A new 20-membered macrocyclic dilactam: An unexpected product of a tri-n-butyltin hydride-mediated radical reaction

Article abstract of DOI:10.1016/j.tetlet.2004.02.116

The tri-n-butyltin hydride-mediated reaction of methyl 3-O-allyl-4,6-di-O- benzyl-2-deoxy-2-(2-iodobenzoylamino)-α-D-glucopyranoside affords an unexpected benzomacrodilactam. The structure of this new 20-membered macrocyclic dilactam has been elucidated by electrospray mass and tandem mass spectrometry (ESI-MS/MS) and by ¹H, ¹³C NMR spectroscopy, COSY, TOCSY, HMQC and HMBC experiments.

Full text of DOI:10.1016/j.tetlet.2004.02.116

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3317–3320
A new 20-membered macrocyclic dilactam: an unexpected product
of a tri-n-butyltin hydride-mediated radical reactionq
a
Andre A. G. Faraco, Maria Auxiliadora F. Prado, Rosemeire B. Alves,
b,
a
*
ꢀ
^
b
b
a
c
ꢀ
Renata F. P. Faraco, Ricardo J. Alves, Jose D. Souza-Filho, Eduardo C. Meurer
and Marcos N. Eberlinc
aDepartamento de Quꢀımica, Instituto de Ci^encias Exatas, Universidade Federal de Minas Gerais, Avenida Ant^onio Carlos 6627,
31.270-901 Belo Horizonte, MG, Brazil
bDepartamento de Produtos Farmac^euticos, Faculdade de Farmꢀacia, Universidade Federal de Minas Gerais,
Avenida Olegꢀario Maciel 2360, 30.180-112 Belo Horizonte, MG, Brazil
c
ꢀ
ꢀ
Instituto de Quımica, Laboratorio Thomson de Espectrometria de Massas, Universidade Estadual de Campinas,
13.083-970 Campinas, SP, Brazil
Received 20 October 2003; revised 3 February 2004; accepted 9 February 2004
Abstract—The tri-n-butyltin hydride-mediated reaction of methyl 3-O-allyl-4,6-di-O-benzyl-2-deoxy-2-(2-iodobenzoylamino)-a-D-
glucopyranoside affords an unexpected benzomacrodilactam. The structure of this new 20-membered macrocyclic dilactam has been
elucidated by electrospray mass and tandem mass spectrometry (ESI-MS/MS) and by 1H, 13C NMR spectroscopy, COSY, TOCSY,
HMQC and HMBC experiments.
ꢀ 2004 Elsevier Ltd. All rights reserved.
In continuing studies1–4 of Bu3SnH-mediated radical
cyclizations, we have applied unsaturated organohalides
to synthesize lactones and lactams, most particularly
benzomacrolactams from ortho-iodobenzamides bearing
a side allyloxy group.1–3 These studies confirmed that 12-
and 11-endo cyclizations are preferred over the corre-
sponding 11- and 10-exo cyclizations, in agreement with
boththe general guideline for radical macrocyclization
that states that Ôendo cyclization modes are favoredÕ5 and
aryl radical cyclizations.1;2 Based on these encouraging
results, we decided to test the Bu3SnH-mediated 10-endo
radical cyclization reaction withmethyl 3- O-allyl-4,6-di-
O-benzyl-2-deoxy-2-(2-iodobenzoylamino)-a-D-gluco-
pyranoside (2) as a route to synthesize the 10-membered
benzomacrolactam 1.
BnO
BnO
BnO
BnO
O
O
6–12
OCH3
OCH3
withother experimental results on macrocyclization.
But in contrast withthe larger ones, small macrocycles
(10–12 membered) are known to be extremely difficult (if
not impossible) to synthesize.13;14 It was therefore
important to find that, by an endo-selective intramolec-
ular attack of an aryl radical to an unsaturated carbon–
carbon bound, a 10-membered ring lactam could be
obtained in 45% yield.14 We have also shown that a
sugar unit in the ortho-iodobenzamides aids the 11-endo
O
NH
O
NH
O
2
O
I
1
The iodobenzamide 2 was prepared from D-glucosamine
hydrochloride (3) in six conventional synthetic steps
15
(Scheme 1): reaction of 3 with2-iodobenzoyl chloride,
treatment of 4 with methanol in the presence of acidic
resin (IR-120), protection of the C-4 and C-6 hydroxy
groups of methyl glycoside 5 as benzylidene acetal,16
treatment of 6 withallyl bromide under phase transfer
catalyst,17 removal of benzylidene group under mild
Keywords: Macrolactam; Aryl radical cyclization; Macrocycle.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.02.116
* Corresponding author. Tel.: +55-31-3339-7687; fax: +55-31-3339-
7663; e-mail: doraprad@dedalus.lcc.ufmg.br
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.116

3318
A. A. G. Faraco et al. / Tetrahedron Letters 45 (2004) 3317–3320
O
O
HO
HO
HO
HO
HO
HO
O
O
O
O
iii
i
ii
OCH3
OH
OH
OCH3
HO
6
NH
HO
NH2.HCl
HO
4
NH
HO
5
NH
O
I
O
I
3
O
I
iv
O
O
HO
HO
BnO
BnO
O
O
O
v
vi
OCH3
OCH3
OCH3
O
NH
O
NH
O
NH
O
O
I
O
I
I
8
7
2
Scheme 1. Reagents, conditions and yields: (i) 6 equiv NaHCO3 (aq), 1.5 equiv 2-iodobenzoyl chloride (acetone), 0 ꢁC 3 h , 25ꢁC rt, 73%; (ii)
anhydrous methanol, IR-120 resin (cat.), reflux, 58%; (iii) 13.4 equiv benzaldehyde, 2 equiv ZnCl2, rt, 64%; (iv) 0.5 equiv Bu4NBr, 10% aq NaOH,
CH2Cl2, 2.0 equiv allyl bromide, rt, 76%; (v) acetone, aqueous HCl (cat.), reflux, 73%; (vi) 3.5 equiv KOH, 8 equiv BnCl, 80 ꢁC, 2 25%, 8 50%.
acidic conditions18 and O-benzylation of hydroxy
2). The NMR and MS data of the major product were
found, however, to be incompatible with the structure of
the expected macrolactam 1. A detailed analysis of the
MS and NMR data, as discussed below, allows us to
identify this major product (40% yield) as the interest-
ing, new 20-membered benzomacrodilactam 1022
(Scheme 2).
groups at C-4 and C-619 of 8.
The benzamide 2 was submitted to the recommended
Bu3SnH-mediated reaction conditions.13;20;21 A mixture
of Bu3SnH (1.5 equiv) and AIBN (catalytic amount) in
nitrogen-saturated anhydrous benzene was added over
1 hto a solution of 2 in nitrogen-saturated anhydrous
benzene maintained at 80 ꢁC to give a reaction mixture
0.012 mol Lꢀ1 in Bu3SnH. After addition was completed,
the reaction mixture was heated under reflux for an
hour. Solvent removal and column chromatography on
silica gel of the crude product provided two main
products. The minor product (27% yield) was readily
identified from its 1H NMR data as the uncyclized
reduced product: methyl 3-O-allyl-4,6-di-O-benzyl-2-
MS analysis: Mass (MS) and tandem mass spectrometry
(MS/MS) withelectrospray ionization (ESI) has been
incorporated into the major techniques particularly for
the structural characterization of large and/or more
polar molecules.23 We have therefore use these MS
techniques for the structural characterization of the
unknown, unexpected product. The ESI-MS spectrum
in the positive ion mode of a methanolic solution of the
major product shows an ion of m=z 1035.624 (m=z
benzoylamino-2-deoxy-a-
D
-glucopyranoside 9 (Scheme
5
O
OCH3
O
1c
1
O
1a
1b
O
N
H
3
O
'
9
7
8
'
8
1c
'
7
1b'
9
O
H
N
O
1b
'
O
1
3
O
1c'
4
O
OCH3
1a'
i
'
'
10
6
O
1
O
7
'
5
H3CO
O
O
NH
1a
8
I
2a
O
BnO
9
H
a
O
H
b
1
Bn4O
OCH3
2
7
O
NH
8
9
O
H
a
H
b
H
9
Scheme 2. Reagents, conditions and yields: (i) 1.5 equiv Bu3SnH, AIBN (cat.), benzene, reflux, 9 27% 10 40%.

A. A. G. Faraco et al. / Tetrahedron Letters 45 (2004) 3317–3320
3319
1035.5001 calculated for C62H70N2O12+Hþ), which dis-
plays a m=z ratio and an isotopic distribution that
matches that of the protonated molecule of a dimer of
lactam 1 (2 · C31H35NO6). The ESI-MS/MS spectrum of
the protonated molecule (MHþ) is also very indicative of
dimerization since it shows that MHþ dissociates to a
great extent by Ôin-halfÕ breaking, that is, by loosing a
neutral molecule of C31H35NO6 composition (517 u,
likely a neutral molecule of the monomeric lactam 1) to
form a fragment ion of m=z 518 witha [C 31H35NO6+H]þ
composition. The ESI-MS and ESI-MS/MS data indi-
cates therefore that a dimer of 1 has been formed, likely
the new 20-membered benzomacrodilactam 10.
for fellowship. The authors thank CNPq, the Fundaßcao
~
de Amparo a Pesquisa do Estado de Minas Gerais
ꢁ
~
ꢁ
(FAPEMIG) and Fundaßcao de Amparo a Pesquisa
~
do Estado de Sao Paulo (FAPESP) for financial
support.
References and notes
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product, likely 10, reveals the presence of two carbo-
hydrate moieties, two metoxy groups, two amide car-
bonyl, two amide hydrogen, six phenyl and twelve sp3
metylenes, eight of them bearing an oxygen atom (two
of sugar unit, four benzyloxy groups and two methylene
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ortho-allyloxyiodobenzamide 2 fails to proceeds through
a 10-endo mode, which we expected to afford the 10-
membered lactam 1. Instead, 2 forms predominantly the
macrolactam 10, as indicated by MS and NMR analysis.
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tam 10 shows the potential of Bu3SnH-mediated aryl
radical cyclization in the synthesis of macrocycles
incorporating large rings and polyfunctional groups.
22. The 20-membered dilactam is an oil; ½aꢁ +18 (c 0.57,
D
CHCl3); ESIMS m=z [Mꢀ], 1034.4929, [M+H]þ 1035.4962.
C62H70N2O12 requires for [Mꢀ] 1034.492876 and for
[M+H]þ 1035.500701.
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Acknowledgements
A.A.G.F. and M.A.F.P. thank the Conselho Nacional
ꢀ ꢀ
de Desenvolvimento Cientıfico e Tecnologico (CNPq)

3320
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