A straightforward approach to the galanthan ring system using the imine Michael reaction followed by a radical cyclization

Article abstract of DOI:10.1016/S0040-4039(01)01679-3

A two-step procedure based on the Michael reaction of imines followed by a radical cyclization has proved to be a regioselective and stereoselective method for the construction of the skeleton of galanthan-type alkaloids.

Full text of DOI:10.1016/S0040-4039(01)01679-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7823–7827
A straightforward approach to the galanthan ring system using
the imine Michael reaction followed by a radical cyclization
Ivan Jabin* and Pierre Netchita¨ılo
URCOM, Universite´ du Havre, Faculte´ des Sciences et Techniques, 25 rue Philippe Lebon, BP 540,
76058 Le Havre Cedex, France
Received 25 June 2001; accepted 7 September 2001
Abstract—A two-step procedure based on the Michael reaction of imines followed by a radical cyclization has proved to be a
regioselective and stereoselective method for the construction of the skeleton of galanthan-type alkaloids. © 2001 Elsevier Science
Ltd. All rights reserved.
The Michael type reaction of imines with electrophilic
olefins can afford stereoselectively polycyclic function-
alized enamides.1 Since numerous alkaloids possess
polycyclic aza-heterocycles structures, our aim was to
develop a simple procedure based on the Michael type
reaction of imines for the stereoselective approach to
the skeleton of biologically important alkaloids. Our
synthetic strategy was directed toward the preparation
of type I and II polycyclic structures (Scheme 1). A
straightforward construction of type I skeleton would
constitute an interesting approach of the galanthan ring
system III, common to many Amaryllidacae alkaloids.
Most natural substances of this family possess impor-
tant biological activities, as for instance lycorine IV.2 In
the literature, the C-ring of the galanthan ring system is
generally prepared through an intramolecular Diels–
Alder reaction and a subsequent radical cyclization
usually affords the B-ring.3 In the present paper, we
describe a new synthetic route for the elaboration of
type I and II structures based on a Michael type
reaction of easily available imines followed by a radical
cyclization. The electrophilic olefins used for the
Michael reactions were maleic anhydride and phenyl
acrylate4 since these olefins are known5 to lead in situ
to 5- or 6-ring enamides, respectively (Scheme 1). Con-
trol of the stereochemistry of the B/C-ring junction is
an important aspect of this approach; therefore,
stereoselectivity of the two key steps will be discussed.
In order to study the feasibility of our synthetic
approach and in particular the regioselectivity of the
radical cyclization (5-exo versus 6-endo cyclization), we
Scheme 1.
Keywords: imines; Michael reaction; radical cyclization; stereoselectivity; galanthan.
* Corresponding author. Tel.: +332 32 74 43 94; fax: +332 32 74 43 91; e-mail: ivan.jabin@univ-lehavre.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01679-3

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I. Jabin, P. Netchita¨ılo / Tetrahedron Letters 42 (2001) 7823–7827
11 gave the expected cyclized compounds 10 and 12 in
good yields (79 and 91%, respectively) without any
significant amount of reduced compounds. Cyclization
of lactam 9a proceeded stereoselectively since a 79:2112
mixture of only two diastereomers (10a7 and 10b7) was
obtained. These compounds were separated by FC and
first performed the Michael reaction with a model, i.e.
an acyclic imine. Thus, crude imine 26 was reacted on
one hand with maleic anhydride (1.1 equiv., THF, rt,
15 h) and on the other hand with phenyl acrylate (1.1
equiv., neat, rt, 15 h). The resulting cyclized Michael
adducts 37 (produced after esterification of the interme-
diate lactam acid: 1.1 equiv. of DCC, trace of DMAP,
MeOH/CH2Cl2, rt, 1 h) and 57 were obtained, respec-
tively, in 29 and 36% overall yields from 1. Both radical
cyclizations8 proceeded regioselectively giving tricyclic
lactams 47 and 67 in 74 and 88% yields, respectively
(Scheme 2). It is known that radical cyclizations with
cyclic enamides generally produce an important amount
of the uncyclized product of reduction.3,9 To our
delight, with starting enamides 3 and 5 these undesired
reduced products were not formed in both cases. A
similar result was reported previously on very closely
related compounds.10 Radical cyclization of 3 pro-
ceeded with a good diastereoselectivity (85:15, deter-
1
their stereochemistry was determined by H NMR and
NOEDIFF experiments. For instance, 10a and 10b
exhibit coupling constants for Ha of 11.7 and 3.9 Hz,
which are compatible for trans and cis ring junctions,
respectively. The presence of the trans-B/C ring fusion
in the major diastereomer 10a, which was a requisite
for a stereoselective approach of lycoryne-type alka-
loids, is in agreement with earlier literature
reports.3,9a,9b,10 This result is consistent with studies on
closely related enamides dealing with facial selectivity
during radical cyclization.9a First, it was suggested that
the b face of the enamide double bond is sterically more
accessible and secondly that the stereoselectivity of the
reduction with Bu3SnH correlates with product stabil-
ity. On the other hand cyclization of lactam 11 pro-
ceeded with a poor stereoselectivity since the four
possible diastereomers (12a,7 12b,7 12c7 and 12d7) were
formed in close relative proportions. Compared to the
cyclization of 9a, the loss of stereoselectivity for reduc-
tion of the intermediate tertiary radical presumably
results from the loss of large ring strain difference
between the diastereomers of 12. These diastereomers
were separated by FC and their stereochemistry was
1
mined by H NMR analysis of crude 4) but cis and
trans diastereomers were not separable by FC11 and
therefore the stereochemistry of the major diastereomer
was not determined.
We have then tested our approach with the cyclic imine
8.6 Thus, Michael reactions with maleic anhydride (1.1
equiv., THF, rt, 15 h, then esterification of the interme-
diate lactam acid: 1.1 equiv. of DCC, trace of DMAP,
MeOH/CH2Cl2, rt, 1 h) and with phenyl acrylate (1.1
equiv., neat, rt, 15 h) led, respectively, to lactams 9 and
117 in 48 and 53% overall yields from 7. Lactam 9 was
obtained as a 83:1712 mixture of cis/trans diastereomers
(9a7 and 9b7), which were separated by FC. The
diastereoselectivity of the Michael reaction is in accor-
dance with theoretical studies1g,h and with previous
results on closely related compounds.1a The relative
configuration of the major diastereomer (i.e. cis) is
given by analogy with these earlier results and has been
confirmed with the stereochemical assignment for com-
pound 10a.7 Radical cyclizations8 of enamides 9a and
1
determined by H NMR and NOEDIFF experiments.13
In particular, the major isomer 12a exhibits a coupling
constant of 7.0 Hz for Hb (cis-B/C ring fusion) and
isomer 12d a coupling constant of 11.7 Hz for Hc
(trans-B/C ring fusion) (Scheme 3).
Scheme 2.
Scheme 3.

I. Jabin, P. Netchita¨ılo / Tetrahedron Letters 42 (2001) 7823–7827
7825
Scheme 4.
References
Finally, a study on the regioselectivity of the radical
cyclization has been undertaken in order to see if 5-exo
cyclization can take place with our enamide system.
Thus, an enamide (i.e. lactam 15) which can cyclize
only through a 5-exo way was prepared. The Michael
reaction of crude enaminone 146 with phenyl acrylate
(1.3 equiv., 1,4-dioxane, 110°C, 3 days) yielded lactam
157 (58% overall yield from 13) and its radical cycliza-
tion led to a 54:4612 mixture of spirocyclic lactam 167
(38% yield) and reduced compound 177 (34% yield)
(Scheme 4). This result suggests that 5-exo cyclization
of enamides 3, 5, 9a and 11 could have taken place, but
it is less favorable than the 6-endo one. It is noteworthy
1. (a) Pfau, M.; Tomas, A.; Lim, S.; Revial, G. J. Org. Chem.
1995, 60, 1143–1147; (b) Jabin, I.; Revial, G.; Tomas, A.;
Lemoine, P.; Pfau, M. Tetrahedron: Asymmetry 1995, 6,
1795–1812; (c) Jabin, I.; Revial, G.; Pfau, M.; Decroix, B.;
Netchita¨ılo, P. Org. Lett. 1999, 1, 1901–1904; (d) Revial,
G.; Jabin, I.; Pfau, M. Tetrahedron: Asymmetry 2000, 11,
4975–4983; (e) Jabin, I.; Revial, G.; Monnier-Benoit, N.;
Netchita¨ılo, P. J. Org. Chem. 2001, 66, 256–261; (f) Revial,
G.; Jabin, I.; Redolfi, M.; Pfau, M. Tetrahedron: Asymme-
try 2001, 12, 1683–1688; (g) Sevin, A.; Tortajada, J.; Pfau,
M. J. Org. Chem. 1986, 51, 2671–2675; (h) Sevin, A.;
Masure, D.; Giessner-Prettre, C.; Pfau, M. Helv. Chim.
Acta 1990, 73, 552–573.
2. (a) Cook, J. W.; Loudon, J. D. In The Alkaloids; Manske,
R. H. F.; Holmes, H. L., Eds.; Academic Press: New York,
1952; Vol. 2, p. 331; (b) Ghosal, S.; Saini, K. S.; Razdan,
S. Phytochemistry 1985, 24, 2141.
3. Padwa, A.; Brodney, M. A.; Lynch, S. M. J. Org. Chem.
2001, 66, 1716–1724 and references cited therein.
4. Phenyl acrylate was prepared according to the literature:
Ahlbretch, A.; Codding, D. W. J. Am. Chem. Soc. 1953,
75, 984.
that the lactam 16 was obtained as
a single
diastereomer. This result can be rationalized if we
suppose that the diastereomer of 16, which would have
been produced by a-facial attack of the double bond,
has important ring strain and is thus not formed.
Moreover, the reaction was also performed under the
1
same conditions but with Bu3SnD. In this case, the H
NMR analysis of the deuterated compound 17 revealed
the presence of the deuterium atom at the allylic posi-
tion instead of the expected aromatic one. This result
shows that formation of 17 does not result from direct
reduction of the aryl radical, but that intramolecular
allylic to aryl 1,6-hydrogen atom transfer followed by
reduction takes place.
5. See Ref. 1c.
6. Imines 2, 8 and enaminone 14 were obtained from the
corresponding ketones and 2-bromobenzylamine (1 equiv.)
in refluxing toluene in a Dean–Stark water separator for
24 h.
7. 3: oil, EIMS m/z (rel. int.) 367 (M+, <1), 286 (base), 254
In conclusion, we have reported a two-step procedure
based on the Michael reaction of imines followed by a
radical cyclization, which can lead regioselectively to
polycyclic lactams. The stereoselectively of the radical
cyclization depends on the nature of the starting
bicyclic enamide. Moreover, we have shown the syn-
thetic utility of this procedure with a stereoselective
approach of lycoryne-type alkaloids. The application of
this study to chiral imines and other electrophilic olefins
is under investigation in our Laboratory in order to
develop straightforward enantioselective syntheses of
galanthan alkaloids.
(74), 226 (42), 169 (32), 90 (32). IR (neat) 1721, 1654 cm−1
.
1H NMR (200 MHz, CDCl3) l 1.11 (s, 3H), 1.31 (s, 3H),
2.47 (dd, J1=8.6 Hz, J2=16.4 Hz, 1H), 2.83 (dd, J1=6.3
Hz, J2=16.4 Hz, 1H), 3.02 (dd, J1=6.3 Hz, J2=7.8 Hz,
1H), 3.73 (s, 3H), 4.08 (d, J=2.3 Hz, 1H), 4.15 (d, J=2.3
Hz, 1H), 4.74 (s, 2H), 6.95 (dd, J1=1.6 Hz, J2=7.8 Hz,
1H), 7.09 (ddd, J1=1.6 Hz, J2:J3:8 Hz, 1H), 7.22 (ddd,
J1=1.6 Hz, J2:J3:8 Hz, 1H), 7.53 (dd, J1=1.6 Hz,
J2=7.8 Hz, 1H). 13C NMR (50 MHz, CDCl3) l 25.38,
27.49, 31.03, 40.43, 44.30, 48.60, 52.40, 84.97, 123.1, 127.6,
128.0, 129.1, 133.2, 134.8, 155.6, 173.0, 175.3.
4 (major diastereomer): oil, EIMS m/z (rel. int.) 287 (M+,
92), 272 (31), 256 (24), 227 (25), 132 (58), 130 (49), 104
(base). IR (neat) 1738, 1682 cm−1. H NMR (200 MHz,
1
Acknowledgements
CDCl3) l 0.87 (s, 3H), 1.17 (s, 3H), 2.31 (dd, J1=7.8 Hz,
J2=15.7 Hz, 1H), 2.62–2.92 (m, 4H), 3.39 (dd, J1=4.1 Hz,
J2=10.3 Hz, 1H), 3.70 (s, 3H), 4.42 (d, J=17.2 Hz, 1H),
4.59 (d, J=17.2 Hz, 1H), 7.06–7.30 (m, 4H). 13C NMR (50
MHz, CDCl3) l 17.70, 25.52, 30.03, 30.20, 41.01, 43.48,
50.75, 52.16, 62.83, 127.1, 127.2, 128.9, 132.1, 134.4, 173.4,
174.4.
We thank the students of the MST CIC RSA1 2001
class for the preliminary study made during their prac-
tical work and Dr. G. Revial and Dr. M. Pfau for their
help.

7826
I. Jabin, P. Netchita¨ılo / Tetrahedron Letters 42 (2001) 7823–7827
5: white solid, mp 65°C (hexane), EIMS m/z (rel. int.) 309
(M++1, <1), 307 (M+−1, <1), 228 (base), 171 (20), 90 (25).
IR (CHCl3) 1666, 1620 cm−1 1H NMR (200 MHz,
3.67 (s, 3H), 4.44 (d, J=18.0 Hz, 1H), 4.61 (d, J=18.0
Hz, 1H), 7.08–7.25 (m, 4H). 13C NMR (50 MHz, CDCl3)
l 18.38, 21.46, 30.15, 31.80, 35.30, 38.31, 39.11, 43.15,
51.84, 52.31, 60.03, 127.2, 127.3, 127.4, 129.0, 130.7,
138.9, 172.7, 176.6.
.
CDCl3) l 1.20 (s, 6H), 1.72 (t, J=7.0 Hz, 2H), 2.69 (t,
J=7.0 Hz, 2H), 4.10 (d, J=2.3 Hz, 1H), 4.27 (d, J=2.3
Hz, 1H), 4.96 (s, 2H), 6.88 (d, J=7.8 Hz, 1H), 7.06 (ddd,
J1=1.6 Hz, J2:J3:8 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H),
7.52 (dd, J1=1.6 Hz, J2=7.8 Hz, 1H). 13C NMR (50
MHz, CDCl3) l 27.96, 29.80, 33.47, 34.42, 48.60, 92.13,
122.8, 127.0, 127.8, 128.6, 133.0, 135.9, 152.7, 169.8.
Anal. calcd for C15H18BrNO: C, 58.45; H, 5.89; N, 4.54.
Found: C, 58.37; H, 5.91; N, 4.63.
11: white solid, mp 73°C (hexane:EtOAc, 7:3), EIMS m/z
(rel. int.) 335 (M++1, 3), 333 (M+−1, 3), 254 (base). IR
(neat) 1670, 1644 cm−1 1H NMR (200 MHz, CDCl3) l
.
1.13 (s, 3H), 1.35–2.15 (m, 8H), 2.68 (dd, J1=7.0 Hz,
J2=10.7 Hz, 1H), 4.49 (d, J=16.7 Hz, 1H), 4.72 (dd,
J1=2.7 Hz, J2=4.8 Hz, 1H), 5.23 (d, J=16.7 Hz, 1H),
6.87 (d, J=7.5 Hz, 1H), 7.04 (ddd, J1=1.6 Hz, J2:J3:8
Hz, 1H), 7.19 (ddd, J1=1.6 Hz, J2:J3:8 Hz, 1H), 7.49
(dd, J1=1.6 Hz, J2=8.1 Hz, 1H). 13C NMR (50 MHz,
CDCl3) l 17.80, 23.01, 24.65, 29.34, 32.60, 34.36, 38.16,
48.58, 106.1, 122.5, 127.0, 127.6, 128.3, 132.7, 136.2,
142.2, 169.0. Anal. calcd for C17H20BrNO: C, 61.09; H,
6.03; N, 4.19. Found: C, 60.73; H, 6.02; N, 4.21.
6: white solid, mp 104°C (hexane:EtOAc, 10:1), EIMS
m/z (rel. int.) 229 (M+, 81), 173 (21), 145 (base), 104 (94).
IR (CHCl3) 1634 cm−1 1H NMR (200 MHz, CDCl3) l
.
1.03 (s, 3H), 1.12 (s, 3H), 1.53 (ddd, J1:J2:6 Hz,
J3=13 Hz, 1H), 1.76 (ddd, J1:J2:7 Hz, J3=14 Hz,
1H), 2.58 (t, J=6.3 Hz, 2H), 2.68–2.92 (m, 2H), 3.27 (dd,
J1=3.9 Hz, J2=11.0 Hz, 1H), 4.36 (d, J=17.2 Hz, 1H),
5.18 (d, J=16.4 Hz, 1H), 7.03–7.20 (m, 4H). 13C NMR
(50 MHz, CDCl3) l 23.75, 27.03, 28.76, 31.77, 31.91,
31.96, 46.48, 63.86, 126.7, 127.0, 127.1, 128.6, 132.8,
134.5, 170.2. Anal. calcd for C15H19NO: C, 78.56; H,
8.35; N, 6.11. Found: C, 78.48; H, 8.43; N, 6.21.
12a: white solid, mp 138–140°C (hexane:EtOAc, 3:2),
EIMS m/z (rel. int.) 255 (M+, base), 254 (58), 130 (46). IR
1
(CHCl3) 1622 cm−1. H NMR (200 MHz, CDCl3) l 0.15
(s, 3H), 1.11–1.90 (m, 7H), 2.25–2.70 (m, 3H), 3.17 (sl,
1H), 3.68 (d, J=7.0 Hz, 1H), 3.81 (d, J=14.9 Hz, 1H),
5.50 (d, J=14.9 Hz, 1H), 7.10–7.50 (m, 4H). 13C NMR
(50 MHz, CDCl3) l 17.31, 17.72, 25.03, 29.04, 34.78,
34.94, 37.38, 38.89, 42.32, 60.86, 123.4, 126.4, 126.5,
128.0, 135.9, 138.5, 170.3. Anal. calcd for C17H21NO: C,
79.96; H, 8.29; N, 5.49. Found: C, 79.52; H, 8.68; N,
5.58.
9a: oil, EIMS m/z (rel. int.) 393 (M++1, 3), 391 (M+−1,
3), 313 (21), 312 (base), 252 (56), 171 (28), 169 (30). IR
(neat) 1754–1654 cm−1 1H NMR (200 MHz, CDCl3) l
.
1.09 (s, 3H), 1.50–2.15 (m, 6H), 2.45 (dd, J1=10.1 Hz,
J2=18.0 Hz, 1H), 2.83–2.98 (m, 2H), 3.71 (s, 3H), 4.61
(d, J=16.4 Hz, 1H), 4.71 (t, J=3.9 Hz, 1H), 4.77 (d,
J=16.4 Hz, 1H), 7.00 (dd, J1=1.6 Hz, J2=7.8 Hz, 1H),
7.08 (ddd, J1=1.6 Hz, J2:J3:8 Hz, 1H), 7.22 (ddd,
J1=1.6 Hz, J2:J3:8 Hz, 1H), 7.51 (dd, J1=1.6 Hz,
J2=7.8 Hz, 1H). 13C NMR (50 MHz, CDCl3) l 18.47,
21.22, 23.02, 29.91, 34.17, 39.93, 43.97, 50.92, 52.26,
99.58, 123.1, 127.9, 128.1, 129.1, 133.1, 135.5, 144.1,
173.2, 174.9.
1
12b: oil, EIMS m/z (rel. int.) 255 (M+, base), 254 (47) H
NMR (200 MHz, CDCl3) l 1.09–1.87 (m, 7H), 1.14 (s,
3H), 2.17–2.91 (m, 4H), 2.95 (d, J=12.1 Hz, 1H), 4.08 (d,
J=16.8 Hz, 1H), 5.67 (d, J=16.8 Hz, 1H), 7.00–7.30 (m,
4H). 13C NMR (50 MHz, CDCl3) l 21.16, 26.70, 26.75,
28.90, 29.78, 32.19, 39.42, 40.46, 46.33, 66.00, 125.9,
126.6, 126.7, 126.8, 133.4, 138.5, 168.1.
12c: EIMS m/z (rel. int.) 255 (M+, base), 254 (43), 130
(30).
9b: oil, EIMS m/z (rel. int.) 393 (M++1, 5), 391 (M+−1,
5), 312 (base), 280 (33), 252 (64), 171 (31), 169 (34). IR
12d: oil, EIMS m/z (rel. int.) 255 (M+, 88), 254 (base). IR
(neat) 1738–1681 cm−1
.
1H NMR (200 MHz, CDCl3) l
(neat) 1633 cm−1. H NMR (200 MHz, CDCl3) l 1.02 (s,
1
1.13–2.20 (m, 6H), 1.29 (s, 3H), 2.38–2.58 (m, 2H),
2.81–3.00 (m, 1H), 3.70 (s, 3H), 4.59 (d, J=16.4 Hz, 1H),
4.68–4.79 (m, 2H), 7.00 (d, J=7.0 Hz, 1H), 7.10 (dd,
J1:J2:8 Hz, 1H), 7.24 (dd, J1:J2:7 Hz, 1H), 7.53 (d,
J=7.5 Hz, 1H).
3H), 1.10–1.90 (m, 8H), 2.40–2.78 (m, 3H), 2.86 (d,
J=11.7 Hz, 1H), 4.09 (d, J=16.4 Hz, 1H), 5.21 (d,
J=16.4 Hz, 1H), 7.07–7.40 (m, 4H). 13C NMR (50 MHz,
CDCl3) l 15.92, 20.53, 28.54, 29.46, 34.58, 35.59, 36.21,
38.35, 44.58, 64.70, 123.9, 126.8, 126.9, 127.6, 133.6,
139.4, 170.4.
10a: white solid, mp 144–145°C (hexane:EtOAc, 1:2),
EIMS m/z (rel. int.) 313 (M+, base), 238 (34), 212 (39),
210 (82), 130 (28). IR (CHCl3) 1734, 1682 cm−1. 1H NMR
(200 MHz, CDCl3) l 1.03 (s, 3H), 1.10–1.93 (m, 5H),
2.28–2.41 (m, 1H), 2.37 (dd, J1=8.6 Hz, J2=15.6 Hz,
1H), 2.54 (ddd, J1=3.1 Hz, J2:J3:11 Hz, 1H), 2.78 (d,
J=11.7 Hz, 1H), 2.84 (dd, J1=5.5 Hz, J2=16.4 Hz, 1H),
3.03 (dd, J1=6.5 Hz, J2=8.6 Hz, 1H), 3.71 (s, 3H), 4.31
(d, J=17.2 Hz, 1H), 5.07 (d, J=17.2 Hz, 1H), 7.05–7.28
(m, 4H). 13C NMR (50 MHz, CDCl3) l 21.75, 24.82,
24.95, 29.97, 33.59, 38.06, 39.49, 44.06, 45.01, 52.22,
65.69, 124.7, 126.7, 126.8, 126.9, 132.6, 139.1, 173.6,
175.0. Anal. calcd for C19H23NO3: C, 72.82; H, 7.40; N,
4.47. Found: C, 72.84; H, 7.45; N, 4.32.
15: yellow solid, mp 127–129°C (hexane:EtOAc, 3:7),
EIMS m/z (rel. int.) 335 (M++1, 8), 333 (M+−1, 8), 254
(base), 171 (25), 169 (26). IR (CHCl3) 1694, 1644, 1614
1
cm−1. H NMR (200 MHz, CDCl3) l 1.86–2.01 (m, 2H),
2.30–2.43 (m, 4H), 2.66 (s, 4H), 5.00 (s, 2H), 6.85 (d,
J=7.8 Hz, 1H), 7.12 (ddd, J1=1.6 Hz, J2:J3:8 Hz,
1H), 7.25 (ddd, J1=1.6 Hz, J2:J3:8 Hz, 1H), 7.55 (dd,
J1=1.6 Hz, J2=7.8 Hz, 1H). 13C NMR (50 MHz,
CDCl3) l 17.42, 22.06, 26.49, 31.33, 36.28, 45.73, 117.0,
122.3, 126.5, 128.3, 129.2, 133.4, 135.9, 155.0, 171.3,
196.6. Anal. calcd for C16H16BrNO2: C, 57.50; H, 4.83;
N, 4.19. Found: C, 57.49; H, 4.92; N, 4.28.
16: white solid, mp 149–150°C (hexane:EtOAc, 1:2),
EIMS m/z (rel. int.) 255 (M+, 47), 212 (base), 185 (97),
184 (47), 156 (35). IR (CHCl3) 1713, 1640 cm−1. 1H NMR
(200 MHz, CDCl3) l 1.50–2.70 (m, 11H), 4.43 (d, J=15.6
Hz, 1H), 5.11 (d, J=15.6 Hz, 1H), 6.90 (d, J=7.1 Hz,
10b: oil, EIMS m/z (rel. int.) 313 (M+, base), 270 (80),
240 (64), 210 (36). 1H NMR (200 MHz, CDCl3) l 1.09 (s,
3H), 1.12–1.78 (m, 6H), 2.49–2.66 (m, 3H), 2.86 (ddd,
J1=3.9 Hz, J2:J3:9 Hz, 1H), 3.46 (d, J=3.9 Hz, 1H),

I. Jabin, P. Netchita¨ılo / Tetrahedron Letters 42 (2001) 7823–7827
7827
1H), 7.10–7.32 (m, 3H). 13C NMR (50 MHz, CDCl3) l
19.38, 23.70, 30.06, 32.28, 37.17, 49.10, 53.91, 69.91, 122.3,
123.4, 127.3, 128.5, 136.3, 144.4, 167.4, 205.9. Anal. calcd
for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C,
75.22; H, 6.72; N, 5.36.
of AIBN, refluxing benzene, 2 h.
9. (a) Schultz, A. G.; Guzzo, P. R.; Nowak, D. M. J. Org.
Chem. 1995, 60, 8044–8050; (b) Schultz, A. G.; Holoboski,
M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118,
6210–6219.
10. Rigby, J. H.; Mateo, M. E. Tetrahedron 1996, 52, 10569–
10582.
17: oil, EIMS m/z (rel. int.) 255 (M+, 49), 164 (43), 91
1
(base). IR (neat) 1682, 1634 cm−1. H NMR (200 MHz,
CDCl3) l 1.89 (dddd, J1:J2:J3:J4:6 Hz, 2H), 2.18 (dd,
J1:J2:7 Hz, 2H), 2.42 (dd, J1:J2:6 Hz, 2H), 2.58 (s,
4H), 4.95 (s, 2H), 7.00–7.33 (m, 5H). 13C NMR (50 MHz,
CDCl3) l 17.28, 21.93, 26.66, 31.24, 36.12, 45.05, 116.7,
126.1 (2C), 127.6, 129.1 (2C), 137.2, 155.3, 171.2, 196.4.
8. All the radical cyclizations were performed according to
the following procedure: 1.2 equiv. of Bu3SnH, 0.1 equiv.
11. Flash chromatographies (FC) were performed with silica
gel 230–400 Mesh.
12. The relative% values were determined by a GC–MS
analysis of the reaction medium.
13. Except for isomer 12c which has not been separated by FC
and whose stereochemistry has been deduced after assign-
ment of the three other isomers.