Synthesis of aza/oxaspiro-γ-lactams by radical translocation cyclization reactions

Article abstract of DOI:10.1055/s-2005-871563

A cascade radical translocation cyclization of the N-allyl-N-(2′- bromophenyl)amide moiety of heterocyclic carboxylic acids and its N-propynyl analogues were investigated. It provides a convenient method for the preparation of aza/oxaspiro-γ-lactams that

Full text of DOI:10.1055/s-2005-871563

LETTER
1865
Synthesis of Aza/Oxaspiro-g-lactams by Radical Translocation Cyclization
Reactions
Synthesis of
A
za/O
i
xaspir
a
o-
g
-lactam
nbyRadical
x
T
ranslocatio
i
nCycli
u
zationReactions Xu, Xin Che, Shu Gao, Jinchang Wu, Xu Bai*
The Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Jinlai St., Changchun, Jilin 130012, P. R. China
Fax +86(431)5188900; E-mail: xbai@jlu.edu.cn
Received 5 March 2005
been employed in the synthesis of natural products with
unusual structural features7 and carbospirocarboncycles.6b
To our knowledge no applications of radical translocation
reactions in the preparation of aza/oxaspirolactams have
been reported.
Abstract: A cascade radical translocation cyclization of the N-
allyl-N-(2¢-bromophenyl)amide moiety of heterocyclic carboxylic
acids and its N-propynyl analogues were investigated. It provides a
convenient method for the preparation of aza/oxaspiro-g-lactams
that are useful g-turn mimetics in drug discovery.
Key words: radical translocation, [1,5]-hydrogen transfer, spiro-g-
lactams
It is anticipated that the aza/oxaspiro-g-lactam frame-
works 8 could be constructed from amides 5 through rad-
ical translocation cyclization reactions (Scheme 1). This
strategy involves a cascade of radical reactions initiated
by generation of aryl radical 6 from its bromo precursor 5.
Radical 6 abstracts the a-proton on the heterocycle to
yield new radical 7. Radical 7 undergoes exo cyclization
with the N-allyl double bond to give the spirolactam 8.
The details of the investigations are presented in this
paper.
Great efforts have been spent on the design and synthesis
of conformationally constrained analogues (peptidomi-
metics) to improve the potency, selectivity, and metabolic
stability of peptide-based drugs in recent years. Spiro-
lactams 1–4 (Figure 1), with fixed angles resembling
naturally occurring g-turns of peptides, are of interest in
the pursuit of peptidomimetic drugs.1 Thus far, their syn-
thesis has primarily involved intramolecular Mitsunobu
reaction,2 amide-coupling reaction,3 or Michael addition
followed by subsequent nitro-reductive cyclization
reactions4 to yield the bispirolactam skeleton. In addition,
both solution and solid-phase synthesis of structurally
similar spiro-oxindoles were reported.5
O
O
N
N
X
X
Br
6
5
O
O
NH
O
N
N
1,5-radical
translocation
O
N
cyclization
N
N
Boc
O
H
X
H
t-BuO2C
Ph
X
1
2
8
7
O
O
O
O
Scheme 1 Strategic approach to aza/oxaspiro-g-lactams by radical
translocation cyclization
N
N
NH2
NH2
N
N
R
R
Radical precursors 5 were prepared from readily available
acids 9 according to Scheme 2. Acids 9 [N-Boc L-proline,
( )-N-Boc piperidine-2-carboxylic acid, or ( )-tetra-
hydrofuran-2-carboxylic acid] coupled with 2-bromo- or
4-methoxy-2-bromoaniline 10 to provide amides 11 in
nearly quantitative yields. Amides 11 reacted with allyl
bromide in the presence of potassium hydroxide in DMSO
to afford radical precursors 5. The Boc group of com-
pounds 5 (a–c, X = N-Boc) was readily cleaved by hydro-
chloric acid in ethyl acetate to give unprotected 5 (e–g,
X = NH) in good yields. Compounds 5a, 5b, 5e, and 5f
were obtained in optically active form (5a: [a]D20 = 153.2,
5b: [a]D20 = 142.6, 5e: [a]D20 = 28.0, 5f: [a]D20 = 27.4)
from L-proline. The other precursors 5 were synthesized
from racemic acids 9.
3
4
Figure 1 Spirolactam peptidomimetics
Over the last couple of decades, radical translocation re-
actions in which the key bond-forming radical was gener-
ated by intramolecular abstraction of an atom (usually
hydrogen) or group by a radical center, which then sub-
sequently reacts with a site normally unreactive towards
external reagents have been well developed.6 They have
SYNLETT 2005, No. 12, pp 1865–1868
Advanced online publication: 22.06.2005
DOI: 10.1055/s-2005-871563; Art ID: U06105ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.0
8
.2
0
0
5

1866
X. Xu et al.
LETTER
were determined on the basis of their H and 13C NMR
spectra, LC-MS, and elemental analyses. The diastereo-
meric ratio (1:8–9) of 12 to 13 remained constant regard-
less of the N-substituent on the heterocycles (Table 1,
entries 1, 2, 3, 5, 6, and 7), although Boc caused an in-
crease in the yield of non-translocation cyclization prod-
ucts 14 (Table 1, entries 1, 2, and 3 vs 5, 6, and 7).
Replacement of N with O resulted in an increase in the
yield of product 12d (Table 1, entry 4). Varying the ring-
size from five to six (Table 1, entries 1 vs 3 and 5 vs 7) had
no effect on the product ratio, neither did placing a meth-
oxy group at the para-position of the phenyl ring (Table 1,
entries 1 vs 2 and 5 vs 6). In the case of optically active
substrates 5a, 5b, 5e, and 5f (Table 1, entries 1, 2, 5, and
6) no optical rotation of their corresponding products 12
and 13 was observed (14 was not measured due to the
small amount obtained), which indicated complete race-
mization at the initial chiral a-position. All these facts are
consistent with a plane of symmetry at the translocated
radical center at the a-position that is stabilized by the
captodative effect with the adjacent heteroatom and
carbonyl group.
1
NH2
R
O
O
Br
n
DCC, CH2Cl2
r.t.
n
+
OH
N
X
H
X
Br
R
10
9
11
11a n = 1, X = NBoc, R = H, 95%
11b n = 1, X = NBoc, R = OMe, 97%
11c n = 2, X = NBoc, R = H, 93%
11d n = 1, X = O, R = H, 94%
O
N
n
DMSO, KOH, r.t.
allyl bromide
X
Br
R
5a - 5d
5a n = 1, X = NBoc, R = H, 83%
5b n = 1, X = NBoc, R = OMe, 85%
5c n = 2, X = NBoc, R = H, 80%
5d n = 1, X = O, R = H, 86%
HCl(g)/EtOAc
5g n = 2, X = NH, R = H, 94%
5f n = 1, X = NH, R = OMe, 96%
5e n =1, X = NH, R = H, 92%
Scheme 2 Preparation of the radical precursors 5
The stereochemical configuration of compound 13f was
determined on the basis of X-ray diffraction analysis
(Figure 2). Its NOESY spectrum (Figure 3) is consistent
with the X-ray structure. As shown in Figure 3 there is a
clear NOE effect between one of the protons at C-4 (1.91–
2.03 ppm) and the methyl protons at C-9 (1.15 ppm) indi-
cating that they are close to each other. The stereochemis-
try of 13b was confirmed by its conversion to 13f after
treatment with hydrochloric acid in ethyl acetate.9 The
stereochemical structures of the rest of the products 12
and 13 were assigned by analogy with their NMR spectra.
The stereochemical configuration of 14 was not deter-
mined.
A routine method using AIBN6c as an initiator was applied
to the radical reactions of compounds 5;8 translocation
cyclization aza/oxaspirolactams 12 and 13, along with
non-translocation cyclization products 14 resulted. It was
observed that the ratio of 12a, 13a, and 14a was un-
changed when the concentration of starting 5a was varied
(0.1 M, 0.05 M, 0.01 M). Several substrates 5 with differ-
ent heteroatoms (X = N or O) on the ring, different ring
size (n = 1 or 2), or different substituent on the nitrogen of
the heterocycle (X = N-Boc or NH) were investigated.
The results are summarized in Table 1. All the structures
Table 1 Cascade Radical Reaction of 5 Leading to Aza/Oxaspirolactam 12, 13, and Compound 14
R
R
O
n
N
R
O
O
X
n-Bu3SnH/AIBN
n
N
R
Br
N
N
n
n
+
+
slow addition
X
X
X
O
5
13
14
12
Entry
5
a
b
c
d
e
f
n
1
1
2
1
1
1
2
R
X
12 (%)a
a (7)
b (7)
c (6)
13 (%)
a (52)
b (51)
c (50)
d (38)
e (64)
f (66)
g (65)
14 (%)
a (25)
b (22)
c (23)
d (23)
e (9)
1
2
3
4
5
6
7
H
N-Boc
N-Boc
N-Boc
O
OMe
H
H
d (25)
e (7)
H
NH
OMe
H
NH
f (7)
f (8)
g
NH
g (7)
g (9)
Synlett 2005, No. 12, 1865–1868 © Thieme Stuttgart · New York

LETTER
Synthesis of Aza/Oxaspiro-g-lactams by Radical Translocation Cyclization Reactions
1867
In summary, the N-allyl-N-(2¢-bromoaryl)amide moiety
of heterocyclic 2-carboxylic acids and their N-propynyl
analogues were found to undergo radical translocation
cyclization to form aza/oxaspirolactams in good yield.
This approach provides a convenient methodology for the
preparation of aza/oxaspirolactams that may be used as
peptidomimetics in drug discovery.
Acknowledgment
This work was supported by a grant from Jilin Provincial Fund for
Young Talented Scientists (No. 20010105) and by Changchun
Discovery Sciences, Ltd.
References
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Gedrath, I.; Walter, A. Bioorg. Chem. 1999, 185.
(b) Hanessian, S.; McNaughton-Simth, G.; Lombart, H.-G.;
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(d) Alonso, E.; López-Ortiz, F.; Del Pozo, C.; Peralta, E.;
Macías, A.; Gonzalez, J. J. Org. Chem. 2001, 66, 6333.
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(3) (a) Fernández, M. M.; Diez, A.; Rubiralta, M.; Montenegro,
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(b) Genin, M. J.; Gleason, W. B.; Johnson, R. L. J. Org.
Chem. 1993, 58, 860.
Figure 2 X-ray structure of compound 13f
OMe
1.91–2.03 ppm
H
O
4
N
H
N
H
H3C
9
1.15 ppm
Figure 3 NOESY spectra of compound 13f
(4) Braña, M. F.; Garranzo, M.; Pascual, T. B.; Pérez-Castells,
J.; Torres, M. R. Tetrahedron 2002, 58, 4825.
The above radical transformations could be extended to
N-propynyl analogues 15 of heterocyclic substrates. Un-
like compounds 5, precursors 15, prepared in a similar
procedure using 3-bromopropyne instead of allyl bro-
mide, underwent only radical translocation cyclization to
afford products 16 under similar conditions. As shown in
Table 2, exo-cyclized products 16 were obtained in mod-
erate to good chemical yields.
(5) (a) Ganguly, A. K.; Seah, N.; Popv, V.; Wang, C. H.; Kuang,
R.; Saksena, A. K.; Pramanik, B. N.; Chan, T. M.; McPhail,
A. T. Tetrahedron Lett. 2002, 43, 8981. (b) Nair, V.;
Rajesh, C.; Dhanya, R.; Rath, N. P. Tetrahedron Lett. 2002,
43, 5349. (c) Nair, V.; Sheela, K. C.; Rath, N. P. Chem. Lett.
2000, 9, 980.
Table 2 Cascade Radical Reaction of 15 Leading to Aza/Oxaspirolactam 16
R
R
O
n
O
O
N
n-Bu3SnH/AIBN
HCl(g)/EtOAc
X
N
N
n
n
Br
slow addition
X
N
H
15
R
17
16
Entry
15
a
X
n
1
2
1
1
R
16 (%)
a (80)
b (75)
c (79)
d (55)
17 (%)
a (91)
b (90)
c (94)
1
2
3
4
N-Boc
N-Boc
N-Boc
O
H
b
H
c
OMe
H
d
Synlett 2005, No. 12, 1865–1868 © Thieme Stuttgart · New York

1868
X. Xu et al.
LETTER
(6) For a review see: (a) Robertson, J.; Pillai, J.; Lush, R. K.
Chem. Soc. Rev. 2001, 30, 94. For typical examples see:
(b) Storey, J. M. D. Tetrahedron Lett. 2000, 41, 8173.
(c) Curran, D. P.; Shen, W. J. Am. Chem. Soc. 1993, 115,
6051. (d) Beaulieu, F.; Arora, J.; Veith, U.; Taylor, N. J.;
Chapell, B. J.; Snieckus, V. J. Am. Chem. Soc. 1996, 118,
8727. (e) Curran, D. P.; Xu, J. J. Am. Chem. Soc. 1996, 118,
3142. (f) Curran, D. P.; Yu, H.; Liu, H. Tetrahedron 1994,
50, 7343. (g) Curran, D. P.; Liu, H. T. J. Chem. Soc., Perkin
Trans. 1 1994, 1377. (h) Curran, D. P.; Kim, D.; Liu, H.;
Shen, W. J. Am. Chem. Soc. 1988, 110, 5900. (i) Beaufils,
F.; Dénès, F.; Renaud, P. Org. Lett. 2004, 6, 2563.
Hz), 4.79 (br s, 1 H, D2O exchangeable), 6.89 (d, 2 H, J = 9.0
Hz), 7.53 (d, 2 H, J = 9.0 Hz); 13C NMR (75 MHz, CDCl3):
d = 14.22, 26.10, 35.32, 37.67, 47.47, 52.97, 55.44, 71.07,
114.02, 121.26, 132.95, 156.49, 176.39; MS (ESI): m/z =
261.1 [M + H+]; Anal. Calcd for C15H20N2O2: C, 69.20; H,
7.74; N, 10.76. Found: C, 68.02; H, 7.65; N, 10.83.
Compound 13f: 66%; light yellowish solid; mp 82.4–83.6
°C. 1H NMR (300 MHz, CDCl3): d = 1.15 (d, 3 H, J = 7.2
Hz), 1.59–1.69 (m, 1 H), 1.76–1.86 (m, 1 H), 1.91–2.03 (m,
2 H), 2.31–2.39 (m, 1 H), 2.97–3.04 (m, 1 H), 3.23–3.30 (m,
2 H), 3.68–3.73 (m, 1 H, J = 7.5 Hz, J = 9.6 Hz), 3.80 (s, 3
H), 4.78 (br s, 1 H, D2O exchangeable), 6.90 (d, 2 H, J = 9.0
Hz), 7.53 (d, 2 H, J = 9.0 Hz); 13C NMR (75 MHz, CDCl3):
d = 11.89, 26.26, 28.78, 39.34, 47.62, 52.08, 55.44, 70.64,
114.02, 121.09, 132.80, 156.47, 177.70; MS (ESI): m/z =
261.1 [M + H+]; Anal. Calcd for C15H20N2O2: C, 69.20; H,
7.74; N, 10.76. Found: C, 68.97; H, 7.62; N, 10.51.
(7) (a) Sato, T.; Yamazaki, T.; Nakanishi, Y.; Uenishi, J.; Ikeda,
M. J. Chem. Soc., Perkin Trans. 1 2002, 1438. (b) Takasu,
K.; Ohsato, H.; Ihara, M. Org. Lett. 2003, 5, 3017.
(c) Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Schulte, M.;
Jones, K. Chem. Commun. 2001, 209.
(8) Genenal procedure: To a stirred solution of 5 (2 mmol) in
degassed toluene (50 mL), Bu3SnH (0.688 mL, 2.4 mmol)
and AIBN (33 mg, 0.2 mmol) in toluene (20 mL) were added
dropwise over 7 h using a syringe pump under reflux. After
addition, the solution was heated at reflux for a further 2 h.
The solvent was removed, and the residue was purified by
flash chromatography on silica gel (petroleum ether–
EtOAc, 5:1–1:1) to give products 12, 13, and 14 (order of
elution).
Compound 14f: 8%; light yellowish oil. 1H NMR (300 MHz,
CDCl3): d = 1.35 (d, 3 H, J = 6.9), 1.78–1.89 (m, 2 H), 2.17–
2.25 (m, 1 H), 2.88–2.91 (m, 1 H), 3.20–3.25 (m, 1 H), 3.44–
3.58 (m, 2 H), 3.64–3.70 (m, 1 H), 3.80 (s, 3 H), 3.91–3.93
(m, 1 H), 4.18–4.32 (m, 1 H), 4.76 (br s, 1 H, D2O
exchangeable), 6.73 (d, 2 H), 8.10 (m, 1 H); MS (ESI):
m/z = 261.1 [M + H+].
(9) To a solution of 13b (180 mg, 0.5 mmol) in EtOAc (4 mL)
at r.t. was added a saturated solution of HCl in EtOAc (5
mL). After stirring for 2 h, the reaction was quenched with
30 % aq NaOH, and extracted with EtOAc (3 × 15 mL).The
organic layer was washed with brine (2 × 10 mL), dried over
MgSO4, and concentrated in vacuo to give 13f (113 mg,
87%) as a light yellowish solid (mp 82.1–84.0 °C).
Compound 12f: 7%; light yellowish oil. 1H NMR (300 MHz,
CDCl3): d = 1.10 (d, 3 H, J = 7.2 Hz, 1.79–1.89 (m, 2 H),
1.92–2.04 (m, 2 H), 2.21–2.26 (m, 1 H), 2.87–2.95 (m, 1 H),
3.22–3.30 (m, 1 H), 3.34–3.38 (dd, 1 H, J = 3.6 Hz, J = 9.6
Hz), 3.80 (s, 3 H), 3.81–3.86 (dd, 1 H, J = 6.3 Hz, J = 9.8
Synlett 2005, No. 12, 1865–1868 © Thieme Stuttgart · New York