Synthesis of 3-aminopyrrolidines by cyclization of neutral C-centered α-aminoalkyl radicals

Article abstract of DOI:10.1016/S0040-4020(02)00621-X

3-Aminopyrrolidines are prepared by SmI₂-promoted cyclization of neutral α-aminoalkyl radicals generated from N-(α-benzotriazolyl)alkenylamines. Appropriate manipulation of the two N-protecting groups allows further manipulation of the products

Full text of DOI:10.1016/S0040-4020(02)00621-X

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 6211±6221
Synthesis of 3-aminopyrrolidines by cyclization of neutral
C-centered a-aminoalkyl radicals
p
  Â
Ruben Suero, Jose M. Gorgojo and Jose M. Aurrecoechea
  Â
Departamento de Quõmica Organica II, Facultad de Ciencias, Universidad del Paõs Vasco, Apartado 644, 48080 Bilbao, Spain
Received 13 March 2002; revised 11 June 2002; accepted 17June 2002
AbstractÐ3-Aminopyrrolidines are prepared by SmI2-promoted cyclization of neutral a-aminoalkyl radicals generated from N-(a-benzo-
triazolyl)alkenylamines. Appropriate manipulation of the two N-protecting groups allows further manipulation of the products, which is
exempli®ed with the preparation of a triamide derivative. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
a-amino radicals 7 and 11, respectively. These would be
derived from aldehydes of general structures 5 or 9, where
a CH2 group of 1 has been replaced by a conveniently
protected amino group. The choice of electron-de®cient
double bonds as radical traps in these reactions was dictated
by previous experience with a-aminoalkyl radicals showing
that the use of electron-withdrawing substituents on the
alkene moiety results in cyclizations that take place under
simpler and milder conditions, as well as with higher yields
and stereoselectivities.3,7,20 While substrates of type 6
contain a double bond with similar electronic and otherwise
character as those previously used in a-amino radical cycli-
zations (Scheme 1), the use of b-aminoacrylate derivatives
(e.g. 10) as radical traps, although known21±25 had not been
investigated to date in reactions of a-aminoalkyl radicals.
The intramolecular addition of neutral C-centered
a-aminoalkyl radicals1 to C±C double bonds has found
extensive application in the synthesis of functionalized
carbocycles and heterocycles.2±7 In these and other applica-
tions various methods for generation of reactive a-amino
radicals have been employed, that include the homolysis of
a C±X bond from suitable a-substituted amino deriva-
tives,8±14 radical addition on enamide derivatives,15 radical
translocation,2,5,16 decarbonylation of b-amino acyl
radicals,4 photochemically-induced electron transfer from
tertiary amines17±19 and SmI2-promoted reduction of
a-aminoalkyl benzotriazoles.3,6,7 This last method can be
particularly convenient in terms of convergence since
cyclization substrates 2 are easily assembled from readily
available aldehyde and secondary amine fragments (Scheme
1). Thus, ef®cient syntheses of cyclopentylamines3 4 and
2,3-dialkylpyrrolidines6,7 have already been reported using
this strategy via 5-exo-trig radical ring closures. Along these
lines, the synthesis of 3-aminopyrrolidines of types 8 and 12
can be easily envisaged through the intermediacy of
The 3-aminopyrrolidine substructure present in products 8
and 12 can be found in a large number of compounds with
an extensive range of biological activities,26±35 and has also
seen application in chromatography36,37 and as chiral
auxiliary in synthesis.38 Earlier to this work, the synthesis
of 3-aminopyrrolidines had mainly involved the structural
Scheme 1.
Keywords: radical cyclizations; pyrrolidines; samarium.
Corresponding author. Tel.: 134-946-01-2578; fax: 134-944-64-8500; e-mail: qopaufem@lg.ehu.es
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00621-X

6212
R. Suero et al. / Tetrahedron 58(2002) 6211±6221
Scheme 2.
modi®cation of preformed pyrrolidine or pyrrolidinone
structures to introduce the 3-amino group31,33,35,38±43 or the
cyclization of appropriate diamine and related pre-
cursors.28±30,34,44±47 However, their convergent preparation
from acyclic precursors and amine derivatives was much
less common.48±53 Therefore, our radical approach to the
convergent synthesis of 3-aminopyrrolidines from readily
available aldehyde (5, 9) and amine fragments would be a
valuable addition to the synthetic repertoire for formation of
these compounds.54 Additionally, if the amino groups
present in products 8 and 12 are orthogonally protected,
further manipulation of up to three functionalized sites
could lead to substantial structural diversity. This paper
reports on the results of our radical cyclization approach
to the direct synthesis of 3-aminopyrrolidines and some
transformations of these leading to more complex
structures.
Following our previously reported protocol,7 aldehydes 5
and 9 were condensed with secondary amines and benzo-
triazole at room temperature to yield adducts of type 6 or 10,
respectively, that were then treated with SmI2/t-BuOH from
2788C to room temperature to afford the expected pyrroli-
dine products 8, 12 (Scheme 3). Results are collected in
Table 1. Adducts 6, 10 were used directly as crude
products;7 therefore, cyclization yields reported in Table 1
are referred in all cases to two steps starting from aldehydes
5 or 9. No cyclic product was obtained starting with benzyl-
amino aldehyde 5a. Condensation of this aldehyde with
morpholine and benzotriazole gave an unstable adduct 6
that even upon immediate treatment with SmI2/t-BuOH,7
resulted in extensive degradation with no characterizable
product being obtained. On the other hand, under the
same reaction conditions, the use of sulfonamido aldehyde
5b led to the formation of the expected 3-aminopyrrolidines
8a±c, that were isolated in moderate yields (Table 1). A
limitation was found in this reaction in that amines contain-
ing allyl or benzyl groups, such as dibenzylamine,
N-methylbenzylamine or diallylamine, did not perform
well. The formation of adducts 6 proceeded normally with
high conversions but the ensuing cyclizations were messy
and the products could not be conveniently puri®ed.55
2. Results and discussion
2.1. Preparation of 3-aminopyrrrolidines
Suitable aldehydes of general structures 5 and 9 were
prepared as outlined in Scheme 2. Thus, alkylation of
N-benzylethanolamine or 2,2-dimethoxyethylamine with
ethyl (E)-4-bromocrotonate, followed by either alcohol
oxidation or tosylation and acetal hydrolysis afforded
aldehydes 5a or 5b, respectively (Scheme 2). On the other
hand, a procedure closely related to that reported for the
N-Cbz aldehyde 9a25a was followed in the preparation of
benzamide 9b and N-Boc aldehyde 9c (Scheme 2). Thus,
secondary amine 13d was acylated with various reagents
and the resulting N-protected diethyl acetals were
hydrolyzed to yield aldehydes 9b,c. In the base-promoted25a
benzoylation of 13d, substantial amounts of the C-acylated
product 16b were obtained, besides the desired benzamide
(Section 4). Upon attempted N-tri¯uoroacetylation of 13d,
under similar base-promoted conditions,25a only the
C-acylated product 16d was observed (Section 4).
A different regiochemical possibility for synthesis of
3-aminopyrrolidines using this radical approach involves
the use of aldehydes of type 9 containing a b-aminoacrylate
moiety. In this case, condensation of 9a25 with amines and
benzotriazole, followed by reduction of the resulting
adducts 10, led in all cases to the expected 3-aminopyrroli-
dines 12 that were isolated in moderate to high yields
Scheme 3.

R. Suero et al. / Tetrahedron 58(2002) 6211±6221
6213
Table 1. Preparation of 3-aminopyrrolidines 8, 12
Aldehyde
R1
R2
Product
Yield (%)a
cis/trans
5b
5b
5b
9a
9a
9a
9a
(CH2)2O(CH2)2
8a
8b
8c
12a
12b
12c
12d
61
58
4755:45
72
82
47:53b
(CH2)2N(Ph)(CH2)2
(CH2)5
(CH2)2O(CH2)2
62:38b
b
40:60b
43:57c
40:60c
40:60c
Me
3,4-Dimethoxyphenethyl
(CH2)2N(Ph)(CH2)2
Bn
Allyl
52
84
a
Two-step yields starting from 5b or 9a.
Diastereomeric ratio determined by weight of isolated diastereoisomers after chromatographic separation.
b
c
1
Diastereomeric ratio determined by H NMR integration on the puri®ed isomer mixture.
(Table 1). Products 12 were obtained as diastereomeric
mixtures from which the individual isomers were readily
separated either by chromatographic or chemical means
(vide infra). This reaction appears to be more general than
that discussed above in that benzyl and allyl groups are well
tolerated in the amino moiety and this results in the
incorporation into the products of functionality useful for
further manipulation (vide infra). The cyclization was
totally ineffective starting from benzotriazole adducts
derived from N-Bz- or N-Boc-protected aldehydes 9b,c, as
only uncharacterized degradation products were observed
upon treatment with SmI2/t-BuOH.
mational changes associated with the shorter ring C±N bond
lengths in this radical compared to the corresponding C±C
in 3. This could in turn lead to a tighter TS where the
combined steric demands of dialkylamino and ethoxy-
carbonylmethyl groups outweigh the stereoelectronic
bene®ts usually associated with a cis-TS.3,60
On the other hand, the low diastereoselectivity observed in
the cyclizations of radicals 11 was not completely
unexpected, as the normal preference for a chair-like TS
18 leading to cis-products3 is now counterbalanced by the
pseudoallylic-1,3-strain that develops between the ethoxy-
carbonylmethyl group and the N-protecting group. This in
fact leads to a slight preference for the trans-isomer through
the alternative boat-like TS 19. A somewhat related pre-
cedent exists in the work of Speckamp where a trans prefer-
ence in pyrrolidine formation was the result of a pseudoaxial
disposition of the radical C-1 substituent (e.g. 20) to avoid
interactions with the N-substituent in the alternative pseudo-
equatorial disposition.61,62
2.2. Stereochemistry of cyclization
The stereochemistry of the 3-aminopyrrolidine products
was assigned in all cases from the observation of an up®eld
shift in the 13C NMR spectrum for the ring C-3 methine
carbon (CH±N) of one diastereoisomer (accordingly
assigned a cis stereochemistry7,56) relative to the other
isomer (Table 2). This assignment was con®rmed
chemically in the case of 12c by spontaneous conversion
of the deallylated cis-isomer into a bicyclic lactam (vide
infra).
Contrary to other a-aminoalkyl radical cyclizations, the
present reactions proceed with poor stereoselectivity. The
lack of stereocontrol observed in the formation of pyrroli-
dines 8 appears surprising. Thus, the all-carbon radical 3
cyclizes with excellent cis-selectivity,3 whereas other
N-tosyl-1-alkyl-3-aza radicals, structurally related to 7,
have been shown to cyclize with a moderate cis-
preference.57±59 The apparently anomalous low selectivity
encountered with radical 7 could then be due to the confor-
Table 2. 13C NMR resonances for C-3 of pyrrolidines 8, 12
2.3. Deprotection-functionalization of 3-amino-
pyrrolidines
8, 12
C-3a
8, 12
C-3a
68.7
68.6
69.4
68.9, 69.8
67.7, 68.6
65.1, 66.1
68.5, 69.5
cis-8a
cis-8b
cis-8c
cis-12a
cis-12bb
cis-12cb
cis-12db
65.4
65.1
65.8
66.0
65.9, 66.5
62.4, 63.2
65.7, 66.4
trans-8a
trans-8b
trans-8c
Compounds 8 and 12 contain three reactive sites including
protected exocyclic and endocyclic N-atoms, as well as an
ethoxycarbonyl group. Therefore, substantial systematic
structural diversi®cation is in principle feasible from these
compounds if adequate deprotection-functionalization
sequences are employed. As an example, selective deprotec-
tion of the allylamine moiety of 12c with Pd(PPh3)4/
NDMBA63 took place in almost quantitative yield with
concomitant cyclization of the deallylated cis-isomer to
afford an easily separable mixture of trans-pyrrolidine
21 and bicyclic lactam 22 (Scheme 4). Gram quantities of
trans-12ab
trans-12bb
trans-12cb
trans-12db
a
Determined on the individually isomers from DEPT experiments, except
for 12b where, additionally, the two isomers were identi®ed in the
mixture according to signal intensity and by analogy with the other
compounds 12.
b
Mixture of rotamers.

6214
R. Suero et al. / Tetrahedron 58(2002) 6211±6221
4. Experimental
4.1. General methods
All reactions involving air- and moisture-sensitive materials
were performed under an atmosphere of dry Ar. Tetra-
hydrofuran (THF) was freshly distilled from sodium/benzo-
phenone and, for reactions with SmI2, it was deoxygenated
prior to use. 2-Methylpropan-2-ol and ethanol were distilled
from Mg/I2. CH2Cl2 and triethylamine were distilled from
CaH2. p-Toluenesulfonyl chloride was puri®ed according to
the reported procedure.64 SmI2 (ca. 0.1 M in THF) was
prepared from Sm and diiodomethane using a literature
procedure.65 Flash chromatography66 was performed on
silica gel (230±400 mesh). HPLC puri®cations were carried
out with a m-Bondapak column (10 mm, 19 mm£15 cm)
using a refraction index detector. Routine 1H and 13C
Scheme 4.
Scheme 5.
21 are readily obtained in this manner. Secondary amine 21
was then processed in high yield to benzamide 23
(Scheme 5). Removal of the Cbz-protection of 23 and a
second acylation provided diamide 25 in high overall
yield. Finally, conversion of the ethoxycarbonyl group of
25 into a secondary amide led to triply functionalized
pyrrolidine 27 through the corresponding carboxylic acid
26 (Scheme 5).
NMR spectra were obtained at 250 and 62.9 MHz, respec-
tively, using CDCl3 as solvent and internal reference (d 7.26
1
for H and d 77.0 for 13C). IR data include only character-
istic absorptions. Mass spectra were obtained at 70 eV.
4.2. Preparation of aldehydes 5, 9
4.2.1. Ethyl (E)-4-[N-benzyl-N-(2-hydroxyethyl)amino]-
but-2-enoate (13a). A solution of ethyl (E)-4-bromobut-2-
enoate (1.00 mL, 7.3 mmol) in THF (5.4 mL) was added
dropwise to a mixture of N-benzylethanolamine (1.09 mL,
7.3 mmol) and K2CO3 (1.33 g, 9.6 mmol) in THF (9.0 mL).
The resulting mixture was stirred at room temperature for
12 h and then ®ltered through Celite. The crude after
evaporation was puri®ed by ¯ash chromatography (60:40
3. Conclusions
The intramolecular addition of 1-amino-3- or 4-azahex-5-
enyl radicals to suitably positioned C±C double bonds
provides an entry into functionalized 3-aminopyrrolidines.
With an appropriate selection of N-substituents, these
products can be manipulated at three different sites,
thus providing ample opportunity for structural
diversi®cation.
1
hexanes/EtOAc) to yield 13a (1.22 g, 64%): H NMR d
1.29 (t, Jˆ7.1 Hz, 3H, CH3), 2.46 (br s, 1H, OH), 2.69 (t,
Jˆ5.3 Hz, 2H, H-10), 3.28 (dd, Jˆ6.3, 1.6 Hz, 2H, H-4),
3.61 (t, Jˆ5.4 Hz, 2H, H-20), 4.20 (q, Jˆ7.1 Hz, 2H,
OCH2CH3), 5.98 (dt, Jˆ15.7, 1.6 Hz, 1H, H-2), 6.96 (dt,

R. Suero et al. / Tetrahedron 58(2002) 6211±6221
6215
Jˆ15.7, 6.3 Hz, 1H, H-3), 7.23±7.37 (m, 5H, Ar); 13C NMR
d 14.0, 54.2, 54.9, 58.0, 58.6, 60.2, 123.2, 127.1, 128.2,
128.6, 138.0, 145.1, 165.8; IR (neat) n 3440, 1725,
1660 cm21; LRMS (EI) m/z 233 (22), 232 (base), 218 (5),
91 (68); HRMS calcd for C15H21NO3 263.1521, found
263.1510.
(dd, Jˆ6.5, 1.8 Hz, 2H, Ar); 13C NMR d 14.1, 21.4, 49.4,
49.9, 54.9, 60.4, 104.4, 123.6, 127.1, 129.7, 136.6, 142.4,
143.6, 165.6; IR (neat) n 1730, 1600 cm21; LRMS (EI) m/z
224 (17), 184 (35), 152 (20), 128 (base), 114 (15), 84 (89);
HRMS calcd for C17H25NO6S (M11) 372.1481, found
372.1468.
4.2.2. Ethyl (E)-5-aza-5-benzyl-7-oxohept-2-enoate (5a).
DMSO (0.16 mL, 2.25 mmol) was added to a solution of
oxalyl chloride (0.1 mL, 1.13 mmol) in CH2Cl2 (3.3 mL) at
2848C. The solution was stirred for 10 min and then a solu-
tion of 13a (0.293 g, 1.11 mmol) in CH2Cl2 (3.3 mL) was
added dropwise. The resulting mixture was stirred for
20 min and Et3N (0.65 mL, 4.66 mmol) was added. The
reaction mixture was allowed to warm to room temperature
and stirred for 2 h. To the resulting suspension were added
CH2Cl2 (50 mL), H2O (20 mL) and sat. NaHCO3 (30 mL).
The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3£50 mL). The combined organic
extracts were dried (Na2SO4) and evaporated to dryness to
yield 5a (0.273 g, 93%) as an orange oil, unstable to chro-
matography, that was used without puri®cation: 1H NMR d
1.29 (t, Jˆ6.7Hz, 3H, OCH 2CH3), 3.26 (s, 2H, H-6), 3.35
(d, Jˆ4.9 Hz, 2H, H-4), 3.72 (s, 2H, PhCH2), 4.20 (q,
Jˆ6.8 Hz, 2H, OCH2), 6.04 (d, Jˆ15.3 Hz, 1H, H-2), 6.96
(dt, Jˆ15.3, 5.0 Hz, 1H, H-3), 7.26±7.34 (m, 5H, Ar), 9.60
(s, 1H, CHO).
4.2.5. Ethyl (E)-5-aza-7-oxo-5-tosylhept-2-enoate (5b). A
solution of TFA/H2O (1:1, 3.5 mL) was added dropwise to
14 (1.86 g, 5.0 mmol) in CH2Cl2 (15.0 mL) at 08C. After
vigorously stirring the mixture for 7days at room tempera-
ture, the solvent was removed in vacuo, residue dissolved in
EtOAc (20 mL), washed with sat. K2CO3 (25 mL), dried
(Na2SO4) and evaporated, to yield a 9/1 mixture of 5b/14
1
(1.56 g, 85% estimated yield for 5b by H NMR), as an
orange oil, that was used in subsequent reactions. For
characterization purposes, a portion of this crude mixture
(0.240 g) in CH2Cl2 (0.2 mL) was resubmitted to the
hydrolysis conditions, with TFA/H2O (1:1, 40 mL) for 5
days. The solvent was removed in vacuo, the residue
dissolved in EtOAc (25 mL) and washed with sat. K2CO3
(10 mL). The aqueous layer was back-extracted with EtOAc
(3£25 mL) and the combined organic extracts were washed
with brine (10 mL), dried (Na2SO4) and evaporated to yield
pure 5b (94 mg, 37% from 14): 1H NMR d 1.27(t,
Jˆ7.1 Hz, 3H, CH2CH3), 2.44 (s, 3H, ArCH3), 3.87(s,
2H, H-6), 3.98 (dd, Jˆ6.1, 1.3 Hz, 2H, H-4), 4.17(q,
Jˆ7.1 Hz, 2H, CH2CH3), 5.90 (dd, Jˆ15.6, 1.3 Hz, 1H,
H-2), 6.71 (dd, Jˆ15.6, 6.1 Hz, 1H, H-3), 7.33 (d,
Jˆ8.4 Hz, 2H, Ar), 7.69 (d, Jˆ8.4 Hz, 2H, Ar), 9.57(s,
1H, H-7); 13C NMR d 14.1, 21.5, 49.8, 56.4, 60.7, 125.0,
127.4, 130.0, 135.2, 140.8, 144.3, 165.2, 197.0; IR (neat) n
1713, 1648 cm21; LRMS (EI) m/z 322 (2), 297(16), 296
(base), 96 (35), 91 (74), 88 (51), 73 (39), 70 (70); HRMS
calcd for C15H19NO5S 325.0984, found 325.0971.
4.2.3. Ethyl (E)-5-aza-7,7-dimethoxyhept-2-enoate (13b).
To a solution of aminoacetaldehyde dimethyl acetal
(4.80 mL, 43.6 mmol) in CH2Cl2 (55 mL) was added drop-
wise ethyl (E)-4-bromobut-2-enoate (3.00 mL, 21.8 mmol),
the mixture was stirred at room temperature for 5 h and then
poured into sat. NaHCO3 (50 mL). The aqueous layer was
extracted with CH2Cl2 (2£50 mL). The combined organic
extracts were dried (Na2SO4) and evaporated to dryness.
The crude product was puri®ed by ¯ash chromatography
4.2.6. Methyl 4-aza-7,7-diethoxyhept-2-enote (13d). The
procedure reported for the corresponding ethyl ester25b was
followed from methyl propiolate (2.47mL, 27.5 mmol) and
1-amino-3,3-diethoxypropane (4.58 mL, 27.5 mmol) to
1
(EtOAc) to yield 13b (2.63 g, 55%). H NMR d 1.28 (t,
Jˆ7.1 Hz, 3H, CH2CH3), 1.43 (br s, 1H, NH), 2.74 (d,
Jˆ5.4 Hz, 2H, H-6), 3.39 (s, 6H, OCH3), 3.42 (dd, Jˆ5.5,
1.8 Hz, 2H, H-4), 4.18 (q, Jˆ7.1 Hz, 2H, OCH2), 4.45 (t,
Jˆ5.5 Hz, 1H, H-7), 5.98 (dt, Jˆ15.8, 1.7Hz, 1H, H-2),
6.97(dt, Jˆ15.7, 5.4 Hz, 1H, H-3); 13C NMR d 13.7,
49.7, 50.1, 53.5, 59.7, 103.3, 121.0, 146.1, 165.7; IR
1
yield 13d (6.50 g, 1:2 E/Z, 100%) as an oil: H NMR d
1.19 (t, Jˆ7.1 Hz, 6H, CH2CH3), 1.79±1.90 (m, 2H, H-6),
3.11 (q, Jˆ6.0 Hz, 2H, H-5, E isomer), 3.21±3.28 (m, 2H,
H-5, Z isomer), 3.41±3.54 (m, 2H), 3.57±3.71 (m, 5H), 3.62
and 3.63 (2 s, included in m at 3.57±3.71, CO2CH3), 4.44 (d,
Jˆ8.3 Hz, 1H, H-2, Z isomer), 4.54 (t, Jˆ5.6 Hz, 1H, H-7),
4.68 (d, Jˆ13.1 Hz, 1H, H-2, E isomer), 5.09 (br s, 1H, NH,
E isomer), 6.59 (dd, Jˆ13.1, 7.9 Hz, 1H, H-3, Z isomer),
7.43±7.52 (m, 1H, H-3, E isomer), 7.82 (br s, 1H, NH, Z
isomer); 13C NMR d 15.2, 35.0, 44.6, 50.1, 50.5, 61.5, 62.0,
81.3, 84.8, 100.6, 102.0, 152.3, 170.0, 171.0; IR (neat) n
3350, 1720, 1616 cm21; LRMS (EI) m/z 231 (M, 32), 186
(17), 185 (24), 126 (22), 114 (base), 85 (26), 82 (84); HRMS
calcd for C11H21NO4 231.1471, found 231.1464.
(neat) n 3320, 1720, 1660 cm21
.
4.2.4. Ethyl (E)-5-aza-7,7-dimethoxy-5-tosylhept-2-
enoate (14). A solution of p-toluenesulfonyl chloride
(419 mg, 2.20 mmol) in CH2Cl2 (5 mL) was added dropwise
over 5 min to 13b (434 mg, 2.00 mmol) and Et3N
(0.310 mL, 2.22 mmol) in CH2Cl2 (5 mL) at 08C. The reac-
tion mixture was allowed to warm to room temperature,
stirred for 90 min and evaporated. The residue was
dissolved in EtOAc (20 mL), washed with water (20 mL)
and brine (20 mL), and dried (Na2SO4). The crude product
after evaporation was puri®ed by ¯ash chromatography
(80:20 hexanes/EtOAc), to yield 14 (704 mg, 95%) as a
4.2.7. Methyl (E)-4-aza-4-benzoyl-7,7-diethoxyhept-2-
enoate (15) and methyl 4-aza-2-benzoyl-7,7-diethoxy-
hept-2-enoate (16b). n-BuLi (1.3 M in hexanes, 24 mL,
30.7mmol) was added dropwise over 45 min to 13d
(6.88 g, 29.7mmol) in THF (60 mL) at 2788C under Ar
to give a yellow±green solution. After 1 h, benzoyl chloride
(3.6 mL, 31.0 mmol) in THF (6 mL) was added over
30 min. The resulting mixture was stirred for 30 min,
1
colorless oil: H NMR d 1.24 (t, Jˆ7.1 Hz, 3H, CH2CH3),
2.40 (s, 3H, ArCH3), 3.18 (d, Jˆ5.2 Hz, 2H, H-6), 3.34 (s,
6H, CH3O), 4.05 (dd, Jˆ5.6, 1.6 Hz, 2H, H-4), 4.13 (q,
Jˆ7.1 Hz, 2H, CH3±CH2), 4.44 (t, Jˆ5.4 Hz, 1H, H-7),
5.82 (dt, Jˆ15.7, 1.6 Hz, 1H, H-2), 6.65 (dt, Jˆ15.7,
5.8 Hz, 1H, H-3), 7.29 (dd, Jˆ8.5, 0.6 Hz, 2H, Ar), 7.68

6216
R. Suero et al. / Tetrahedron 58(2002) 6211±6221
allowed to warm to room temperature, stirred further 1 h
and quenched with sat. NH4Cl (75 mL). After separation,
the aqueous layer was extracted with EtOAc (3£75 mL).
The combined organic extracts were washed with brine
(50 mL), dried (Na2SO4) and concentrated in vacuo to afford
an oil that was puri®ed by ¯ash chromatography (silica gel
saturated with Et3N, 83:15:2 hexanes/EtOAc/Et3N) to yield
4.2.10.
Methyl
(E)-4-aza-4-benzoyl-6-formylhex-2-
enoate (9b). A solution of 15 (0.55 g, 1.65 mmol) in
AcOH/H2O (2:1, 8 mL) was stirred at room temperature
for 24 h, poured into H2O (20 mL) and basi®ed with solid
NaHCO3 to pHˆ7. The mixture was extracted with EtOAc
(3£50 mL), the combined organic extracts were washed
with brine (25 mL), dried (Na2SO4) and concentrated in
vacuo to afford 9b (0.35 g, 81%) as an oil unstable to
chromatography, that was used without further
1
15 (4.40 g, 44%) and 16b (2.57g, 26%). Data for 15: H
NMR d 1.17(t, Jˆ7.1 Hz, 6H, CH2CH3), 1.91±1.99 (m, 2H,
H-6), 3.40±3.52 (m, 2H), 3.57±3.69 (m, 5H), 3.62 (s,
CO2CH3, included in m at 3.57±3.69), 3.85 (t, Jˆ7.4 Hz,
2H, H-5), 4.54 (t, Jˆ5.4 Hz, 1H, H-7), 5.41 (d, Jˆ14.0 Hz,
1H, H-2), 7.33±7.51 (m, 5H, Ar), 7.87 (d, Jˆ14.0 Hz, 1H,
H-3); 13C NMR d 15.1, 30.6, 40.0, 51.2, 61.5, 98.2, 100.8,
128.2, 128.6, 131.2, 133.4, 143.7, 167.6, 171.1; IR (neat) n
1720, 1685, 1625 cm21; LRMS m/z 335 (M, 3), 291 (4), 290
(10), 276 (20), 129 (30), 105 (base), 85 (21); HRMS calcd
for C18H25NO5 335.1733, found 335.1728. Data for 16b: 1H
NMR d 1.20±1.26 (m, 6H), 1.90±2.00 (m, 2H, H-6), 3.44±
3.58 (m, 7H), 3.51 and 3.53 (2 s, CO2CH3, included in m at
3.44±3.58), 3.62±3.74 (m, 2H), 4.57±4.62 (m, 1H, H-7),
7.30±7.58 (m, 5H, Ar), 7.77 (d, Jˆ14.3 Hz) and 8.04 (d,
Jˆ13.9 Hz) (total 1H), 9.22 and 10.63 (br s, 1H, NH); 13C
NMR d 15.0, 34.0, 45.6, 45.9, 50.2, 50.5, 61.7, 99.0, 99.3,
100.4, 100.7, 126.8, 127.2, 127.3, 128.0, 129.5, 130.3,
141.2, 142.1, 159.8, 159.9, 167.9, 169.1, 193.2, 195.4; IR
(neat) n 3250, 1720, 1685, 1636 cm21; LRMS (EI) m/z 335
(M, 34), 289 (58), 260 (14), 228 (25), 218 (35), 217(28),
186 (65), 184 (16), 140 (16), 105 (base); HRMS calcd for
C18H25NO5 335.1733, found 335.1727.
1
puri®cation: H NMR d 2.84±2.90 (m, 2H, H-5), 3.68 (s,
3H, CO2CH3), 4.14 (t, Jˆ7.2 Hz, 2H, H-6), 5.35 (d,
Jˆ14.0 Hz, 1H, H-2), 7.46±7.55 (m, 5H, Ar), 7.88 (d,
Jˆ14.0 Hz, 1H, H-3), 9.86 (t, Jˆ1.1 Hz, 1H, CHO); 13C
NMR d 37.5, 40.5, 51.4, 98.4, 128.4, 128.7, 131.6, 132.8,
143.2, 167.3, 171.3, 199.4; IR (neat) n 1714, 1680,
1619 cm21; LRMS (EI) m/z 261 (M, 2), 230 (6), 202 (25),
105 (base), 77 (24); HRMS calcd for C14H15NO4 261.1001,
found 261.0994.
4.2.11. Methyl (E)-4-aza-4-tert-butoxycarbonyl-7-oxo-
hept-2-enoate (9c). The procedure described above for 9b
was followed from 17 to afford 9c (0.364 g, 70%) as an oil
unstable to chromatography, that was used without further
puri®cation: 1H NMR d 1.42 (s, 9H, CCH3), 2.64 (t,
Jˆ7.1 Hz, 2H), 3.61 (s, 3H, CO2CH3), 3.78 (t, Jˆ7.1 Hz,
2H), 5.05 (d, Jˆ14.3 Hz, 1H, H-2), 8.04 (d, Jˆ14.3 Hz, 1H,
H-3), 9.69 (s, 1H, CHO); 13C NMR d 27.7, 37.6, 40.8, 51.1,
83.4, 96.6, 141.9, 151.4, 167.7, 199.4.
4.3. Preparation of pyrrolidines 8 and 12
4.2.8.
Methyl
(E)-4-aza-4-tert-butoxycarbonyl-7,7-
4.3.1. General procedure. In a typical experiment, a
mixture of aldehyde 5 or 9 (2.0 mmol), a secondary amine
(2.1 mmol), benzotriazole (2.1 mmol) and molecular sieves
diethoxyhept-2-enoate (17). The procedure described
above for 15 was followed using di-tert-butildicarbonate
instead of benzoyl chloride. The crude product was puri®ed
by ¯ash chromatography (silica gel saturated with Et31N,
96:2:2 hexanes/EtOAc/Et3N) to yield 17 in 92% yield: H
NMR d 1.08 (t, Jˆ7.1 Hz, 6H, CH2CH3), 1.40 (s, 9H,
CCH3), 1.70±1.78 (m, 2H, H-6), 3.29±3.56 (m, 6H), 3.58
(s, 3H, CO2CH3), 4.38 (t, Jˆ5.4 Hz, 1H, H-7), 5.11 (d,
Jˆ14.3 Hz, 1H, H-2), 8.05 (d, Jˆ14.3 Hz, 1H, H-3); 13C
NMR d 15.0, 27.7, 30.8, 40.0, 50.8, 61.2, 82.6, 96.3,
Ê
(4 A, 1.0 g) in dry THF (12 mL) was stirred overnight at
room temperature. The reaction mixture was ®ltered over
Celite and vacuum-dried (0.1 mm Hg) for 2 h to give crude
6 or 10, which was dissolved with t-BuOH (0.38 mL,
4.0 mmol) in THF (40 mL) and added dropwise over
30 min to a solution of SmI2 (ca. 0.1 M in THF, 62 mL,
6.2 mmol) at 2788C. The mixture was stirred at 2788C
for an additional 30 min and allowed to warm to room
temperature. After further stirring for 90 min the reaction
mixture was quenched with a mixture of sat. K2CO3
(50 mL) and water (50 mL). After separation, the aqueous
layer was extracted with EtOAc (3£75 mL), the combined
organic extracts were washed with brine (50 mL), dried
(Na2SO4) and evaporated to give a crude product that was
puri®ed by ¯ash chromatography (silica gel saturated with
Et3N, with mixtures of hexanes/EtOAc/Et3N as eluent) to
give the pure products.
100.4, 142.4, 151.6, 168.0; IR (neat) n 1735, 1630 cm21
LRMS (EI) m/z 331 (M, 3), 275 (11), 230 (54), 202 (18), 186
(32), 156 (26), 141 (54), 126 (53), 114 (55), 85 (base);
HRMS calcd for C16H29NO6 331.1995, found 331.1995.
;
4.2.9. Methyl 4-aza-7,7-diethoxy-2-tri¯uoroacetylhept-2-
enoate (16d). The foregoing procedure was followed, using
in this case tri¯uoroacetic anhydride. The crude product was
puri®ed by ¯ash chromatography (silica gel saturated with
Et3N, 92:6:2 hexanes/EtOAc/Et3N) to yield 16d in 66%
1
yield as a 3:8 mixture of isomers: H NMR d 1.17(t,
4.3.2. cis- and trans-4-Ethoxycarbonylmethyl-3-
(morpholin-1-yl)-1-tosylpyrrolidine (8a). Prepared from
5b (9:1 mixture with 14) and morpholine. Elution with
78:20:2 hexanes/EtOAc/Et3N, separated the two isomers,
that were obtained in 29 and 32% yields, respectively, as
Jˆ7.1 Hz, 6H, CH2CH3), 1.87±1.94 (m, 2H, H-6), 3.39±
3.71 (m, 9H), 3.68 (s, included in m at 3.39±3.71,
CO2CH3), 4.51±4.56 (m, 1H, H-7), 7.93 and 8.07 (2 d,
Jˆ14.7Hz, 1H, H-3), 9.81 and 10.66 (br s, 1H, N H); 13C
NMR d 15.0, 33.6, 46.5, 46.6, 51.0, 51.2, 62.3, 95.3, 96.3,
100.9, 101.0, 116.9, 117.2, 160.9, 162.3, 165.5, 167.8,
1
oils. Data for cis-8a: H NMR d 1.18 (t, Jˆ7.1 Hz, 3H,
CH2CH3), 1.67(dd, Jˆ17.0, 10.3 Hz, 1H), 2.14±2.58 (m,
10H), 2.38 (s, Ar-CH3, included in m at 2.14±2.58), 2.94 (t,
Jˆ9.5 Hz, 1H), 3.23±3.43 (m, 3H), 3.56 (t, Jˆ4.8 Hz, 4H),
4.03 (q, Jˆ7.1 Hz, 2H, OCH2CH3), 7.28 (d, Jˆ7.9 Hz, 2H,
Ar), 7.64 (d, Jˆ7.9 Hz, 2H, Ar); 13C NMR d 14.0, 21.3,
176.8, 177.9; IR (neat) n 3240, 1730, 1650, 1600 cm21
LRMS (EI) m/z 327(M, 24), 281 (63), 212 (18), 210 (60),
184 (61), 178 (base), 140 (59), 85 (50), 72 (92); HRMS
calcd for C13H20NO5F3 327.1294, found 327.1302.
;

R. Suero et al. / Tetrahedron 58(2002) 6211±6221
6217
30.8, 35.8, 48.5, 51.9, 52.0, 60.3, 65.4, 66.3, 127.1, 129.6,
133.5, 143.4, 172.4; IR (neat) n 1735 cm21; LRMS (EI) m/z
351 (18), 241 (base), 212 (79), 126 (7); HRMS calcd for
C19H28N2O5S 396.1719, found 396.1693. Data for trans-8a:
1H NMR d 1.20 (t, Jˆ7.1 Hz, 3H), 2.20 (dd, Jˆ17.1,
10.2 Hz, 1H), 2.36±2.50 (m, 10H), 2.39 (s, Ar-CH3,
included in m at 2.36±2.50), 2.67(dd, Jˆ14.1, 6.9 Hz,
1H), 2.86 (dd, Jˆ9.9, 6.5 Hz, 1H), 3.02 (dd, Jˆ9.9,
6.9 Hz, 1H), 3.28 (dd, Jˆ9.8, 7.2 Hz, 1H), 3.41 (dd,
Jˆ9.9, 7.5 Hz, 1H), 3.54±3.57 (m, 4H), 4.06 (q,
Jˆ7.1 Hz, 2H), 7.30 (d, Jˆ8.4 Hz, 2H), 7.64 (d,
Jˆ8.4 Hz, 2H); 13C NMR d 14.0, 21.4, 35.8, 37.2, 46.8,
50.0, 51.7, 60.6, 66.8, 68.7, 127.6, 129.6, 132.4, 143.6,
171.6; IR (neat) n 1730 cm21; LRMS m/z 241 (base), 212
(46), 140 (6), 126 (9); HRMS calcd for C19H28N2O5S
396.1719, found 396.1730.
m/z 394 (M, 1), 349 (15), 239 (base), 210 (63), 198 (7),
124 (8); HRMS calcd for C20H30N2O4S 394.1926, found
394.1909. Data for trans-8c: 1H NMR d 1.23 (t,
Jˆ7.1 Hz, 3H, CH2CH3), 1.37±1.46 (m, 6H), 2.17±2.52
(m, 10H), 2.42 (s, ArCH3, included in m at 2.17±2.52),
2.66 (dd, Jˆ14.7, 7.1 Hz, 1H), 2.86±2.98 (m, 2H), 3.31±
3.40 (m, 2H), 4.09 (q, Jˆ7.1 Hz, 2H, OCH2CH3), 7.32 (d,
Jˆ7.9 Hz, 2H, Ar), 7.67 (d, Jˆ7.9 Hz, 2H, Ar); 13C NMR d
14.1, 21.5, 24.3, 26.0, 36.2, 37.9, 47.6, 52.1, 60.6, 69.4,
127.8, 129.6, 132.3, 143.6, 172.0; IR (neat) n 1735 cm21
;
LRMS (EI) m/z 349 (12), 239 (base), 210 (49), 198 (6), 124
(8); HRMS calcd for C20H30N2O4S 394.1926, found
394.1910.
4.3.5. cis- and trans-1-(Benzyloxycarbonyl)-2-ethoxy-
carbonylmethyl-3-(morpholin-1-yl)pyrrolidine
(12a).
Prepared from 9b and morpholine. Elution with 73:25:2
hexanes/EtOAc/Et3N separated the two isomers, that were
obtained in 29 and 43% yields, respectively, as oils. Data for
4.3.3. cis- and trans-4-Ethoxycarbonylmethyl-3-(4-
phenylpiperazin-1-yl)-1-tosylpyrrolidine (8b). Prepared
from 5b (9:1 mixture with 14) and N-phenylpiperazine.
Elution with 78:20:2 hexanes/EtOAc/Et3N separated the
two isomers, that were obtained in 36 and 23% yields,
1
cis-12a (rotamer mixture): H NMR d 1.13 and 1.23 (2 t,
Jˆ7.1 Hz, 3H), 1.60±1.84 (m, 1H), 1.97±2.06 (m, 1H), 2.19
(dd, Jˆ15.4, 5.9 Hz) and 2.24±2.32 (m) (total 1H), 2.38±
2.55 (m, 4H), 2.62±2.81 (m, 2H), 3.30±3.56 (m, 2H), 3.63
(s, 4H), 3.88 and 4.10 (2 q, Jˆ7.1 Hz, 2H), 4.45±4.56 (m,
1H), 5.00±5.17 (m, 2H), 7.27±7.34 (m, 5H); 13C NMR d
14.0, 25.6, 26.3, 34.7, 35.0, 43.6, 43.8, 52.4, 55.5, 56.0,
60.2, 60.4, 66.0, 66.6, 66.7, 66.8, 127.7, 127.8, 128.3,
1
respectively, as oils. Data for cis-8b: H NMR d 1.24 (t,
Jˆ7.1 Hz, 3H, CH2CH3), 1.76 (dd, Jˆ16.9, 10.4 Hz, 1H),
2.37±2.69 (m, 10H), 2.44 (s, ArCH3, included in m at 2.37±
2.69), 3.01±3.13 (m, 5H), 3.32±3.42 (m, 2H), 3.48±3.54
(m, 1H), 4.10 (q, Jˆ7.1 Hz, 2H, CH2CH3), 6.82±6.90 (m,
3H, Ar), 7.22±7.28 (m, 2H, Ar), 7.34 (d, Jˆ8.0 Hz, 2H, Ar),
7.73 (d, Jˆ8.0 Hz, 2H, Ar); 13C NMR d 14.1, 21.4, 31.0,
36.0, 48.6, 48.9, 51.6, 52.0, 60.4, 65.1, 115.8, 119.7, 127.2,
128.9, 129.7, 133.5, 143.5, 150.8, 172.6; IR (neat) n
1730 cm21; LRMS (EI) m/z 471 (M, 12), 426 (7), 316
(base), 287(29), 160 ()7, 132 (11); HRMS calcd for
C25H33N3O4S 471.2192, found 471.2185. Data for trans-
8b: the characterized sample was obtained after HPLC
(m-Bondapak-NH2, 10 mm, 19 mm£15 cm, 72:28 hexanes/
EtOAc, 7mL/min, tRˆ11 min); 1H NMR d 1.24 (t,
Jˆ7.1 Hz, 3H, CH2CH3), 2.28 (dd, Jˆ16.3, 9.4 Hz, 1H),
2.44 (s, 3H, ArCH3), 2.46±2.62 (m, 6H), 2.77±2.85 (m,
1H), 2.89±2.96 (m, 1H), 3.05±3.12 (m, 5H), 3.34±3.50
(m, 2H), 4.11 (q, Jˆ7.1 Hz, 2H, CH2CH3), 6.83±6.90 (m,
3H), 7.22±7.29 (m, 2H), 7.34 (d, Jˆ8.0 Hz, 2H, Ar), 7.70
(d, Jˆ8.3 Hz, 2H, Ar); 13C NMR d 14.2, 21.5, 36.2, 37.6,
47.2, 49.2, 49.7, 52.0, 60.7, 68.6, 116.1, 120.0, 127.8, 129.1,
136.4, 136.6, 154.5, 171.9; IR (neat) n 1740, 1710 cm21
;
LRMS (EI) m/z 376 (M, 35), 331 (26), 303 (16), 288 (19),
281 (15), 241 (base); HRMS calcd for C20H28N2O5
376.1998, found 376.2005. Data for trans-12a (rotamer
mixture): The characterized sample was obtained after
HPLC (m-Bondapak-NH2, 10 mm, 19 mm£15 cm, 75:25
hexanes/EtOAc, 8 mL/min, tRˆ7min); 1H NMR d 1.23
and 1.24 (2 t, Jˆ7.1 Hz, 3H), 1.95±2.02 (m, 2H), 2.37±
2.57(m, 5H), 2.07 (dd,
Jˆ15.1, 3.6 Hz) and 2.86 (dd,
Jˆ15.3, 3.8 Hz) (total 2H), 3.34±3.69 (m, 6H), 4.03±4.16
(m, 2H), 4.23±4.25 (m, 1H), 5.05±5.21 (m, 2H), 7.29±7.37
(m, 5H); 13C NMR d 14.2, 24.7, 25.2, 37.7, 38.8, 45.0, 45.4,
50.4, 50.5, 56.0, 56.6, 60.5, 66.7, 67.0, 68.9, 69.8, 127.8,
127.9, 128.4, 136.7, 154.4, 170.9, 171.1; IR (neat) n 1730,
1705 cm21; LRMS (EI) m/z 376 (M, 35), 331 (8), 303 (12),
289 (19), 288 (15), 241 (base); HRMS calcd for C20H28N2O5
376.1998, found 376.1999.
129.7, 132.3, 143.8, 151.0, 171.8; IR (neat) n 1730 cm21
;
LRMS (EI) m/z 471 (M, 11), 426 (7), 316 (base), 287 (31),
160 (6), 132 (9); HRMS calcd for C25H33N3O4S 471.2192,
found 471.2195.
4.3.6.
3-(N-Benzyl-N-methylamino)-1-benzyloxycar-
bonyl-2-ethoxycarbonylmethylpyrrolidine (12b). Pre-
pared from 9a and N-benzyl-N-methylamine. Elution with
88:10:2 hexanes/EtOAc/Et3N yielded 12b (82%, 1:1.3 cis/
trans mixture) as an oil. Data for the diastereomeric mixture
4.3.4. cis- and trans-4-Ethoxycarbonylmethyl-3-(piperi-
din-1-yl)-1-tosylpyrrolidine (8c). Prepared from 5b (9:1
mixture with 14) and piperidine. Elution with 88:10:2
hexanes/EtOAc/Et3N separated the two isomers, that were
obtained in 26 and 21% yields, respectively, as oils. Data for
cis-8c: 1H NMR d 1.21 (t, Jˆ7.2 Hz, 3H, CH2CH3), 1.34±
1.46 (m, 6H), 1.66 (dd, Jˆ17.0, 11.1 Hz, 1H), 2.13±2.23
(m, 4H), 2.40 (s, ArCH3, included in m at 2.40±2.60), 2.40±
2.60 (m, 6H), 2.93 (t, Jˆ9.5 Hz, 1H), 3.25±3.35 (m, 2H),
3.43 (dd, Jˆ9.2, 7.2 Hz, 1H), 4.06 (q, Jˆ7.1 Hz, 2H,
OCH2CH3), 7.30 (d, Jˆ8.1 Hz, 2H, Ar), 7.67 (d,
Jˆ8.1 Hz, 2H, Ar); 13C NMR d 14.1, 21.4, 24.0, 25.5,
30.9, 36.2, 49.2, 51.9, 52.9, 60.3, 65.8, 127.2, 129.6,
133.6, 143.4, 172.8; IR (neat) n 1735 cm21; LRMS (EI)
1
(mixtures of rotamers): H NMR d 1.11 and 1.24 (2 t,
Jˆ7.1 Hz, 3H), 1.71±3.24 (m, 8H), 2.11 and 2.18 (2 s,
included in m at 1.71±3.24), 3.36±3.89 (m) and 4.01±
4.15 (m) (total 6H), 4.27(br s) and 4.61±4.65 (m) (total
1H), 5.04±5.23 (m, 2H), 7.27±7.38 (m, 5H); 13C NMR d
14.0, 23.9, 24.6, 27.0, 27.7, 34.6, 34.9, 37.4, 37.7, 38.6,
40.5, 43.8, 44.0, 45.1, 45.5, 56.2, 56.4, 56.8, 58.8, 60.1,
60.4, 65.9, 66.5, 66.7, 67.7, 68.6, 126.8, 127.6, 127.7,
128.1, 128.2, 128.4, 136.4, 136.7, 138.6, 139.1, 154.3,
154.5, 170.8, 171.0, 172.0, 172.1; IR (neat) n 1730,
1710 cm21; LRMS (EI) m/z 410 (M, 8), 337(9), 319 (15),
275 (60), 160 (17), 91 (base); HRMS calcd for C24H30N2O4
410.2206, found 410.2193.

6218
R. Suero et al. / Tetrahedron 58(2002) 6211±6221
4.3.7. 3-[N-Allyl-N-[2-(3,4-dimethoxyphenyl)ethyl]amino]-
1-benzyloxycarbonyl-2-ethoxycarbonylmethylpyrrolidine
(12c). Prepared from 9a and 3,4-dimethoxyphenethylamine.
Elution with 83:15:2 hexanes/EtOAc/Et3N yielded 12c
(82%, 2:3 cis/trans mixture) as an oil. The cis isomer was
partially separated by HPLC (m-Bondapak-NH2, 10 mm,
(14), 364 (13), 316 (37), 201 (23), 187 (15), 173 (26), 163
(14), 162 (base); HRMS calcd for C26H33N3O4 451.2471,
found 451.2468.
4.4. Deprotection-functionalization of 3-amino-
pyrrolidines
19 mm£15 cm,
90:10
hexanes/EtOAc,
8 mL/min,
tRˆ27min). Data for the diastereomeric mixture (mixtures
of rotamers): 1H NMR d 1.11 (t, Jˆ7.1 Hz) and 1.18±1.25
(m) (total 3H), 1.77±2.28 (m, 3H), 2.45±2.85 (m, 6H),
3.09±3.84 (m, 5H), 3.84 and 3.86 (2 s, 6H, OCH3), 3.91±
4.12 (m) and 4.52 (br s) (total 3H), 5.01±5.29 (m, 4H),
5.79±5.93 (m, 1H, CH2vCH), 6.67±6.79 (m, 3H, Ar),
7.26±7.36 (m, 5H, Ar); 13C NMR d 14.1, 24.3, 24.7, 26.7,
27.4, 31.5, 34.2, 34.6, 34.8, 36.9, 38.1, 43.9, 44.1, 45.2,
45.5, 52.3, 52.7, 53.6, 53.9, 55.7, 55.8, 56.4, 56.6, 56.9,
60.3, 60.4, 62.4, 63.2, 65.1, 66.1, 66.6, 66.8, 111.1, 111.9,
116.8, 117.6, 120.4, 120.5, 127.7, 127.8, 128.4, 132.7,
132.8, 134.4, 134.5, 136.4, 136.8, 147.1, 147.2, 148.6,
148.7, 154.4, 154.6, 154.7, 171.1, 171.3, 172.2, 172.3; IR
(neat) n 1740, 1710, 1650 cm21. Data for cis-12c (rotamer
mixture): 1H NMR d 1.11 (t, Jˆ7.1 Hz) and 1.20 (distorted
t) (total 3H), 1.71±2.28 (m, 3H), 2.60±2.85 (m, 5H), 3.12±
3.56 (m, 5H), 3.84 and 3.87(2 s, overlapped with m from
another H, total 7H), 4.12 (q, Jˆ7.1 Hz, 1H, CH3CH2),
4.49±4.51 (m, 1H), 5.01±5.29 (m, 4H), 5.79±5.95 (m,
1H), 6.66±6.79 (m, 3H), 7.26±7.36 (m, 5H); 13C NMR d
14.1, 15.2, 26.7, 27.4, 31.5, 34.7, 34.8, 43.9, 44.1, 52.7,
53.5, 55.7, 55.8, 56.4, 57.0, 60.2, 60.4, 62.4, 63.2, 65.8,
66.6, 66.8, 111.0, 111.8, 117.6, 120.4, 127.8, 127.8, 128.3,
132.7, 134.4, 136.5, 136.8, 147.2, 148.7, 154.7, 172.2,
172.3; IR (neat) n 1740, 1710, 1650 cm21; LRMS (EI)
m/z 465 (1), 421 (3), 360 (32), 359 (base), 91 (58); HRMS
calcd for C29H39N2O6 (M11) 511.2808, found 511.2807.
4.4.1. trans-3-[N-[2-(3,4-Dimethoxyphenyl)ethyl]amino]-
1-benzyloxycarbonyl-2-ethoxycarbonylmethylpyrroli-
dine (21) and cis-5-benzyloxycarbonyl-1,5-diaza-1-[2-
(3,4-dimethoxyphenyl)ethyl]-2-oxoperhydropentalene
(22). A mixture of 12c (0.510 g, 1.0 mmol, 2:3 cis/trans
mixture), Pd(PPh3)4 (12 mg, 0.01 mmol) and N,N-dimethyl-
barbituric acid (NDMBA) (0.47g, 3.0 mmol) in dry
degassed CH2Cl2 (2 mL), under Ar, was stirred for 24 h at
room temperature, the solvent was evaporated and the
residue was redissolved in EtOAc (25 mL). The resulting
solution was washed with sat. K2CO3 (3£10 mL) and brine
(10 mL), and dried (Na2SO4). The crude after evaporation
was puri®ed by ¯ash chromatography (silica gel saturated
with Et3N, 83:15:2 hexanes/EtOAc/Et3N and then 63:35:2
hexanes/EtOAc/Et3N) and HPLC (m-Bondapak-NH2,
10 mm, 19 mm£15 cm, 40:60 hexanes/EtOAc, 8 mL/min)
to yield 21 (279 mg, 60%) and 22 (148 mg, 35%). Data
for 21: tRˆ7min; 1H NMR d 1.19 (t, Jˆ7.1 Hz, 3H,
CH3CH2), 1.59±1.70 (m, 1H), 1.95±2.09 (m, 1H), 2.28
(dd, Jˆ15.8, 10.3 Hz, 1H), 2.70±2.96 (m, 5H), 3.14±3.16
(m, 1H), 3.38±3.58 (m, 2H), 3.82 and 3.84 (2 s, 6H, CH3O),
4.01±4.12 (m, 3H), 5.03±5.19 (m, 2H), 6.70±6.79 (m, 3H),
7.27±7.33 (m, 5H, Ar); 13C NMR d 14.0, 29.0, 29.8, 35.6,
37.0, 38.1, 44.5, 44.8, 48.8, 55.6, 55.7, 59.5, 60.0, 60.3,
61.7, 62.6, 66.5, 66.6, 111.0, 111.6, 120.4, 127.6, 127.7,
128.3, 132.2, 136.6, 147.2, 148.7, 154.6, 170.9, 171.1; IR
(neat) n 3450, 1745, 1730, 1715, 1700 cm21; LRMS (EI)
m/z 425 (5), 383 (1), 320 (24), 319 (99), 275 (14), 91 (base);
HRMS calcd for C26H34N2O6 470.2417, found 470.2417.
4.3.8. cis- and trans-1-Benzyloxycarbonyl-2-ethoxycar-
bonylmethyl-3-(4-phenylpiperazin-1-yl)pyrrolidine (12d).
Prepared from 9a and 4-phenylpiperazine. Elution with
88:10:2 hexanes/EtOAc/Et3N yielded 12d (84%, 2:3 cis/
trans mixture) as an oil. Partial separation of the two
isomers allowed their individual characterization. Data for
1
Data for 22: tRˆ11 min; H NMR d 1.78±2.07 (m, 2H),
2.48±2.95 (m, 4H), 3.12±3.31 (m, 2H), 3.64±3.92 (m,
8H), 3.86 and 3.87(2 s, included in m at 3.64±3.92,
CH3O), 4.05 (t, Jˆ5.1 Hz, 1H), 4.26±4.36 (m, 1H), 5.05±
5.20 (m, 2H, PhCH2), 6.74±6.84 (m, 3H, Ar), 7.27±7.39 (m,
5H, Ar); 13C NMR d 27.9, 28.4, 33.0, 37.7, 38.6, 42.0, 43.8,
44.2, 54.2, 54.9, 55.8, 55.8, 61.9, 62.8, 66.9, 67.1, 111.1,
111.5, 120.4, 127.9, 128.0, 128.1, 128.4, 128.5, 130.7,
130.8, 136.2, 136.3, 147.6, 148.8, 153.9, 154.1, 173.2,
173.6; IR (neat) n 1710, 1700 cm21; LRMS (EI) m/z 424
(M, 16), 165 (24), 164 (base), 151 (14), 91 (21); HRMS
calcd for C24H28N2O5 424.1998, found 424.2019.
1
cis-12d (rotamer mixture): H NMR d 1.15 and 1.25 (2 t,
Jˆ7.1 Hz, 3H, CH2CH3), 1.72±1.87 (m, 1H), 2.06 (m, 1H),
2.20±2.37(m, 1H), 2.62±2.87(m, 6H), 3.15 (br s, 4H),
3.42±3.61 (m, 2H), 3.92 (q, Jˆ7.1 Hz, 1H), 4.12±4.15
(m, 1H), 4.56±4.59 (m, 1H), 5.05±5.22 (m, 2H, PhCH2),
6.84±6.93 (m, 3H), 7.24±7.36 (m, 7H); 13C NMR d 14.0,
25.9, 26.7, 34.8, 35.1, 43.7, 43.9, 48.8, 51.9, 55.7, 56.2,
60.2, 60.4, 65.7, 66.4, 66.6, 66.8, 115.8, 119.6, 127.7,
127.8, 128.3, 129.0, 136.4, 136.7, 151.0, 154.5, 171.9; IR
(neat) n 1740±1690, 1600 cm21; LRMS (EI) m/z 451 (M,
84), 406 (16), 364 (11), 316 (35), 201 (22), 187(14), 173
(24), 163 (14), 162 (base); HRMS calcd for C26H33N3O4
451.2471, found 451.2472. Data for trans-12d (rotamer
4.4.2. trans-1-Benzyloxycarbonyl-3-[[2-(3,4-dimethoxy-
phenyl)ethyl]benzoylamino]-2-ethoxycarbonylmethyl-
pyrrolidine (23). To a solution of 21 (0.259 g, 0.55 mmol)
and Et3N (0.140 mL, 1.0 mmol) in CH2Cl2 (10 mL) at 08C
was added dropwise over 5 min benzoyl chloride
(0.080 mL, 0.66 mmol). The mixture was stirred for 1 h,
allowed to warm to room temperature and stirred further
2 h. The reaction mixture was poured into sat. NH4Cl
(15 mL), the layers were separated and the aqueous layer
was extracted with CH2Cl2 (3£20 mL). The combined
organic extracts were washed with brine (20 mL), dried
(Na2SO4) and the solvent was removed in vacuo. The
crude product was puri®ed by ¯ash chromatography (silica
gel saturated with Et3N, 88:10:2 hexanes/EtOAc/Et3N) to
1
mixture): H NMR d 1.22±1.29 (m, 3H, CH3), 2.02±2.07
(m, 2H), 2.42±2.94 (m, 6H), 3.02±3.17(m, 5H), 3.43±3.45
(m, 1H), 3.56±3.71 (m, 1H), 4.05±4.18 (m, 2H, CH3CH2),
4.30±4.31 (m, 1H), 5.14±5.24 (m, 2H, PhCH2), 6.84±6.94
(m, 3H), 7.24±7.38 (m, 7H); 13C NMR d 14.1, 24.8, 25.2,
37.7, 38.8, 45.0, 45.4, 49.1, 49.7, 49.9, 55.9, 56.6, 60.4,
66.6, 66.8, 68.5, 69.5, 115.9, 119.6, 127.7, 127.8, 128.3,
129.0, 136.5, 136.7, 151.1, 154.3, 170.8, 171.0; IR (neat)
n 1740±1690, 1600 cm21; LRMS (EI) m/z 451 (M, 95), 406

R. Suero et al. / Tetrahedron 58(2002) 6211±6221
6219
yield 23 (289 mg, 92%) as an oil: 1H NMR (408C) d 1.12±
1.18 (m, 3H, CH2CH3), 1.97(br s, W 1/2ˆ25.5 Hz, 2H), 2.64
(br s, W1/2ˆ20.3 Hz, 2H), 2.83 (br s, W1/2ˆ20.3 Hz, 2H),
3.26±3.58 (m, 3H), 3.76 and 3.81 (2 s, overlapped with
signals from another H, total 7H), 3.98±4.16 (m and br s,
3H), 4.62 (br s, W1/2ˆ22.0 Hz, 1H), 5.06±5.16 (m, 2H,
PhCH2O), 6.56±6.74 (m, 3H, Ar), 7.27±7.37 (m, 10H).);
13C NMR (408C) d 13.9, 28.3, 35.2, 36.5, 44.8, 46.5, 55.8,
55.9, 56.4, 60.2, 61.9, 66.8, 111.7, 112.3, 120.7, 126.4,
127.7, 127.8, 128.3, 128.3, 129.3, 131.2, 136.4, 136.8,
147.8, 149.1, 154.1, 170.2, 172.1; IR (neat) n 1725, 1695,
1631 cm21; LRMS (EI) m/z 574 (M, 4), 529 (6), 423 (7),
285 (23), 211 (20), 169 (25), 165 (26), 164 (base), 105
(62); HRMS calcd for C33H38N2O7 574.2679, found
574.2683.
(90 mL, 0.09 mmol) and the mixture was stirred for 20 h
at room temperature. After removal of the solvents, the
residue was dissolved in H2O (4 mL) and extracted with
CH2Cl2 (3£4 mL). The aqueous layer was acidi®ed with
1 M HCl to pHˆ2 and extracted with CH2Cl2 (3£6 mL).
The latter organic extracts were dried (Na2SO4) and the
solvent evaporated to afford 26. The crude acid 26 and
carbonyldiimidazole (CDI) (10 mg, 0.06 mmol) were
dissolved in MeCN (0.34 mL) and the mixture was stirred
at room temperature for 1.5 h. Benzylamine (100 mL,
0.09 mmol) was added dropwise and the mixture was stirred
for 20 h. The solvent was removed in vacuo and the residue
was dissolved in CH2Cl2/H2O (1:1, 8 mL). After separation,
the organic layer was washed with 10% HCl (2 mL) and sat.
NaHCO3 (2 mL), and dried (Na2SO4). The crude after
evaporation was puri®ed by ¯ash chromatography (silica
gel saturated with Et3N, 48:50:2 hexanes/EtOAc/Et3N) to
4.4.3. trans-3-[[2-(3,4-Dimethoxyphenyl)ethyl]benzoyl-
amino]-2-ethoxycarbonylmethylpyrrolidine (24). A stir-
red mixture of 23 (81 mg, 0.14 mmol) and 10% Pd/C
(11 mg) in EtOH (1 mL) was treated with H2 (1 atm)at
room temperature for 5 h. The reaction mixture was ®ltered
through Celite and the ®ltrate was concentrated in vacuo.
The crude product was puri®ed by ¯ash chromatography
(silica gel saturated with Et3N, 18:80:2 hexanes/EtOAc/
1
yield 27 (29 mg, 52%, over two steps) as an oil: H NMR
(408C) d 1.94±2.07(m, 2H), 2.37(s, 3H, ArCH ), 2.60 (br s,
3
1H), 2.84 (br s, 3H), 3.41±3.72 (m, 4H), 3.79 and 3.83 (2 s,
6H, OCH3), 4.32±4.49 (m, 3H), 4.97(br s, 1H), 6.42±6.77
(m, 4H), 7.13±7.40 (m, 14H); 13C NMR (408C) d 21.3, 28.9,
35.4, 37.2, 43.5, 48.7, 49.6, 56.0, 56.1, 56.5, 61.4, 111.8,
112.4, 120.9, 126.6, 127.3, 127.5, 127.8, 128.6, 129.0,
129.5, 131.2, 133.1, 137.1, 138.4, 140.6, 148.0, 149.3,
1
Et3N), to yield 24 (58 mg, 94%) as a colorless solid. H
NMR (408C) d 1.24 (t, Jˆ7.1 Hz, 3H, CH2CH3), 1.78±
2.08 (m, 2H), 2.12±2.30 (m, 1H), 2.52±2.70 (m, 1H),
2.88±3.10 (m, 5H), 3.50±3.56 (m, 3H), 3.82 and 3.84 (2 s,
6H, CH3O), 3.92±4.04 (m, 1H), 4.12 (q, Jˆ7.1 Hz, 2H,
CH2CH3), 6.65±6.80 (m, 3H, Ar), 7.31±7.41 (m, 5H, Ar);
13C NMR (408C) d 14.2, 29.0, 35.2, 38.1, 44.3, 56.0, 56.1,
57.0, 60.6, 63.4, 111.9, 112.6, 120.9, 126.5, 128.6, 129.4,
137.3, 148.0, 149.3, 171.8, 172.5; IR (neat) n 3435, 1730,
1630 cm21; LRMS (EI) m/z 440 (M, 3), 353 (7), 165 (10),
164 (28), 156 (10), 155 (base), 105 (48); HRMS calcd for
C25H32N2O5 440.2311, found 440.2295.
169.8, 170.2, 172.8; IR (neat) n 3295, 1660, 1620 cm21
;
LRMS (EI) m/z 410 (6), 393 (13), 346 (11), 334 (20), 322
(65), 164 (base), 119 (33), 105 (29); HRMS calcd for
C38H42N3O5 (M11) 620.3124, found 620.3126.
Acknowledgements
Financial support provided by Janssen-Cilag is gratefully
acknowledged.
4.4.4. trans-3-[[2-(3,4-Dimethoxyphenyl)ethyl]benzoyl-
amino]-2-ethoxycarbonylmethyl-1-(p-methylbenzoyl)-
pyrrolidine (25). The procedure described above for 23 was
followed form 24 and p-methylbenzoyl chloride. The crude
product was puri®ed by ¯ash chromatography (silica gel
saturated with Et3N, 58:40:2 hexanes/EtOAc/Et3N) to
References
1. Renaud, P.; Giraud, L. Synthesis 1996, 913±926.
2. Robertson, J.; Peplow, M. A.; Pillai, J. Tetrahedron Lett. 1996,
37, 5825±5828.
 Â
3. Aurrecoechea, J. M.; Lopez, B.; Fernandez, A.; Arrieta, A.;
Â
Cossõo, F. P. J. Org. Chem. 1997, 62, 1125±1135.
1
yield 25 (34 mg, 76%) as an oil: H NMR (408C) d 1.18
(t, Jˆ7.1 Hz, 3H, CH2CH3), 1.89±1.94 (m, 2H), 2.36 (s, 3H,
ArCH3), 2.61±2.66 (m, 1H), 2.89 (br s, W1/2ˆ19.9 Hz, 3H),
3.27±3.67 (m, 4H), 3.81 and 3.84 (2 s, 6H, CH3O), 3.99±
4.02 (m, 2H, CH2CH3), 4.42 (br s, W1/2ˆ18.3 Hz, 2H), 4.81
(br s, W1/2ˆ25.0 Hz, 2H), 6.62 (br s, W1/2ˆ25.2 Hz, 2H),
6.78 (d, Jˆ7.9 Hz, 1H), 7.17 (d, Jˆ7.9 Hz, 2H), 7.36±
7.40 (m, 7H); 13C NMR (408C) d 14.1, 21.3, 29.4, 35.1,
35.2, 46.0, 48.3, 55.4, 56.0, 56.1, 60.4, 61.2, 111.9, 112.6,
121.0, 126.6, 127.6, 128.6, 128.9, 129.5, 131.4, 133.1,
137.0, 140.6, 148.1, 149.4, 169.8, 170.6, 172.5; IR (neat)
n 1730, 1680, 1625 cm21; LRMS (EI) m/z 407(12), 285 (9),
273 (36), 245 (4), 165 (14), 164 (base), 151 (9), 119 (51),
105 (70); HRMS calcd for C33H38N2O6 558.2730, found
558.2711.
4. (a) Quirante, J.; Escolano, C.; Bonjoch, J. Synlett 1997, 17 9±
180. (b) Quirante, J.; Vila, X.; Escolano, C.; Bonjoch, J.
J. Org. Chem. 2002, 67, 2323±2328.
5. Ishizaki, M.; Takano, H.; Hoshino, O. Heterocycles 1998, 49,
305±314.
6. Katritzky, A. R.; Feng, D. M.; Qi, M.; Aurrecoechea, J. M.;
Suero, R.; Aurrekoetxea, N. J. Org. Chem. 1999, 64, 3335±
3338.
7. Aurrecoechea, J. M.; Fernandez, A.; Gorgojo, J. M.; Saornil,
C. Tetrahedron 1999, 55, 7345±7362.
8. Arya, P.; Wayner, D. M. Tetrahedron Lett. 1991, 32, 6265±
6268.
9. Tsai, Y.-M.; Nieh, H.-C.; Pan, J.-S.; Hsiao, D.-D. Chem.
Commun. 1996, 2469±2470.
10. Lesage, M.; Arya, P. Synlett 1996, 237±238.
11. Easton, C. J. Chem. Rev. 1997, 97, 53±82.
12. Atarashi, S.; Choi, J. K.; Ha, D. C.; Hart, D. J.; Kuzmich, D.;
Lee, C. S.; Ramesh, S.; Wu, S. C. J. Am. Chem. Soc. 1997,
119, 6226±6241.
4.4.5. trans-2-Benzylamidomethyl-3-[[2-(3,4-dimethoxy-
phenyl)ethyl]benzoylamino]-1-(p-methylbenzoyl)pyr-
rolidine (27). To a solution of 25 (50 mg, 0.09 mmol) in
THF/H2O (6:1, 0.7mL) was added dropwise 1 M NaOH

6220
R. Suero et al. / Tetrahedron 58(2002) 6211±6221
13. Clauss, R.; Hunter, R. J. Chem. Soc., Perkin Trans. 1 1997,
71±76.
P. A.; Omer, C. A.; Rodrigues, A. D.; Walsh, E. S.; Williams,
T. M. J. Med. Chem. 2001, 44, 2933±2949.
14. Clive, D. L. J.; Yeh, V. S. C. Tetrahedron Lett. 1998, 39,
4789±4792.
35. (a) Nagamani, D.; Ganesh, K. N. Org. Lett. 2001, 3, 103±106.
(b) Kumar, V.; Pallan, P. S.; Meena; Ganesh, K. N. Org. Lett.
2001, 3, 1269±1272. (c) Vilaivan, T.; Suparpprom, C.;
Harnyuttanakorn, P.; Lowe, G. Tetrahedron Lett. 2001, 42,
5533±5536. (d) D'Costa, M.; Kumar, V.; Ganesh, K. N.
Tetrahedron Lett. 2002, 43, 883±886.
15. Baker, S. R.; Burton, K. I.; Parsons, A. F.; Pons, J. F.; Wilson,
M. J. Chem. Soc., Perkin Trans. 1 1999, 427±436.
16. (a) Curran, D. P.; Liu, H. T. J. Chem. Soc., Perkin Trans. 1
1994, 1377±1393. (b) Sato, T.; Okamoto, K.; Nakano, Y.;
Uenishi, J.; Ikeda, M. Heterocycles 2001, 54, 747±755.
17. Yoon, U. C.; Mariano, P. S. Acc. Chem. Res. 1992, 25, 233±
240.
36. Al-Kindy, S.; Santa, T.; Fukushima, T.; Homma, H.; Imai, K.
Biomed. Chromatogr. 1997, 11, 137±142.
37. Zhao, S.; Liu, Y.-M. Anal. Chim. Acta 2001, 426, 65±70.
38. Corruble, A.; Valnot, J.-Y.; Maddaluno, J.; Duhamel, P.
J. Org. Chem. 1998, 63, 8266±8275.
18. Santamaria, J. Pure Appl. Chem. 1995, 67, 141±147.
19. Jonas, M.; Blechert, S.; Steckhan, E. J. Org. Chem. 2001, 66,
6896±6904 and references cited therein.
39. Wang, X.; Espinosa, J. F.; Gellman, S. H. J. Am. Chem. Soc.
2000, 122, 4821±4822.
20. A review on intramolecular radical conjugate additions:
Zhang, W. Tetrahedron 2001, 57, 7237±7261.
21. Lee, E.; Kang, T. S.; Joo, B. J.; Tae, J. S.; Li, K. S.; Chung,
C. K. Tetrahedron Lett. 1995, 36, 417±420.
40. Chan, P. W. H.; Cottrell, I. F.; Moloney, M. G. J. Chem. Soc.,
Perkin Trans. 1 2001, 2997±3006.
41. Lee, H. S.; LePlae, P. R.; Porter, E. A.; Gellman, S. H. J. Org.
Chem. 2001, 66, 3597±3599.
22. Lee, E.; Li, K. S.; Lim, J. Tetrahedron Lett. 1996, 37, 1445±
1446.
42. Norton Matos, M. R. P.; Afonso, C. A. M.; Batey, R. A.
Tetrahedron Lett. 2001, 42, 7007±7010.
23. Lee, E.; Jeong, E. J.; Min, S. J.; Hong, S.; Lim, J.; Kim, S. K.;
Kim, H. J.; Choi, B. G.; Koo, K. C. Org. Lett. 2000, 2, 2169±
2171.
43. Jean, L.; Baglin, I.; Rouden, J.; Maddaluno, J.; Lasne, M.-C.
Tetrahedron Lett. 2001, 42, 5645±5649.
44. Funaki, I.; Thijs, L.; Zwaneburg, B. Tetrahedron 1996, 52,
9909±9924.
24. Lee, E.; Kim, S. K.; Kim, J. Y.; Lim, J. Tetrahedron Lett.
2000, 41, 5915±5916.
45. Tomori, H.; Shibutani, K.; Ogura, K. Heterocycles 1997, 44,
213±225.
25. (a) Macdonald, S. J. F.; Mills, K.; Spooner, J. E.; Upton, R. J.;
Dowle, M. D. J. Chem. Soc., Perkin Trans. 1 1998, 3931±
3936. (b) Lee, E.; Li, K. S.; Lim, J. Tetrahedron Lett. 1996, 37,
1445±1446.
46. Moon, S. H.; Lee, S. Synth. Commun. 1998, 28, 3919±3926.
47. Bell, I. M.; Beshore, D. C.; Gallicchio, S. N.; Williams, T. M.
Tetrahedron Lett. 2000, 41, 1141±1145.
26. (a) Yoshida, T.; Yamamoto, Y.; Orita, H.; Kakiuchi, M.;
Takahashi, Y.; Itakura, M.; Kado, N.; Yasuda, S.; Kato, H.;
Itoh, Y. Chem. Pharm. Bull. 1996, 44, 1376±1386.
(b) Kawakami, K.; Takahashi, H.; Ohki, H.; Kimura, K.;
Miyauchi, S.; Miyauchi, R.; Takemura, M. Chem. Pharm.
Bull. 2000, 48, 1667±1672.
48. Miyata, O.; Muroya, J. K.; Naito, T. Synlett 1998, 271±272.
49. Miyabe, H.; Kanehira, S.; Kume, K.; Kandori, H.; Naito, T.
Tetrahedron 1998, 54, 5883±5892.
50. El Kaim, L.; Gacon, A.; Perroux, A. Tetrahedron Lett. 1998,
39, 371±374.
27. Rajeev, K. G.; Sanjayan, G. J.; Ganesh, K. N. J. Org. Chem.
1997, 62, 5169±5173.
51. Naito, T.; Fukumoto, D.; Takebayashi, K.; Kiguchi, T.
Heterocycles 1999, 51, 489±492.
28. Macdonald, S. J. F.; Belton, D. J.; Buckley, D. M.; Spooner,
J. E.; Anson, M. S.; Harrison, L. A.; Mills, K.; Upton, R. J.;
Dowle, M. D.; Smith, R. A.; Molloy, C. R.; Risley, C. J. Med.
Chem. 1998, 41, 3919±3922.
52. Dell'Erba, C.; Mugnoli, A.; Novi, M.; Pani, M.; Petrillo, G.;
Tavani, C. Eur. J. Org. Chem 2000, 903±912.
53. Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem. 2000, 65,
5043±5047.
29. Ewing, W. R.; Becker, M. R.; Manetta, V. E.; Davis, R. S.;
Pauls, H. W.; Mason, H.; Choi-Sledeski, Y. M.; Green, D.;
Cha, D.; Spada, A. P.; Cheney, D. L.; Mason, J. S.; Maignan,
S.; Guilloteau, J. P.; Brown, K.; Colussi, D.; Bentley, R.;
Bostwick, J.; Kasiewski, C. J.; Morgan, S. R.; Leadley, R. J.;
Dunwiddie, C. T.; Perrone, M. H.; Chu, V. J. Med. Chem.
1999, 42, 3557±3571.
54. For other radical cyclization approaches see Refs. 48±51, 53.
55. Other dialkyl-substituted acyclic amines were not tested. A
possible source of complications in these reactions is the
b-elimination from radicals 7 to yield a sulfonamidyl radical.
See, for example: Parsons, A. F.; Pettifer, R. M. J. Chem. Soc.,
Perkin Trans. 1 1998, 651±660. In the particular case of allyl-
or benzyl-substituted amines, an additional undesired possi-
bility that should be taken into account, as suggested by a
referee, is 1,5-hydrogen transfer after radical cyclization.
Some precedent for this behaviour exists in the related reac-
tions leading to the formation of cyclopentylamines.3
56. (a) Yadav, V.; Fallis, A. G. Can. J. Chem. 1991, 69, 779±789.
(b) Whitesell, J. K.; Minton, M. A. Stereochemical Analysis of
Alicyclic Compounds by C-13 NMR Spectroscopy; Chapman
& Hall: London, 1987.
30. Falb, E.; Bechor, Y.; Nudelman, A.; Hassner, A.; Albeck, A.;
Gottlieb, H. E. J. Org. Chem. 1999, 64, 498±506.
31. D'Costa, M.; Kumar, V. A.; Ganesh, K. N. Org. Lett. 1999, 1,
1513±1516.
Â
32. Cao, B.; Xiao, D.; Joullie, M. M. Org. Lett. 1999, 1, 1799±
1801.
33. Wang, G. T.; Chen, Y.; Wang, S.; Gentles, R.; Sowin, T.; Kati,
W.; Muchmore, S.; Giranda, V.; Stewart, K.; Sham, H.;
Kempf, D.; Laver, W. G. J. Med. Chem. 2001, 44, 1192±1201.
34. Bell, I. M.; Gallicchio, S. N.; Abrams, M.; Beshore, D. C.;
Buser, C. A.; Culberson, J. C.; Davide, J.; Ellis-Hutchings, M.;
Fernandes, C.; Gibbs, J. B.; Graham, S. L.; Hartman, G. D.;
Heimbrook, D. C.; Homnick, C. F.; Huff, J. R.; Kassahun, K.;
Koblan, K. S.; Kohl, N. E.; Lobell, R. B.; Lynch, J. J.; Miller,
57. Bertrand, M. P.; Deriggi, I.; Lesueur, C.; Gastaldi, S.;
Nouguier, R.; Jaime, C.; Virgili, A. J. Org. Chem. 1995, 60,
6040±6045.
58. Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of
Radical Reactions; VCH: Wienheim, 1996.
59. Hojo, M.; Yoshizawa, J.; Funahashi, Y.; Okada, R.;

R. Suero et al. / Tetrahedron 58(2002) 6211±6221
6221
Nakamura, S.; Tateiwa, J.; Hosomi, A. Heterocycles 1998, 49,
85±88.
61. Esch, P. M.; Hiemstra, H.; de Boer, R. F.; Speckamp, W. N.
Tetrahedron 1992, 48, 4659±4676.
62. Udding, J. H.; Tuijp, C. J. M.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1994, 50, 1907±1918.
60. An alternative explanation that cannot be ruled out would
involve a cis-selective cyclization of radical 7 followed by
competing reduction of the cyclized radical i (to terminate
the reaction) and ring-opening of i to give an a-acylamino
radical ii. This would then be expected to cyclize with
trans-selectivity.58
63. Garrohelion, F.; Merzouk, A.; Guibe, F. J. Org. Chem. 1993,
58, 6109±6113.
64. Perrin, D. D.; Armarego, W. F. L. Puri®cation of Laboratory
Chemicals; 3rd ed; Pergamon: Oxford, 1988; p 291.
65. Molander, G. A. Organic Reactions; Paquette, L. A., Ed.;
Wiley: New York, 1994; Vol. 46, pp 211±367.
66. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923±2925.