahedron 60 (2004) 9901–9908
Scheme 1.
Scheme 2. Reagents, conditions and yields iZcrotonic acid, DCC, DMAP, CH2Cl2 (44%); iiZcinnamic acid, DCC, DMAP, CH2Cl2 (85%); iiiZ(a) PPh3,
THF; (b) 2-iodobenzoic acid, DCC [54% (1), 44% (2)]; ivZ(a) PPh3, (C2H5)2O; (b) HCl, H2O, (c) Na2CO3, 3-iodopropanoyl chloride, acetone [43% (3), 71%
(4)].
corresponding hydrogenolysed products (9) and (12) were
also isolated in 35 and 15% yield, respectively (Scheme 3).
C21H29NO7CNaC) and m/z 446.167 (m/z 446.158 calcu-
lated for C21H29NO7CKC) whereas the ESI-MS/MS
spectra shows the same dissociation sequence displayed
by 10, that is: losses of methanol (m/z 376), methanol plus
water (m/z 358), two methanol molecules (m/z 344) and two
methanol molecules plus a water molecule (m/z 326). For
13, the additional 17 u in mass has therefore not been
observed.
The structures of imides 10 and 13 were determined by ESI-
MS/MS analysis, IR, 1H and 13C NMR spectral data, DEPT
experiment, and 1H–1H COSY, 1H–13C HMQC and HMBC
experiments.
The ESI-MS spectra of 10 in the positive ion mode show
major ions of m/z 472.228, (m/z 472.197 calculated for
C25H29NO8CHC), m/z 494.180 (m/z 494.179 calculated for
C25H29NO8CNaC) and m/z 510.165 (m/z 510.153 calcu-
lated for C25H29NO8CKC). In the negative ion mode, an
abundant ion of m/z 470.465 corresponding to the
deprotonated molecule (m/z 470.181 for C25H29NO8–HC)
is detected, as well as its water adduct of m/z 488.489. The
ESI-MS spectra indicate therefore that a structure with
additional 17 u in mass has been formed. This mass shift
likely corresponds to the incorporation of a new hydroxyl
group. The ESI-MS/MS spectra of the protonated molecule
of m/z 472 is also in agreement with structure 10 as it shows
major dissociation by loss of neutral molecules of methanol
(m/z 440), water plus methanol (m/z 422), two neutral
molecules of methanol (m/z 408) and two methanol
molecules plus a water molecule (m/z 390).
The comparison of 10 and 13 spectral data with those of
their precursors 2 and 4, respectively, are shown in Table 1.
The IR spectrum of 10 and 13 showed the characteristic
absorption bands at 3450 (O–H stretching), 1710 and
1680 cmK1 (C]O stretching of cyclic imide-six-membered
ring).
The 1H and 13C NMR data of 10 and 13 reveal the presence
of a nearly 1:1 mixture of diastereoisomers. The presence of
the hydroxyl group attached to C-4 was deduced on the basis
of the chemical shift of H-4 (d 3.3 ppm) compared to the
downfield signal at d 5.0 and 4.9 ppm for the amido-esters 2
and 4, respectively.
The conversion of amido-esters into the imides was
confirmed by 1H–13C HMBC correlation. The signals
assigned to H-6a and H-6b showed coupling to the carbonyl
carbons (Fig. 1). The regioselectivity of the reaction (exo-
cyclisation mode) was also deduced by 1H–13C HMBC
Similarly, the ESI-MS spectra of 13 in the positive ion mode
show ions of m/z 408.217 (m/z 408.202 calculated for
C21H29NO7CHC), m/z 430.191 (m/z 430.184 calculated for

R. B. de Oliveira et al. / Tetrahedron 60 (2004) 9901–9908
9903
Scheme 3. Reagents, conditions and yields iZBu3SnH, AIBN (cat.), benzene, reflux.
Table 1. Selected spectroscopic data for compounds 2, 4, 10 and 13
Compound
IR (cmK1
)
1H NMRad (ppm)
m, J (Hz)
13C NMRa (DEPT) d (ppm)
nN–H
nO–H
nC]O
H-4
C-7
C-8
(2)
3300
—
1710 (ester), 1640
(amide)
5.0, t, 9.4
117.00 (CH)
146.27 (CH)
(4)
3350
—
—
1700 (ester), 1650
(amide)
1710 and 1680
(imide)
1710 and 1680
(imide)
4.9, t, 9.4
3.3, t, 9.4
3.3, t, 9.2
116.89 (CH)
75.91, 75.82(C)
44.01 (CH)
146.32 (CH)
(10)
(13)
3450
3450
53.58, 53.49 (CH2)
36.36 (CH2)
—
a
Samples were dissolved in CDCl3.
cross peak, which showed coupling between the multiplet at
d 3.12–3.16 ppm, assigned to benzylic hydrogen, and the
ortho carbons at d 130.09 and 130.22 ppm (Fig. 1). The
additional hydroxyl group in imide 10 revealed by MS
analysis was deduced to be at C-7 on the basis of the
chemical shift (d 75.9 ppm) typical of a hydroxylated
tetrasubstituted carbon.
The unexpected formation of six-membered imides 10 and
13 was rationalised as being the result of a 10-exo radical
cyclisation as initially proposed followed by ring contrac-
tion of the unstable ten-membered macrocycles B and D.
The ring strain in macrocycles B and D associated to
proximity between the amide nitrogen atom and the ester
carbonyl group might favour the ring contraction. The

9904
R. B. de Oliveira et al. / Tetrahedron 60 (2004) 9901–9908
Figure 1.
proposed pathways leading to the formation of imides 10
and 13 are outlined in Figure 2.
resulting from exo radical cyclisation. These results can be
attributed to the stability of the intermediate benzyl radical
from cinnamoyl precursors and to the steric retardation of
endo-cyclisation.
In contrast with the guideline that ‘endo-cyclisation modes
are favoured in radical macrocyclisation’,11 we have found
that cinnamoyl precursors provide exclusively macrocycles
We have been intrigued by the presence of the additional
Figure 2.

R. B. de Oliveira et al. / Tetrahedron 60 (2004) 9901–9908
9905
hydroxyl group in the imide 10. It is not so straightforward
to rationalise how this oxidation occurred. However, the
aromatic ring of benzoyl group is likely to play an important
role in the oxidation step, since no such reaction was
observed for 4. The ease of oxidation of a given substrate
depends markedly on the strength of its weakest C–H
bond.12 In this case, the hydrogen abstraction in C-7 forms a
stabilised radical (tertiary, a-carbonyl and benzylic radical),
which could account for the observed autoxidation.
1H, J3,2ZJ3,4Z9.4 Hz, H-3), 3.54 (s, 3H, OMe), 3.49 (s,
6H, 2!OMe), 3.40–3.27 (m, 2H, H-2 and H-6a), 3.20 (dd,
1H, J6b,6aZ13.2 Hz, J6b,5Z2.8 Hz, H-6b), 1.91 (dd, 3H,
JMe,8Z6.8 Hz, JMe,9Z1.6 Hz, Me); 13C NMR (50 MHz,
CDCl3) d (ppm) 165.19 (C]O), 146.41 (C-8), 121.72 (C-7),
97.42 (C-1), 81.14 (C-2 or C-3), 80.53 (C-3 or C-2), 70.98
(C-4), 69.10 (C-5), 60.76, 59.19, 55.40 (3!OMe), 51.27
(C-6), 18.03 (Me).
2.2.2. Methyl 6-azido-4-O-cinnamoyl-6-deoxy-2,3-di-O-
methyl-a-D-glucopyranoside (7). Oil; 1H NMR (200 MHz,
CDCl3) d (ppm) 7.74 (d, 1H, J8,7Z16 Hz, H-8), 7.57–7.38
(m, 5H, Ph), 6.44 (d, 1H, J7,8Z16 Hz, H-7), 4.98 (dd, 1H,
In conclusion, we have described the synthesis of six-
membered cyclic imides bearing a new stereogenic center
via 10-exo-trig radical carbocyclisation followed by ring
contraction on carbohydrate template. This cyclisation,
though regioselective, proved to be nonstereoselective,
affording inseparable mixture of diastereoisomers.
J4,5Z10.1 Hz, J4,3Z9.4 Hz, H-4), 4.90 (d, 1H, J1,2
Z
3.6 Hz, H-1), 3.92 (ddd, 1H, J5,4Z10.1 Hz, J5,6aZ7 Hz,
J5,6bZ3 Hz, H-5), 3.67 (t, 1H, J3,4ZJ3,2Z9.4 Hz, H-3),
3.55 (s, 3H, OMe), 3.52 (s, 3H, OMe), 3.51 (s, 3H, OMe),
3.42–3.31 (m, 2H, H-6a and H-2), 3.25 (dd, 1H, J6b,6a
Z
13.2 Hz, J6b,5Z3 Hz, H-6b); 13C NMR (50 MHz, CDCl3) d
(ppm) 165.63 (C]O), 146.08 (C-8), 133.91–128.08 (Ph),
116.84 (C-7), 97.40 (C-1), 81.14 (C-2 or C-3), 80.51 (C-3 or
C-2), 71.24 (C-4), 69.04 (C-5), 60.74, 59.11, 55.37 (3!
OMe), 51.23 (C-6).
2. Experimental
2.1. General information
All melting points were determined on a Kofler Sybron
apparatus and are uncorrected. Optical rotations were
determined at 25 8C with a Bellingham and Stanley P20
Polarimeter. The IR spectra were recorded on a Shimadsu
IR-408 spectrometer. The NMR spectra were recorded on a
Bruker AVANCE DRX400 or a Bruker AVANCE DPX400
instruments. Samples were dissolved in CDCl3 with TMS as
the internal standard. Chemical shifts are given in d (ppm)
scale and J values are given in Hz. ESI-MS and ESI-MS/MS
data were obtained using a Micromass QTOF hybrid
quadrupole orthogonal time-of-flight mass spectrometer
operating at 7.000 mass resolution and 5 ppm mass accuracy
using typical analytical conditions as described elsewhere.13
ESI-MS spectra for mass measurements were taken using
both positive- and negative-ion electronspray ionization
from 1:1 H2O–MeOH solutions with the addition of either a
few microliters of formic acid or ammonium hydroxide.
Column chromatography was performed with silica gel 60,
70–230 mesh (Merck).
2.3. General procedure for the synthesis of the amido-
esters (1) and (2)
To a 0.08 mol LK1 solution of azido-esters 6 or 7 in THF
was added triphenylphosphine (1.5 equiv). After 6 h at
room temperature, TLC showed complete conversion of the
substrate. Then, N,N0-dicyclohexylcarbodiimide (2.0 equiv)
was added, followed by 2-iodobenzoic acid (2.0 equiv), and
the stirring was continued for 24 h. The dicyclohexylurea
was removed by filtration. The filtrate was concentrated to
give crude amido-ester, which was submitted to chroma-
tography (hexane–EtOAc).
2.3.1. Methyl 4-O-crotonyl-6-deoxy-6-(2-iodobenzoyl-
amino)-2,3-di-O-methyl-a-D-glucopyranoside (1). White
solid; mp 149.6–151.2 8C; [a]DZC105.7 (c 1.4 in CHCl3);
nmax/cmK1 3300 (NH), 1710 (C]O), 1640 (C]O), 1620
(C]C), 1050 (C–O); 1H NMR (200 MHz, CDCl3): d (ppm)
0
0
0
2.2. General procedure for the synthesis of the azido-
esters (6) and (7)
7.85 (d, 1H, J3 ,4 Z7.8 Hz, H-3 ), 7.45–7.33 (m, 2H,
H-50 and H-60), 7.16–7.01 (m, 2H, H-40 and H-8), 6.31 (t,
1H, JNH,6aZJNH,6bZ6.8 Hz, NH), 5.90 (dd, 1H, J7,8
15.5 Hz, J7,MeZ1.6 Hz, H-7), 4.90 (t, 1H, J4,3ZJ4,5
9.6 Hz, H-4), 4.84 (d, 1H, J1,2Z3.6 Hz, H-1), 4.02–3.84 (m,
2H, H-5 and H-6a), 3.64 (t, 1H, J3,4ZJ3,2Z9.6 Hz, H-3)
3.53 (s, 3H, OMe), 3.51 (s, 3H, OMe), 3.46 (s, 3H, OMe),
Z
Z
To a 0.2 mol LK1 solution of 510 in methylene chloride were
added carboxylic acid (crotonic or cinnamic acid)
(1.6 equiv), N,N0-dicyclohexylcarbodiimide (1.6 equiv)
and 4-dimethylaminopyridine (0.16 equiv). The solution
was allowed to stand at room temperature for 12 h. The
dicyclohexylurea, which precipitates, was removed by
filtration. The filtrate was concentrated to give crude
azido-ester, which was submitted to chromatography
(hexane–EtOAc). The azido-esters 6 and 7 were unstable
if stored for a few hours and, thus, they were reacted soon
after their purification.
3.27–3.17 (m, 2H, H-2 and H-6b); 1.91 (dd, 3H, JMe,8
Z
6.8 Hz, JMe,9Z1.6 Hz, Me); 13C NMR (50 MHz, CDCl3) d
(ppm) 169.13, 165.64 (2!C]O), 146.50 (C-8), 0142.08-
128.09 (Ar), 121.80 (C-7), 97.51 (C-1), 92.22 (C-2 ), 81.33
(C-2), 80.58 (C-3), 71.15 (C-4), 67.94 (C-5), 60.85, 59.21,
55.61 (3!OMe), 39.78 (C-6), 18.07 (Me); Anal. Calc. for
C20H26INO7: C, 46.24; H, 5.01; N, 2.70; Found: C, 46.06;
H, 4.64; N, 2.68.
2.2.1. Methyl 6-azido-4-O-crotonyl-6-deoxy-2,3-di-O-
methyl-a-D-glucopyranoside (6). Oil; 1H NMR
(200 MHz, CDCl3): d (ppm) 7.05 (dq, 1H, J8,7Z15.5 Hz,
2.3.2. Methyl 4-O-cinnamoyl-6-deoxy-6-(2-iodobenzoyl-
amino)-2,3-di-O-methyl-a-D-glucopyranoside (2). White
solid; mp 164.2–165.9 8C; [a]DZC211 (c 0.5 in CHCl3);
nmax/cmK1 3300 (NH), 1710 (C]O), 1640 (C]O), 1625
(C]C), 1050 (C–O); 1H NMR (200 MHz, CDCl3): d (ppm)
J8,MeZ6.8 Hz, H-8), 5.85 (dd, 1H, J7,8Z15.5 Hz, J7,Me
Z
1.6 Hz, H-7), 4.93–4.83 (m, 2H, H-1 and H-4), 3.85 (ddd,
1H, J5,4Z10 Hz, J5,6aZ7.2 Hz, J5,6bZ2.8 Hz, H-5), 3.6 (t,

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R. B. de Oliveira et al. / Tetrahedron 60 (2004) 9901–9908
0
0
0
7.85 (d, 1H, J3 ,4 Z7.8 Hz, H-3 ), 7.76 (d, 1H, J8,7Z16 Hz,
(m, 5H, Ph), 6.47 (d, 1H, J7,8Z16 Hz, H-7), 6.16 [s (broad),
1H, NH], 4.90 (t, 1H, J4,3ZJ4,5Z9.4 Hz, H-4),4.86 (d, 1H,
J1,2Z3.6 Hz, H-1), 3.95–3.78 (m, 2H, H-5 and H-6a), 3.68
(t, 1H, J3,4ZJ3,2Z9.4 Hz, H-3), 3.54 (s, 3H, OMe), 3.53 (s,
3H, OMe), 3.46–3.36 (m, 4H, OMe and H-6b), 3.30 (dd, 1H,
J2,3Z9.4 Hz, J2,1Z3.6 Hz H-2), 3.18–2.96 (m, 2H, H-9a,
H-9b), 2.94–2.71 (m, 2H, H-10a and H-10b); 13C NMR
(50 MHz, CDCl3) d (ppm) 170.20, 166.39 (2!C]O),
146.32 (C-8), 133.95–128.20 (Ph), 116.89 (C-7), 97.48
(C-1), 81.36 (C-3), 80.55 (C-2), 71.48 (C-4), 67.91 (C-5),
60.92, 59.21, 55.50 (3!OMe), 40.66 (C-9), 39.28 (C-6),
K1,87 (C-10); Anal. Calc. for C21H28INO7: C, 47.28; H,
5.25; N, 2.67; Found: C, 47.63; H, 5.31; N, 2.55.
0
0
0
0
H-7) 7.58–7.33 (m, 7H, Ar-H), 7.10 (td, 1H, J4 ,3 ZJ4 ,5
Z
0
0
0
7.8 Hz, J4 ,6 Z1.2 Hz, H-4 ), 6.49 (d, 1H, J7,8Z16 Hz, H-7),
6.31 [s (broad), 1H, NH], 4.99 (t, 1H, J4,3ZJ4,5Z9.4 Hz,
H-4), 4.86 (d, 1H, J1,2Z3.6 Hz, H-1), 4.06–3.91 (m, 2H,
H-5 and H-6a), 3.71 (t, 1H, J3,4ZJ3,2Z9.4 Hz, H-3), 3.54
(s, 3H, OMe), 3.53 (s, 3H, OMe), 3.48 (s, 3H, OMe), 3.38–
3.26 (m, 2H, H-2 and H-6b); 13C NMR (50 MHz, CDCl3) d
(ppm) 169.16, 166.25 (2!C]O), 146.27 (C-8), 142.11–
128.13 (Ar), 117.00 (C-7), 97.58 (C-1), 92.26 (C-20), 81.42
(C-2), 80.67 (C-3), 71.54 (C-4), 67.97 (C-5), 60.96, 59.26,
55.69 (3!OMe), 39.88 (C-6); Anal. Calc. for C25H28INO7:
C, 51.64; H, 4.82; N, 2.41; Found: C, 51.44; H, 4.57; N,
2.40.
2.5. General procedure for free radical cyclisation
2.4. General procedure for the synthesis of the amido-
esters (3) and (4)
To a stirring and boiling solution of amido-esters in
nitrogen-saturated benzene (0.01 mol LK1) was added a
solution of Bu3SnH (1.1 equiv) and AIBN (cat.) in nitrogen-
saturated benzene (0.2 mol LK1) via an addition funnel
during 3 h. The reaction mixture was heated under reflux in
nitrogen atmosphere for a further 1 h. After solvent removal
the residue was dissolved in acetonitrile (50 mL). The
solution was extracted three times with hexane (30 mL) to
remove tin compounds. After evaporation of the acetonitrile
the residue was chromatographed (hexane–EtOAc).
To a 0.13 mol LK1 solution of azido-esters 6 or 7 in diethyl
ether was added triphenylphosphine (1.5 equiv). After
completion of the reduction (w4 h) the reaction mixture
was extracted with cold diluted hydrochloric acid
(0.2 mol LK1, 15 mL) to separate the triphenylphosphine
oxide from the amine. The aqueous layer was transferred to
a round-bottom flask immersed in an ice bath and then were
added acetone (20 mL), saturated aqueous sodium
carbonate (ca. 10 mL), followed by a dropwise solution of
the 3-iodopropanoyl chloride (2.5 equiv) in anhydrous
acetone (5 mL). After 1 h at room temperature, TLC
showed complete conversion of the substrate. For workup,
acetone was removed under reduced pressure, water
(50 mL) was added and the aqueous layer was washed
with CHCl3 (3!50 mL). The organic layer was dried
(Na2SO4) and evaporated. The crude product was purified
by column chromatography (hexane–EtOAc).
2.5.1. Free radical cyclisation of amido-ester (1). The
uncyclized product (8) was obtained as a white solid; mp
129.3–130.2; [a]DZC113 (c 1.0 in CHCl3); 1H NMR
0
0
(200 MHz, CDCl3): d0 (ppm) 7.83 (dd, 2H, J2 ,3 Z7.8 Hz,
0
0
J2 ,4 Z1.8 Hz, 2!H-2 ), 7.54–7.34 (m, 3H, Ar-H), 7.10 (dq,
1H, J8,7Z15.6 Hz, J8,MeZ6.8 Hz, H-8), 7.01–6.94 (m, 1H,
NH), 5.91 (dd, 1H, J7,8Z15.6 Hz, J7,MeZ1.6 Hz, H-7), 4.87
(t, 1H, J4,3ZJ4,5Z9.4 Hz, H-4), 4.84 (d, 1H, J1,2Z3.6 Hz,
H-1), 4.13 (ddd, 1H, J6a,6bZ14.3 Hz, J6a,NHZ8.5 Hz,
2.4.1. Methyl 4-O-crotonyl-6-deoxy-6-(3-iodopropanoyl-
amino)-2,3-di-O-methyl-a-D-glucopyranoside (3). White
solid; mp 87.9–88.6 8C; [a]DZC106.2 (c 2.0 in CHCl3);
nmax/cmK1 3350 (NH), 1700 (C]O), 1650 (C]O), 1625
(C]C), 1050 (C–O); 1H NMR (200 MHz, CDCl3): d (ppm)
7.06 (dq, 1H, J8,7Z15.5 Hz, J8,MeZ6.9 Hz, H-8), 6.19 [s
J6a,5Z2.8 Hz, H-6a), 3.85 (ddd, 1H, J5,4Z9.4 Hz, J5,6bZ
5.6 Hz, J5,6aZ2.8 Hz, H-5), 3.65 (t, 1H, J3,4ZJ3,2Z9.4 Hz,
H-3), 3.51 (s, 6H, 2!OMe), 3.42 (s, 3H, OMe), 3.26 (dd,
1H, J2,3Z9.4 Hz, J2,1Z3.6 Hz H-2), 3.09 (ddd, 1H, J6b,6a
Z
14.3 Hz, J6b,NHZ4.2 Hz, J6b,5Z5.6 Hz, H-6b), 1.92 (dd,
3H, JMe,8Z6.8 Hz, JMe,7Z1.6 Hz, Me); 13C NMR
(50 MHz, CDCl3) d (ppm) 167.11, 166.09 (2!C]O),
146.75 (C-8), 134.20-126.89 (Ph), 121.76 (C-7), 97.40
(C-1), 81.31 (C-3), 80.51 (C-2), 71.51 (C-4), 67.93 (C-5),
60.86, 59.12, 55.28 (3!OMe), 39.47 (C-6), 18.06 (Me);
ESI-MS [MCH]C 394.195 C20H27NO7 requires for [MC
H]C 394.187).
(broad), 1H, NH], 5.88 (dd, 1H, J7,8Z15.5 Hz, J7,Me
Z
1.6 Hz, H-7), 4.84 (d, 1H, J1,2Z3.6 Hz, H-1), 4.80 (t, 1H,
J4,3ZJ4,5Z9.4 Hz, H-4), 3.90–3.71 (m, 2H, H-5 and H-6a),
3.61 (t, 1H, J3,4ZJ3,2Z9.4 Hz, H-3), 3.53 (s, 3H, OMe),
3.50 (s, 3H, OMe), 3.44–3.33 (m, 4H, OMe and H-6b), 3.27
(dd, 1H, J2,3Z9.4 Hz, J2,1Z3.6 Hz H-2), 3.08–2.59 (m, 4H,
H-9a, H-9b, H-10a and H-10b), 1.92 (dd, 3H, JMe,8
Z
6.9 Hz, JMe,7Z1.6 Hz, Me); 13C NMR (50 MHz, CDCl3) d
(ppm) 170.19, 165.81 (2!C]O), 146.59 (C-8), 121.77
(C-7), 97.45 (C-1), 81.30 (C-3), 80.50 (C-2), 71.15 (C-4),
67.90 (C-5), 60.83, 59.17, 55.45 (3!OMe), 40.63 (C-9),
39.23 (C-6), 18.07 (Me), -1,92 (C-10); Anal. Calc. for
C16H26INO7: C, 40.76; H, 5.52; N, 2.97; Found: C, 41.44;
H, 5.13; N, 2.89.
2.5.2. Free radical cyclisation of amido-ester (2). The
uncyclized product 9 was obtained as a white solid; mp
80.9–81.5; [a]DZC126.9 (c 0.75 in CHCl3); 1H NMR
0
0
(200 MHz, CDCl3): d 0(ppm) 7.84 (dd, 2H, J2 ,3 Z7.8 Hz,
0
0
J2 ,4 Z1.4 Hz, 2!H-2 ), 7.79 (q, 1H, J8,7Z15.8 Hz, H-8),
7.59–7.39 (m, 8H, Ar-H), 6.96 (dd, 1H, JNH,6aZ8.4 Hz,
JNH,6bZ4.2 Hz, NH), 6.50 (d, 1H, J7,8Z15.8 Hz, H-7), 4.96
(dd, 1H, J4,5Z10.0 Hz, J4,3Z9.4 Hz, H-4), 4.87 (d, 1H,
2.4.2. Methyl 4-O-cinnamoyl-6-deoxy-6-(3-iodopropa-
noylamino)-2,3-di-O-methyl-a-D-glucopyranoside (4).
White solid; mp 101.7–102.8 8C; [a]DZC101.2 (c 1.2 in
CHCl3); nmax/cmK1 3350 (NH), 1700 (C]O), 1650
(C]O), 1625 (C]C); 1050 (C–O); H NMR (200 MHz,
CDCl3): d (ppm) 7.75 (d, 1H, J8,7Z16 Hz, H-8), 7.58–7.38
J1,2Z3.6 Hz, H-1), 4.18 (ddd, 1H, J6a,6bZ14.3 Hz, J6a,NH
8.4 Hz, J6a,5Z2.8 Hz, H-6a), 3.92 (ddd, 1H, J5,4Z10.0 Hz,
J5,6bZ5.4 Hz, J5,6aZ2.8 Hz, H-5), 3.72 (t, 1H, J3,4ZJ3,2
9.4 Hz, H-3), 3.55 (s, 3H, OMe), 3.53 (s, 3H, OMe), 3.44 (s,
3H, OMe), 3.30 (dd, 1H, J2,3Z9.4 Hz, J2,1Z3.6 Hz H-2),
3.24–3.09 (m, 1H, H-6b); 13C NMR (50 MHz, CDCl3) d
Z
Z
1

R. B. de Oliveira et al. / Tetrahedron 60 (2004) 9901–9908
9907
(ppm) 167.20, 166.75 (2!C]O), 146.54 (C-8), 134.24–
126.95 (Ar-C), 116.91 (C-7), 97.50 (C-1), 81.43 (C-2),
80.61 (C-3), 71.96 (C-4), 67.99 (C-5), 61.02, 59.22, 55.40
(3!OMe), 39.59 (C-6); ESI-MS [MCH]C 456.200
C25H29NO7 requires for [MCH]C 456.202).
7.57–7.27 (m, 5H, Ar-H), 6.47 (d, 1H, J7,8Z16 Hz, H-7),
6.06 [s (broad), 1H, NH), 4.93–4.80 (m, 2H, H-1, H-4),
3.95–3.77 (m, 2H, H-6a and H-5), 3.67 (t, 1H, J3,4ZJ3,2
Z
9.4 Hz, H-3), 3.54 (s, 3H, OMe), 3.53 (s, 3H, OMe), 3.44 (s,
3H, OMe), 3.28 (dd, 1H, J2,3Z9.4 Hz, J2,1Z3.4 Hz, H-2),
3.05–2.97 (m, 1H, H-6b), 2.24 (q, 2H, J9,10Z7.6 Hz, H-9a
and H9b), 1.17 (t, 3H, J10,9aZJ10,9bZ7.6 Hz, H-10); 13C
NMR (50 MHz, CDCl3) d (ppm) 173.76, 166.35 (2!
C]O), 146.29 (C-8), 134.05–128.24 (Ar-C), 117.03 (C-7),
97.51 (C-1), 81.45 (C-3), 80.71 (C-2), 71.63 (C-4), 67.98
(C-5), 60.99, 59.26, 55.34 (3!OMe), 39.23 (C-6), 29.76
(C-9), 9.78 (C-10); ESI-MS [MCH]C 408.204 C21H29NO7
requires for [MCH]C 408.202).
The six-membered cyclic imide 10 was obtained as an oil;
nmax/cmK1 3450 (OH), 1710 (C]O), 1680 (C]O), 1050
(C–O); 1H NMR (400 MHz, CDCl3): d (ppm) 8.07–8.02 (m,
2H, H-18 and H-180), 7.66–7.59 (m, 2H, H-16 and H-160),
7.56–7.52 (m, 2H, H-15 and H-150), 7.50–7.45 (m, 2H, H-17
and H-170), 7.23–7.19 (m, 2H, H-12 and H-120), 7.16-7.11
(m, 4H, 2!H-11 and 2!H-110), 6.70–6.65 (m, 4H, 2!
0
H-10 and 2!H-100), 4.76 (d, 1H, J1 ,2 Z3.6 Hz, H-1 ), 4.75
0
0
(d, 1H, J1,2Z3.6 Hz, H-1), 4.30 (dd, 1H, J6a,6bZ14.0 Hz,
The six-membered cyclic imide 13 was obtained as an oil;
nmax/cmK1 3450 (OH), 1710 (C]O), 1680 (C]O), 1050
(C–O); 1H NMR (400 MHz, CDCl3): d (ppm) 7.36–7.18 (m,
10H, Ar-H), 4.79–4.77 (m, 2H, H-1 and H-10), 4.23 (dd, 2H,
J6a,5Z4.8 Hz, H-6a), 4.15–4.13 (m, 2H, H-6b and H-6b0),
0
0
0
0
0
4.08 (dd, 1H, J6a ,6b Z14.0 Hz, J6a ,5 Z4.8 Hz, H-6a ), 3.92
0
0
0
0
0
0
0
(dt, 1H, J5 ,4 Z9.4 Hz, J5 ,6a ZJ5 ,6b Z6.0 Hz, H-5 ), 3.84
(dt, 1H, J5,4Z9.4 Hz, J5,6aZJ5,6bZ4.8 Hz, H-5), 3.62 (s,
3H, OMe), 3.61 (s, 3H, OMe), 3.45 (s, 3H, OMe), 3.44–3.39
0
0
0
0
J6a,6bZJ6a ,6b Z13.6 Hz, J6a,5ZJ6a ,5 Z4.8 Hz, H-6a and
H-6a0), 4.08 (dd, 2H, J6b,6aZJ6b ,6a Z13.6 Hz, J6b,5
Z
0
0
(m, 5H, OMe, H-3 and H-30), 3.33 (t, 1H, J4 ,5 ZJ4 ,3
Z
Z
Z
J6b ,5 Z5.6 Hz, H-6b and H-6b ), 3.79–3.73 (m, 2H, H-5
and H-50), 3.63 (s, 3H, OMe), 3.62 (s, 3H, OMe0), 3.48 (s,
6H, 2!OMe), 3.47–3.41 (m, 2H, H-8a and H-8a ), 03.41 (t,
0
0
0
0
0
0
0
9.4 Hz, H-40), 3.31 (s, 3H, OMe), 3.27 (t, 1H, J4,5ZJ4,3
0
0
9.4 Hz, H-4), 3.24 (s, 3H,0 OMe), 3.19 (dd, 1H, J2 ,3
0
0
0
0
0
0
9.4 Hz, J2 ,1 Z3.6 Hz, H-2 ), 3.16–3.13 (m, 5H, H-2 and
H-8a, H-8a0, H-8b and H-8b0); 13C NMR (100 MHz, CDCl3)
d (ppm) 177.12, 176.60, 164.12, 163.96 (4!C]O), 139.66,
139.53 (C-14 and C-140), 133.93 (C-16 and C-160),
133.24, 133.13 (C-9 and C-90), 130.22, 130.090 (2!C-10
and 2!C-100), 128.58, 128.54 (C-17 and C-17 ), 128.30,
128.15 (C-18 and C-180), 128.06, 127.99 (2!C-11 and 2!
C-1100), 127.64 (C-12 and C-120),0 125.64, 125.50 (C-15 and
C-15 ), 124.43 (C-14 and C-14 ), 97.40, 97.31 (C-1 and
C-10), 82.52, 82.28 (C-3 and C-30), 81.66, 81.60 (C-2
and C-20), 75.91, 75.82 (C-7 and C-70), 73.33 (C-4), 73.50
(C-40), 68.92 (C-5), 68.28 (C-50), 61.24, 58.66, 58.55,
55.18, 55.10 (6!OMe), 53.58, 53.49 (C-8 and C-80), 42.22
(C-6), 41.33 (C-60); ESI-MS [MCH]C 472.228
C25H29NO8 requires for [MCH]C 472.197).
2H, J3,4ZJ3,2ZJ3 ,4 ZJ3 ,2 Z9.2 Hz, H-3 and H-3 ), 3.35
(s, 3H, OMe), 3.34 (s, 3H, OMe), 3.27 (t, 2H, J4,5ZJ4,3
Z
Z
0
0
0
0
0
J4 ,5 ZJ4 ,3 Z9.2 Hz, H-4 and H-4 ), 3.19 (dd, 2H, J2,3
0
0
0
0
0
J2 ,3 Z9.2 Hz, J2,1ZJ2 ,1 Z3.6 Hz, H-2 and H-2 ), 2.80–
2.69 (m, 6H, H-7, H-70, H-8b, H-8b0, H-10a and H-10a0)
2.58–2.47 (m, 2H, H-10b and H-b0), 1.91–1.83 (m, 2H, 2!
H-9a and H-9 ), 1.66–1.55 (m, 2H, H-9b and H-9b0); 13C
a
0
NMR (100 MHz, CDCl3) d (ppm) 174.72, 174.52, 172.80,
172.67 (4!C]O), 138.33, 138.28 (C-11 and C-110),
129.22, 129.17 (2!C-12 and 2!C-120), 128.57, 128.54
(2!C-13 and 2!C-130), 126.62 (0C-14 and C-140), 97.21
(C-1 and C-10), 82.39 (C-3 and C-3 ), 81.55 (C-2 and C-200),
72.96, 72.90 (C-4 and C-40), 68.49, 68.40 (C-5 and C-5 ),
61.14, 58.51, 54.90 (06!OMe), 44.01 (C-7 a0nd C-70), 40.69,
40.64 (C-6 and C-6 ), 36.36 (C-8 and C-8 ), 32.08, 32.02
(C-10 and C-100), 21.70 (C-9 and C-90); ESI-MS [MCH]C
408.217 C21H29NO7 requires for [MCH]C 408.202).
2.5.3. Free radical cyclisation of amido-ester (3). The
uncyclized product 11 was obtained as a white solid; mp
85.5–87.0; [a]DZC118 (c 0.8 in CHCl3); 1H NMR
(200 MHz, CDCl3): d (ppm) 7.06 (qd, 1H, J8,7Z15.6 Hz,
J8,MeZ6.8 Hz, H-8), 6.07 [s (broad), 1H, NH), 5.88 (dd, 1H,
Acknowledgements
J7,8Z15.6 Hz, J7,MeZ1.6 Hz, H-7), 4.83 (d, 1H, J1,2
Z
`
The authors are grateful to Fundac¸a˜o de Amparo a Pesquisa
do Estado de Minas Gerais (FAPEMIG), Fundac¸a˜o de
3.6 Hz, H-1), 4.79 (t, 1H, J4,5ZJ4,3Z9.4 Hz, H-4), 3.89–
3.70 (m, 2H, H-6a and H-5), 3.61 (t, 1H, J3,4ZJ3,2Z9.4 Hz,
H-3), 3.53 (s, 3H, OMe), 3.50 (s, 3H, OMe), 3.42 (s, 3H,
OMe), 3.27 (dd, 1H, J2,3Z9.4 Hz, J2,1Z3.6 Hz, H-2), 3.01–
2.88 (m, 1H, H-6b) 2.23 (q, 2H, J9,10Z7.6 Hz, H-9a and
H9b), 1.91 (dd, 3H, JMe,8Z6.8 Hz, JMe,7Z1.6 Hz, Me),
1.16 (t, 3H, J10,9aZJ10,9bZ7.6 Hz, H-10); 13C NMR
(50 MHz, CDCl3) d (ppm) 173.74, 165.77 (2!C]O),
146.47 (C-8), 121.83 (C-7), 97.43 (C-1), 81.34 (C-3), 80.61
(C-2), 71.25 (C-4), 67.94 (C-5), 60.84, 59.17, 55.23 (3!
OMe), 39.14 (C-6), 29.65 (C-9), 18.06 (Me), 9.70 (C-10);
ESI-MS [MCH]C 346.193 C16H27NO7 requires for [MC
H]C 346.187).
`
Amparo a Pesquisa do Estado de Sa˜o Paulo (FAPESP) and
Conselho Nacional de Desenvolvimento Cientıfico e
´
´
Tecnologico (CNPq), for financial support. The authors
thank the referees for their suggestions.
References and notes
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2.5.4. Free radical cyclisation of amido-ester (4). The
uncyclized product 12 was obtained as a white solid; mp
112.0–113.5; [a]DZC79.2 (c 1.0 in CHCl3); 1H NMR
(200 MHz, CDCl3): d (ppm) 7.76 (d, 1H, J8,7Z16 Hz, H-8),
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