Synthesis of enantiopure 3-amino-1-azaspiro[4.5]decan-8-ones by halonium promoted cyclization of amino-tethered cyclohexenes

Article abstract of DOI:10.1016/S0040-4020(03)00309-0

Haloaminocyclization reactions of polysubstituted γ-aminocyclohexenes give 3-amino-1-azaspiro[4.5]decan-8-one derivatives. The stereocontrol, chemoselectivity (N-attack vs O-attack), and influence of the halonium ion are discussed.

Full text of DOI:10.1016/S0040-4020(03)00309-0

Tetrahedron 59 (2003) 2657–2665
Synthesis of enantiopure 3-amino-1-azaspiro[4.5]decan-8-ones by
halonium promoted cyclization of amino-tethered cyclohexenes
*
´
¨
Gemma Puigbo, Faıza Diaba and Josep Bonjoch
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII sn, 08028 Barcelona, Spain
Received 19 December 2002; revised 29 January 2003; accepted 24 February 2003
Abstract—Haloaminocyclization reactions of polysubstituted g-aminocyclohexenes give 3-amino-1-azaspiro[4.5]decan-8-one derivatives.
The stereocontrol, chemoselectivity (N-attack vs O-attack), and influence of the halonium ion are discussed. q 2003 Elsevier Science Ltd.
All rights reserved.
1. Introduction
The 1-azaspiro[4.5]decane framework is found in some
natural products isolated in the last decade.1–5 Among these
the immunosupressant FR9014831 and the antimuscarinic
TAN1251 derivatives2 incorporate an oxygenated function
at C-8 (Fig. 1). For this reason, there has been a growing
interest over the last few years in the development of
synthetic methodologies to achieve enantiopure 3-amino-1-
azaspiro-[4.5]decan-8-ones, which can be envisaged as
advanced building blocks for the synthesis of the afore-
mentioned natural compounds, since they incorporate two
of their rings and possess suitable functionalities for
assembling the rest of the skeleton.
Several procedures have been described for the preparation
of enantiopure compounds with the target framework I
(Scheme 1), but, apart from the pioneering work of Snider,6
in which the key step consists of an intramolecular nitrone/
alkene cycloaddition, followed by reduction of the labile
Scheme 1. Synthesis of enantiopure 3-amino-1-azaspiro [4.5]decan-8-ones.
N–O bond and lactamization, all other approaches
(Sorensen,7 Ciufolini,8 Wardrop,9 and Honda10) are based
on the oxidative azaspirocyclization of tyrosine derivatives
to give the corresponding 4,4-disubtituted cyclohexa-
dienones, which after hydrogenation give compounds of
type I.
In this paper, we describe the studies about a new synthetic
entry to these azabicyclic compounds, based on the
electrophilic addition of halonium ions to cyclohexene
compounds (g-aminoalkenes of type II, see Scheme 2)
embodying a 2,3-diaminopropyl side chain, in which the
nucleophilic v-nitrogen of the amine can act as a
Figure 1.
neighboring group to promote a haloaminocyclization and
Keywords: FR901483; azaspiro compounds; oxazines; nitrogen
render enantiopure 3-amino-1-azaspiro[4.5]decan-8-ones.11
heterocycles; cyclization.
The alkyl side chain incorporates an additional nitrogen
atom at the b-position, also linked to a stereogenic center, it
*
Corresponding author. Tel.: þ34-934024540; fax: þ34-934024539;
e-mail: bonjoch@farmacia.far.ub.es
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00309-0

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G. Puigbo et al. / Tetrahedron 59 (2003) 2657–2665
2658
Scheme 2. Reagents and conditions: (a) Li, NH3, EtOH, 2788C; (b) BnBr, K2CO3, EtOH, 69%; (c) (CH2OH)2, BF3·Et2O, THF, 73%; (d) LiAlH4, Et2O;
(e) DMSO, (COCl)2; (f) BnNH2, MgSO4, CH2Cl2; then NaBH4, MeOH (78% for three steps); (g) (diOMe)-L-tyrosine, MgSO4, CH2Cl2; then NaBH4, MeOH,
80%; (h) MeI, NaH, DMF, 63%; (i) DIBAL-H, toluene, 2788C; (j) as g, 64% for two steps; (k) I2, NaHCO3, CH2Cl2–H2O, room temperature (19%).
being noteworthy that the two nitrogen atoms come from
two different tyrosine units. Although halocyclizations with
a nitrogen as an intramolecular nucleophile is a well-known
process,12 amine compounds are scarcely used13 and there
are few precedents for the synthesis of azaspiro
derivatives.14
We next directed our attention to the study of the reaction of
unsaturated amine 4, which incorporates a new stereocenter,
with iodine. Using the same reaction conditions as above,
the azaspiro derivative 10 (25% yield), with the same
stereochemistry in C(3) and C(5) as that of the natural
products embodying this substructure, was isolated. In this
series, the unexpected methylenecyclohexanone 11 was also
isolated in some runs (see Scheme 3). The formation of the
rearranged compound 11 can be explained by the intra-
molecular genesis of an aziridinium salt, which is a substrate
that undergoes a Grob fragmentation19 to furnish a
compound with a b-aminoiminium salt side chain that is
lost after several equilibrium processes20 to render the
secondary amine 11. The first halo-amination product of this
2. Results and discussion
The studies were first carried out using the cyclohexene
derivative 3 as a model and then with compounds 4 and 8,
all of which were synthesized from tyrosine derivatives by a
Birch reduction to afford the corresponding dihydroanisole,
in which the enol ether was converted into the ethylene
acetal to avoid the migration of the double bond of the
cyclohexene ring formed (Scheme 2). The carboxylic acid
of this first unit of tyrosine, in which the amino group had
been previously protected either as the dibenzylamino
derivative (i.e 1) or the N(Boc)Me compound (i.e. 5), was
converted to the corresponding aldehyde (compounds 2 and
7).15 The preparation of the substrates 3, 4, and 8 was
concluded with a reductive amination, either with benzyl-
amine to afford 3 or with another tyrosine unit to give
compounds 4 and 8. Having prepared the precursors, we
began to study the haloaminocyclization reaction.16,17
On reacting with iodine the unsaturated amine 3 afforded the
iodo azaspiro derivative 9, although in low yield, as the
result of a 5(N)-exo-trig cyclization.18 The process involves
the formation of two new stereocenters: the C(5) spiro
center and the C(6) incorporating the halogen atom. The
structure of 9 was assigned using a combination of COSY,
NOESY, HMQC, and HMBC experiments. The remaining
materials formed in this reaction were not identified, making
it impossible to discount the formation of other compounds
and evaluate any possible diastereoselection in the
iodonium ion formation step (see below).
Scheme 3. Iodine-promoted process upon aminoalkene 4

Scheme 4. Cyclization processes promoted by halonium ions upon aminoalkene 8.

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G. Puigbo et al. / Tetrahedron 59 (2003) 2657–2665
2660
Table 1. 13C NMR Chemical shifts of 3-amino-1-azaspiro[4.5]decan-8-ones
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
NMe
C-20
CH2Ar
Other
a
b
c
9a
52.0
46.8
47.0
54.8
53.5
51.7
33.4
34.8
32.8
65.3
66.2
66.6
39.4
40.4
56.3
46.7
46.4
44.5
108.8
108.3
108.0
32.5
33.0
32.8
21.4
24.8
27.7
–
29.2
28.7
64.3/64.6
64.3/64.6
64.4/64.6
51.4
38.1
37.4
12aa
12ba
In ppm relative to TMS. Recorded in CDCl3 at 75.4 MHz. Assignments based on HSQC experiments.
a
54.8 (CH2Ar)2, 128.4/128.6 (m-Ar), 128.0/128.1 (o-Ar), 126.6/126.7 (p-Ar), 139.4/140.3 (ipso-Ar).
28.5, 79.5, 155.8 (NBoc), 51.2, 171.8 (CO2Me), 59.0 (CH), 55.2, 113.8, 129.7, 130.1, 158.2 (4-OMeC6H4).
28.5, 79.5, 155.8 (NBoc), 51.2, 173.7 (CO2Me), 58.9 (CH), 55.2, 113.7, 129.9, 130.1, 158.1 (4-OMeC6H4).
b
c
latter process is a diastereomer of 10, indicating that the
initial electrophilic attack upon alkene 4 is not
stereoselective.
azaspirocyclization leading to 12b0 compites with that
of oxacyclization leading to 13b. In all cases the cleavage of
the cyclic halonium ions takes place via a transition state in
which the nucleophile approaches the carbon from the side
opposite to the bond that is to be broken and trans
stereoisomers are exclusively formed. Although these
processes are not diastereoselective, it is true that in the
bromo derivative series, if the halogen was0 removed,
compounds 12b (5R configuration) and 12b (5S) are
precursors of the same azaspiro compound in which carbon
C-5 is not a stereogenic atom.
To avoid the unwanted neighboring of the N–C(4) we
changed the protecting group of the nitrogen bonded to this
carbon from NBn2 to N(Boc)Me. Treatment of cyclohexene
8 with iodine gave azaspiro derivative 12a together with the
oxazinone 13a, the latter resulting again from an undesired
reaction pathway in which the carbamate unit reacts
intramolecularly with the halonium ion intermediate21
(Scheme 4).
The NMR chemical shifts of synthesized bicyclic com-
pounds (for 13C NMR data, see Tables 1 and 2) allows the
assignment of their constitution, the absolute configuration
of either azaspirodecanes or oxazinones being established
from the NOESY data taking into account the known S
configuration of the other stereogenic centers. Compounds
of oxazinone type (13) show NMR data24 similar to that of
the corresponding azaspiroderivatives (9, 10, 12) except in
the absence of the methyl signal corresponding to the
N-Boc, but maintaining a carbonyl group of carbamate type,
which is slightly more upfield (d 153.5), as well as the signal
attributable to the stereogenic methine carbon of the
reduced unit of tyrosine, which appears at d 3.35 instead
of d 4.85 for the azaspiro compounds. The signal of the
N-Me group is diagnostic for compounds 13 (dH 2.95 and dC
33.0), considering the values in the azaspiro derivatives (dH
2.85 and dC 29.0).
Finally, the haloaminocyclization from 8 was carried out
using 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCO) as
a source of bromonium ions.22 In this case the cyclization
product was formed in 52% yield as a mixture of
diastereoisomers (12b, 12b0), the oxazinone 13b being
formed only in 13%. Additionally, we attempted the
cyclization through the N-chloroamine corresponding to
amine 8. When treated with TiCl3 and BF3Et2O it gaves
exclusively the oxazinone 13c in 70% yield, which was
characterized after a reductive step (Bu3SnH, AIBN) that
gave 13d. The formation of 13c implies an ionic mechanism
instead of the desired radical process involving an N-aminyl
species.23
The fact that the aforementioned halonium promoted pro-
cesses differ according to the facial diastereoselection of the
halonium attack upon the cyclohexene ring can be explained
as follows. When the formation of the cyclic halonium
intermediate occurs on the b face, the transition state
associated with the nitrogen attack upon this intermediate is
favored, while when the cyclic halonium ion is formed on
the a face the aminocyclization is disfavored for steric
reasons, and hence the attack of the oxygen atom of the
carbamate unit is now the preferred process, as depicted in
Scheme 4. In the reaction promoted by the bromonium
species, smaller than the iodonium species, the process of
In summary, we have shown that enantiopure aminoalkene
8 undergoes competitive halonium-promoted cyclizations
giving N- or O-cyclised products. From a synthetic
standpoint the bromoaminocyclization reaction is of interest
since although it furnishes azaspiro compound 12b as a
diastereoisomeric mixture, both diastereomers could be
useful as intermediates for the synthesis of TAN1251
derivatives, in which the azaspiro carbon is not a stereogenic
center.25
Table 2. 13C NMR Chemical shifts of 3-methyl-4-[(3S)-3-methoxycarbonyl-4-(4-methoxyphenyl)-2-azabutyl]-1-oxa-3-azaspiro[5.5]undecan-2,9-diones
C-2
NMe
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-11
CH2N
CH
CH2Ar
13aa
13cb
13dc
153.5
153.5
154.3
32.8
32.8
33.0
53.3
53.0
53.5
29.9
31.2
35.5
78.3
79.2
76.1
34.5
61.6
29.8
44.6
40.9
30.8
107.4
106.9
108.2
31.7
29.1
30.0
28.3
26.4
27.8
49.2
49.3
49.5
63.3
63.3
63.5
39.1
39.1
39.1
In ppm relative to TMS. Recorded in CDCl3 at 75.4 MHz. Assignments based on HSQC experiments.
a
51.9, 174.9 (CO2Me), 55.2, 113.8, 129.3, 130.2, 158.3 (4-OMeC6H4).64.5/64.8 (OCH2).
51.8, 174.8 (CO2Me), 55.1, 113.7, 129.2, 130.1, 158.2 (4-OMeC6H4).64.4/64.7 (OCH2).
51.8, 174.9 (CO2Me), 55.2, 113.8, 129.3, 130.2, 158.4 (4-OMeC6H4).64.2/64.4 (OCH2).
b
c

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2661
3. Experimental
(dd, J¼12.3, 9 Hz, 1H), 2.11 (m, 2H), 2.25 (m, 2H), 2.44
(dm, J¼12.3 Hz, 1H), 2.96 (m, 2H), 3.43 and 3.84 (2d,
J¼14 Hz, 2H each), 3.96 (m, 4H), 5.36 (m, 1H), 7.20–7.36
(m, 10H); 13C NMR (50.3 MHz, CDCl3) 27.4 (C-60), 31.0
(C-50), 32.9 (C-3), 35.7 (C-30), 53.0 (CH2Ar), 56.8 (C-2),
60.8 (CH2OH), 64.3 (OCH2), 107.7 (C-40), 121.1 (C-20),
127.1 (p-Ar), 128.4 (o-Ar), 128.9 (m-Ar), 134.3 (C-10),
139.2 (ipso-Ar).
3.1. General
For general procedures, see Ref. 11.
3.1.1. (2S)-2-(N,N-Dibenzylamino)-3-(4-oxocyclohex-1-
enyl)propanoic acid ethyelene acetal (1). O-Methyl-L-
tyrosine hydrochloride (12.5 g, 54.2 mmol) was submitted
to the Birch reduction, following the previously reported
procedure to give lithium (2S)-2-amino-3-(4-methoxy-2,5-
dihydrophenyl)propanoate.26 To a solution of the above
dihydroanisole in EtOH (200 mL) were added K2CO3
(18.7 g, 135.4 mmol) and benzyl bromide (21.9 mL,
184.1 mmol) and the mixture was stirred at reflux
temperature for 7 h. The reaction mixture was filtered, the
solvent removed, and the residue taken up with CH2Cl2
(200 mL). The solution was washed with brine (2£200 mL),
dried, and concentrated. The residue was purified by
chromatography (SiO2, CH2Cl2 to 8:2 CH2Cl2–MeOH)
to give (2S)-2-dibenzylamino-3-(4-methoxy-2,5-dihydro-
phenyl)propionic acid (14.1 g, 69%): IR (NaCl) 2830–
3029, 1699, 1666, 1605, 1217 cm21; 1H NMR (200 MHz) d
2.44–2.60 (m, 4H), 2.68–2.81 (m, 2H), 3.59 (s, 3H, OCH3),
3.65 (m, 1H, H-2), 3.71 and 3.88 (2d, J¼14.8 H0 z, 2H each,
CH2Ar), 4.57 (m, 1H, H-30), 5.48 (m, 1H, H-6 ), 7.28–7.36
(m, 0 10H, Ar); 13C NMR (50 MHz) 28.7 and 29.3 (C-30,
C-6 ), 36.0 (C-3), 54.0 (OCH3), 54.3 (CH2Ar), 58.9 (C-2),
90.3 (C-50), 121.0 (C-20), 127.3 (p-Ar), 128.3 (o-Ar), 129.0
(m-Ar), 131.6 (C-10), 138.5 (ipso-Ar), 152.7 (C-40), 176.9
(CO2H).
A solution of oxalyl chloride (0.13 mL, 1.5 mmol) and
DMSO (0.18 mL, 2.5 mmol) in CH2Cl2 (10 mL) cooled at
2788C was stirred for 5 min. A solution of the above
alcohol (500 mg, 1.3 mmol) in CH2Cl2 (2 mL) was slowly
added and, after 30 min at 2788C, triethylamine (0.71 mL,
5.1 mmol) was added and the mixture was allowed to warm
to room temperature. The solution was poured into H2O
(10 mL), the phases were separated and the aqueous layer
was extracted with CH2Cl2 (4£10 mL). The organic extracts
were washed with brine (3£50 mL), dried and concentrated
to give aldehyde 2 (505 mg), which was used without
1
purification: H NMR (200 MHz, CDCl3) 1.75 (t, J¼7 Hz,
2H), 2.01 (m, 2H), 2.28 (m, 2H), 2.45 (d, J¼8 Hz, 2H), 3.41
(t, J¼8 Hz, 1H), 3.79 (s, 4H), 4.00 (m, 4H), 5.40 (m, 1H),
7.26–7.38 (m, 10H), 9.76 (s, 1H); 13C NMR (50.3 MHz,
CDCl3) 27.2 (C-60), 31.1 (C-50), 32.3 (C-3), 35.9 (C-30), 54.4
(C-2), 64.4/64.6 (CH2O), 107.8 (C-40), 121.8 (C-20), 127.2
(p-Ar), 128.3 (o-Ar), 128.8 (m-Ar), 134.0 (C-10), 139.3
(ipso-Ar).
3.1.3. (2S)-N-Benzyl-2-(N,N-dibenzylamino)-3-(4-oxo-
cyclohex-1-enyl)propanamine ethyelene acetal (3). To a
solution of aldehyde 2 (488 mg, 1.25 mmol) in CH2Cl2
(5 mL) at 08C were added anhydrous MgSO4 (300 mg,
2.50 mmol) and benzaldehyde (0.14 mL, 1.25 mmol). The
mixture was stirred at room temperature for 4 h, filtered
through Celite, and concentrated to give the crude imine. To
a stirred solution of this imine (1.25 mmol) in MeOH
(5 mL) was slowly added NaBH4 (94 mg, 2.50 mmol) at
08C. The mixture was stirred at room temperature for 4 h
and quenched by addition of H2O (15 mL). After removal of
MeOH, the aqueous phase was extracted with CH2Cl2
(4£15 mL). The dried organic extracts were purified by
chromatography (Al2O3, 1:1 CH2Cl2–hexane), to give 3
(470 mg, 78% from acid 1): [a]D¼þ56.2 (c 0.05, CHCl3);
1H NMR (500 MHz, CDCl3, COSY, HSQC, HMBC): 1.70
(m, 2H, H-500), 1.91 (dd, J¼13.6,012 Hz, 2H, H-3, NH), 2.07
(m, 2H, H-6 ), 2.22 (m, 2H, H-3 ), 2.44 (d, J¼13.6 Hz, 1H,
H-3), 2.54 (dd, J¼12.8, 5 Hz, 1H, H-1), 2.67 (dd, J¼12.8,
9.2 Hz, 1H, H-1), 2.98 (m, 1H, H-2), 3.44 and 3.73 (d,
J¼13.6 Hz, 2H each, CH2N), 3.47 and 3.62 (2d, J¼13.5 Hz,
1H each, CH2NH), 3.95 (m, 4H, CH2O), 5.29 (m, 1H, H-20),
7.210–7.28 (m, 15H, Ar); 13C NMR (50.3 MHz, CDCl3) 27.5
(C-6 ), 31.2 (C-50), 34.5 (C-3), 35.8 (C-30), 49.7 (C-1), 53.4
(CH2N), 53.5 (CH2NH), 55.2 (C-2), 64.4 (CH2O), 108.0
(C-40), 120.8 (C-20), 126.7/126.9 (p-Ar), 128.0/128.2 (o-Ar),
128.8 (m-Ar), 135.2 (C-10), 140.1/140.8 (ipso-Ar). Anal.
calcd for C32H38N2O2·1/3H2O: C 78.66, H 7.97, N 5.73.
Found: C 78.49, H 7.95, N 5.77.
To a solution of the above enolether (2.0 g, 5.3 mmol) in
THF (10 mL) at 08C were added ethylene glycol (1.18 mL,
21.2 mmol) and BF3·Et2O (0.13 mL, 1.1 mmol). After
stirring overnight, the reaction mixture was poured into
cooled saturated aqueous NaHCO3 (100 mL) and extracted
with CH2Cl2 (5£100 mL). The dried organic extracts were
concentrated to give a residue, which was purified by
chromatography (SiO2, CH2Cl2 to CH2Cl2–MeOH 98:2) to
afford 1 (1.57 g, 73%) as a solid; 1H NMR (200 MHz,
CDCl3) 1.75 (t, J¼7 Hz, 2H, H-50), 1.99 (m, 2H, H-60), 2.30
(m, 2H, H-30), 2.59 (d, J¼7.4 Hz, 2H, H-3), 3.61 (t,
J¼7.4 Hz, 1H, H-2), 3.73 and 3.90 (2d, J¼13.8 Hz, 2H
each, CH2Ar), 4.03 (m, 4H, CH2O), 5.44 (m, 1H, H-20),
7.270–7.39 (m, 100H, Ar); 13C NMR (50.3 MHz, CDCl3) 26.5
(C-6 ), 31.0 (C-5 ), 35.8 (C-30), 36.4 (C-3), 54.2 (CH2Ar),
59.1 (C-2), 64.4 (CH2O), 108.1 (C-40), 122.0 (C-20), 127.3
(p-Ar), 128.3 (o-Ar), 129.1 (m-Ar), 133.6 (C-10), 138.5
(ipso-Ar), 177.0 (C-1). Anal. calcd for C25H29NO4·1/2H2O:
C 72.09, H 7.26, N 3.36. Found: C 72.16, H 7.09, N 3.41.
3.1.2. (2S)-2-(N,N-Dibenzylamino)-3-(4-oxocyclohex-1-
enyl) propanal ethylene acetal (2). To a solution of
LiAlH4 (224 mg, 5.9 mmol) in Et2O (12 mL) at 08C was
added the acid 1 (2.0 g, 4.9 mmol) and the mixture was
stirred at room temperature overnight. Successively, H2O
(0.2 mL), 15% aqueous NaOH (0.2 mL) and H2O (0.7 mL
were slowly added at 08C. The mixture was filtered through
Celite, dried and concentrated to give (2S)-2-(N,N-dibenzyl-
amino)-3-(4-oxocyclohex-1-enyl)propanol ethylene acetal
(2.0 g), which was used in the next step without purification:
1H NMR (200 MHz, CDCl3) 1.74 (tm, J¼6.5 Hz, 2H), 1.90
3.1.4. Methyl (2S,5S)-5-(N,N-dibenzylamino)-2-(4-meth-
oxyphenyl)methyl-6-(4-oxocyclohex-1-enyl)-3-aza-
hexanoate ethylene acetal (4). Operating as above, from
aldehyde 2 (505 mg, 1.3 mmol) and methyl ester of

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2662
O-methyl-L-tyrosine (319 mg, 1.5 mmol) in CH2Cl2 (3 mL)
and after reduction with NaBH4, 4 (592 mg, 80%) was
isolated after chromatography (Al2O3, CH2Cl2):
[a]D¼þ21.8 (c 0.21, CHCl3); 1H NMR (500 MHz,
CDCl3, COSY, HSQC, HMBC) 1.62 (m, 2H, H-50), 1.81
(dd, J¼13.2, 09.6 Hz, 2H, H-6, NH), 1.93 (m, 2H, H-60), 2.17
(m, 2H, H-3 ), 2.31 (dm, J¼13.2 Hz, 1H, H-6), 2.40 (dd,
J¼11.8, 8 Hz, 1H, H-4), 2.52 (dd, J¼11.8, 4.8 Hz, 1H, H-4),
2.74 (dd, J¼13.6, 8.1 Hz, 1H, CH2Ar), 2.81 (m, 1H, H-5),
2.87 (dd, J¼13.6, 5.4 Hz, 1H, CH2Ar), 3.33 (m, 1H, H-2),
3.37 and 3.56 (2d, J¼13.2 Hz, 2H each, NCH2Ar), 3.58 (s,
3H, CO2CH3), 3.73 (s, 3H, OCH3), 3.89 (m, 4H, CH2O),
5.20 (m, 1H, H-20), 6.81 (d, J¼8.8 Hz, 2H, m-ArOMe), 7.06
(d, J¼8.8 Hz, 2H, o-ArOMe), 7.09–7.20 (m, 10H, Ar); 13C
NMR (50.3 MHz, CDCl3) 27.5 (C-60), 31.2 (C-50), 35.0
(C-6), 35.8 (C-30), 38.8 (CH2Ar), 48.2 (C-4), 51.8
(CO2CH3), 53.5 (NCH2Ar), 55.2 (OCH3), 56.1 (C-5), 63.8
(C-2), 64.4 (CH2O), 108.0 (C-40), 114.0 (m-ArOMe), 120.8
(C-20), 126.9 (p-Ar), 128.2/128.8 (o,m-Ar), 129.5 (ipso-
ArOMe), 130.4 (o-ArOMe), 135.2 (C-10), 139.9 (ipso-Ar),
158.5 (p-ArOMe), 174.4 (C-1). Anal. calcd for
C36H44N2O5·1/4H2O: C 73.38, H 7.61, N 4.75. Found: C
73.31, H 7.64, N 4.73.
3.1.6. Methyl (2S)-2-(N-tert-butoxycarbonyl-N-methyl-
amino)-3-(4-oxocyclohex-1-enyl)propanoate ethylene
acetal (6). To a cooled (08C) solution of acid 5 (400 mg,
1.2 mmol) in DMF (4 mL) NaH (117 mg, 4.9 mmol) and
methyl iodide (0.38 mL, 6.1 mmol) were added and the
solution was stirred overnight at room temperature. 5%
aqueous NaHSO4 (30 mL) was added and the mixture was
extracted with CH2Cl2 (5£30 mL). The dried organic
extracts were concentrated and purified by chromatography
(SiO2, CH2Cl2) to give 6 (272 mg, 63%): [a]D¼217.0 (c
9H, C(CH3)3), 1.75 (m, 2H, H-50), 2.12–2.23 (m, 2H, H-60),
2.23 (m, 2H, H-30), 2.42 (dd, J¼14.4, 11.1 Hz, 1H, H-3),
2.57 (dd, J¼14.4, 6.9 Hz, 1H, H-3), 2.79 (s, 3H, NCH3),
3.70 (s, 3H, CO2CH3), 3.94 (s, 4H, CH2O), 4.14 (dd,
J¼14.1, 6.9 Hz, 1H, H-2), 5.96 (m, 1H, H-20); 13C NMR
(75.5 MHz, CDCl3), major/minor rotamers, 26.5/26.9
(C-60), 28.2 (C(CH3)3), 30.2/30.5 (NCH3), 30.9/31.1
(C-50), 35.7/35.6 (C-30), 36.3/36.6 (C-3), 51.9 (CO2CH3),
55.8/58.0 (C-2), 64.2/64.1 (CH2O), 80.0/80.5 (C(CH3)3),
107.6/107.5 (C-40), 121.4/121.8 (C-20), 133.2/132.8 (C-10),
155.8/154.9 (NCO2), 172.1/171.9 (C-1). Anal. calcd for
C18H29NO6·1/4H2O: C 60.07, H 8.26, N 3.89. Found: C
60.15, H 8.49, N 3.98.
1
0.22, CHCl3); H NMR (300 MHz, CDCl3, 558C) 1.45 (s,
3.1.5. (2S)-2-tert-Butoxycarbonylamino-3-(4-oxocyclo-
hex-1-enyl)propanoic acid ethyelene acetal (5). Ammonia
(225 mL) was added to a cooled (2788C) solution of
O-methyl-N-tert-butoxycarbonyl-L-tyrosine (5 g, 16.9 mmol)
in EtOH (50 mL). Small chips of lithium (705 mg,
101.6 mmol) were added with vigorous stirring until the
solution was a persistent deep blue, and stirring was
maintained for 90 min. The cooling bath was removed, the
ammonia was allowed to evaporate overnight, and the
reaction mixture was concentrated, the residue was taken up
with 5% aqueous NaHSO4 until pH 5 and the aqueous
solution was extracted with CH2Cl2 (4£200 mL). The dried
organic extracts were concentrated to give crude (2S)-2-tert-
butoxycarbonylamino-3-(4-methoxy-2,5-dihydrophenyl)
propanoic acid (4.69 g, 93%); 1H NMR (200 MHz, CDCl3,
two rotamers in a 3:2 ratio), major rotamer: 1.44 (s, 9H),
2.25 (m, 2H), 2.25–2.75 (m, 2H), 2.75 (m, 2H), 3.55 (s, 3H),
4.39 (m, 1H), 4.90 (d, J¼6 Hz, 1H), 4.95 (m, 1H), 5.67 (d,
J¼6 Hz, 1H). For the minor rotamer: 3.57 (s, 3H), 4.61 (m,
1H), 5.53 (m, 1H).
3.1.7. (2S)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-
(4-oxocyclohex-1-enyl)propanal ethylene acetal (7). To a
solution of ester 6 (65 mg, 0.18 mmol) in toluene (1 mL) at
2788C was added dropwise DIBALH (0.27 mL, 1 M in
hexane). After the mixture was stirred for 2.5 h, MeOH
(0.2 mL) was added and the temperature was raised until
room temperature, brine (15 mL) was added and the mixture
extracted with CH2Cl2 (5£15 mL). The dried organic
extracts were concentrated (temperature of bath below
308C to avoid racemization) to give aldehyde 7 (58 mg),
which was used directly in the next step. IR (NaCl) 2927,
1
1738, 1692, 1153 cm21; H NMR (300 MHz, CDCl3) 1.45
(s, 9H), 1.76 (m, 2H), 2.23 (m, 2H), 2.52–2.80 (m, 4H), 2.81
and 2.90 (2 s, 3H), 3.96 (s, 4H), 4.45 (dd, J¼14.1, 6.9 Hz,
1H), 5.38 (m, 1H), 9.60 (s, 1H).
3.1.8. Methyl (2S,5S)-5-(N-tert-butoxycarbonyl-N-
methylamino)-2-(4-methoxyphenyl)methyl-6-(4-oxo-
cyclohex-1-enyl)-3-azahexanoate ethylene acetal (8).
Operating as above from 2, using aldehyde 7 (58 mg,
0.18 mmol) and the methyl ester of O-methyl-L-tyrosine
(31 mg, 0.15 mmol) the corresponding imine was formed,
which was reduced with NaBH4 (14 mg, 0.37 mmol). After
work-up and purification by chromatography (SiO2, CH2Cl2
to CH2Cl2–MeOH 95:5) amine 8 (50 mg, 64%) and the
alcohol coming from the reduction of aldehyde 7 (20 mg)
were isolated. [a]D¼þ3.3 (c 0.26, CHCl3); 1H NMR
(300 MHz, CDCl3, 558C) 1.44 (s, 9H, C(CH3)3), 1.72 (m,
2H, H-50), 1.96–2.14 (m, 4H, H-60, H-6), 2.20 (m, 2H, H-30),
2.45 (dd, J¼12, 9.3 Hz, 1H, H-4), 2.55 (brs, 3H, NCH3),
2.63 (dd, J¼12, 5.4 Hz, 1H, H-4), 2.79 (dd, J¼13.8, 7.5 Hz,
1H, CH2Ar), 2.89 (dd, J¼13.8, 6 Hz, 1H, CH2Ar), 3.41 (dd,
J¼7.5, 6 Hz, 1H, H-2), 3.65 (s, 3H, CO2CH3), 3.77 (s, 3H,
OCH3), 3.93 (s, 4H, CH2O), 4.18 (m, 1H, H-5), 5.26 (m, 1H,
H-20), 6.80 (dm, J¼8.6 Hz, 2H, m-Ar), 7.07 (dm, J¼8.6 Hz,
2H, o-Ar); 13C NMR (75.5 MHz, CDCl3, two rotamers)
26.8/26.9 (C-60), 28.3 (C(CH3)3), 31.0/31.1 (C-50), 35.5/35.7
(C-30), 37.8/38.0 (C-6), 38.4/39.0 (CH2Ar), 49.3/49.6 (C-4),
Ethylene glycol (0.39 mL, 7.1 mmol) and BF3·Et2O (44 mL,
0.35 mmol) were added at 08C to a solution of the above
acid (526 mg, 1.8 mmol in THF (6 mL) and the mixture was
stirred at room temperature overnight. H2O was added
(25 mL) and the mixture was extracted with CH2Cl2
(5£25 mL). The dried organic extracts were concentrated
to give 5 (541 mg, 93%), which was used directly in the next
step: 1H NMR (300 MHz, CDCl3, 508C) 1.44 (s, 9H,
C(CH3)3), 1.77 (t, J¼6.6 Hz, 2H, H-50), 2.21 (t, J¼6.9 Hz,
2H, H-60), 2.27 (m, 2H, H-30), 2.34 (dd, J¼14.1, 8.7 Hz, 1H,
H-3), 2.53 (m, 1H, H-3), 3.98 (s, 4H, CH2O), 4.40 (m, 1H,
H-2), 4.99 (d, J¼7.8 Hz, 1H, NH), 5.43 (m, 1H, H-20), 6.39
(s, 1H, CO2H); 13C NMR (75.5 MHz, CDCl3) 26.9 (C-60),
28.3 (C(CH3)3), 31.0 (C-50), 35.7 (C-30), 39.9 (C-3), 51.7
(C-2), 64.3 (CH2O), 80.1 (C(CH3)3), 107.8 (C-40), 122.8
(C-20), 132.5 (C-10), 155.5 (NCO2), 176.3 (C-1). Anal. calcd
for C16H25NO6: C 58.70, H 7.70, N 4.28. Found C 58.55, H
7.82, N 4.11.

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G. Puigbo et al. / Tetrahedron 59 (2003) 2657–2665
2663
51.4/51.6 (CO2CH3), 51.8/52.4 (C-5), 53.9/55.0 (OCH3),
62.8/63.0 (C-2), 0 64.2 (CH2O), 78.8/79.3 (C(CH3)3),
107.7/107.8 (C-4 ), 113.6/113.7 (m-Ar), 120.4/120.8
(C-200), 129.1/129.4 (ipso-Ar), 130.0 (o-Ar), 133.8/134.3
(C-1 ), 155.8/155.9 (NCO2), 158.1/158.2 (p-Ar), 174.6
(C-1). Anal. calcd for C28H42N2O7·1/4H2O: C 64.29, H
8.19, N 5.35. Found: C 64.19, H 8.19, N 5.31.
(0.29 mmol) of I2, and after chromatography (Al2O3,
hexane to EtOAc), azaspiro derivative 12a (22 mg, 19%)
and oxazinone 13a (35 mg, 31%) were isolated. (3S, 5R,6S)-
3-(N-tert-Butoxycarbonyl-N-methylamino)-6-iodo-1-[(1S)-
1-(methoxycarbonyl)-2-(4-methoxyphenyl) ethyl]-1-aza-
spiro[4.5]decan-8-one ethylene acetal (12a): 1H NMR
(400 MHz, CDCl3, COSY, NOESY, HSQC, HMBC) 1.47
(s, 9H, C(CH3)3), 1.59 (m, 2H, H-10), 1.66 and 1.75 (2m, 1H
each, H-9), 1.87 (tm, J¼9.6 Hz, 1H, H-4), 2.16 (m, 1H,
H-4), 2.23 (t, J¼13.2 Hz, 1H, H-7ax), 2.50 (ddd, J¼13.2, 4,
2.8 Hz, 1H, H-7eq), 2.89 (s, 3H, NCH3), 3.09 (d, J¼8 Hz,
2H, CH2Ar), 3.14 (dd, J¼9.2, 4.8 Hz, 1H, H-2), 3.50 (s, 3H,
CO2CH3), 3.52 (t, J¼8 Hz, 1H, CHCO), 3.55 (t, J¼9.2 Hz,
1H, H-2), 3.78 (s, 3H, OCH3), 3.90 (m, 4H, CH2O), 4.71
(dd, J¼13.2, 4 Hz, 1H, H-6), 4.90 (m, 1H, H-3), 6.81 (d,
J¼8.7 Hz, 2H, m-Ar), 7.13 (d, J¼8.7 Hz, 2H, o-Ar); 13C
NMR, see Table 1. (4S,6S,7R)-7-Iodo-3-methyl-4-[(3S)-3-
(methoxycarbonyl)-4-(4-methoxyphenyl)-2-aza-butyl]-1-
oxa-3-azaspiro[5.5]undecan-2,9-dione ethylene acetal
(13a): 1H NMR (400 MHz, CDCl3, COSY, NOESY,
HSQC, HMBC) 1.45 (m, 1H, H-11), 1.59 (m, 1H,
H-10ax), 1.81 (ddd, J¼14, 6.8, 4 Hz, 1H, H-10eq), 2.01
(m, 1H, H-11), 2.02 (m, 1H, H-5), 2.20 (t, J¼13.6 Hz, 1H,
H-8ax), 2.45 (ddd, J¼13.6, 4.4, 2.8 Hz, 1H, H-8eq), 2.49
(m, 1H, CH2N), 2.48 (m, 1H, H-5), 2.82 (dd, J¼13.6,
7.6 Hz, 1H, CH2Ar), 2.92 (dd, J¼13.6, 6 Hz, 1H, CH2Ar),
2.96 (s, 3H, NCH3), 2.99 (dd, J¼12, 5.2 Hz, 1H, CH2N),
3.27 (m, 1H, H-4), 3.39 (dd, J¼8, 5.6 Hz, 1H, CHCO), 3.70
(s, 3H, CO2CH3), 3.79 (s, 3H, OCH3), 3.94 (m, 4H, CH2O),
4.54 (dd, J¼13.6, 4.4 Hz, 1H, H-7), 6.83 (d, J¼8.6 Hz, 2H,
m-Ar), 7.13 (d, J¼8.6 Hz, 2H, o-Ar); 13C NMR, see Table 2.
HRMS calculated from C24H33IN2O5 588.1332, found
588.1292.
3.1.9. (3S,5R,6S)-1-Benzyl-3-(N,N-dibenzylamino)-6-
iodo-1-azaspiro[4.5]decan-8-one ethyelene acetal (9). To
a solution of amine 3 (50 mg, 0.10 mmol) in CH2Cl2
(0.5 mL) and 5% aqueous NaHCO3 (1 mL) was added
dropwise a solution of I2 (26 mg, 0.10 mmol) in CH2Cl2
(1.5 mL). After stirring at room temperature overnight, 10%
aqueous Na2S2O3 (15 mL) was added and the mixture was
extracted with CH2Cl2 (3£15 mL). The dried organic
extracts were concentrated and the residue was purified by
chromatography (Al2O3, 75:25 hexane–CH2Cl2) to give 9
(12 mg, 19%); 1H NMR (500 MHz, CDCl3, COSY,
NOESY, HSQC, HMBC) 1.58–1.61 (m, 1H, H-10),
1.68–1.71 (m, 2H, H-9, H-10), 1.79–1.82 (m, 1H, H-9),
2.13 (d, J¼8 Hz, 2H, H-4), 2.35 (t, J¼13 Hz, 1H, H-7ax),
2.46 (t, J¼10.5 Hz, 1H, H-2), 2.55 (dt, J¼13, 4 Hz, 1H,
H-7eq), 2.99 (dd, J¼10.5, 3 Hz, 1H, H-2), 3.13 and 3.91 (2d,
J¼13 Hz, 1H each, CH2Ar), 3.46 (m, 1H, H-3), 3.55 and
3.81 (2d, J¼14.5 Hz, 2H each, (CH2Ar)2), 3.93 (m, 4H,
CH2O), 4.77 (dd, J¼13, 4 Hz, H-6ax), 7.20–7.50 (m, 15H,
Ar); 13C NMR, see Table 1.
3.1.10. (3S,5R,6S)-3-(N,N-Dibenzylamino)-6-iodo-1-
[(1S)-1-(methoxycarbonyl)-2-(4-methoxyphenyl)ethyl]-
1-azaspiro[4.5]decan-8-one ethylene acetal (10).
Operating as above, starting from 4 (30 mg, 0.05 mmol)
and after chromatography (Al2O3, 3:1 hexane–CH2Cl2),
iodo derivative 10 (9 mg, 25%) was isolated; 1H NMR
(200 MHz, CDCl3) 1.48–1.69 (m, 4H), 2.00 (m, 2H), 2.27
(t, J¼13.5 Hz, 1H, H-7ax), 2.51 (dm, J¼13.5 Hz, H-7eq),
3.10 (m, 2H), 3.28–3.45 (m, 2H), 3.45 (m, 1H), 3.46 (s, 3H,
CO2CH3), 3.54 (m, 1H), 3.67 and 3.76 (2d, J¼15 Hz, 2H
each, CH2Ar), 3.77 (s, 3H, OCH3), 3.89 (m, 4H, CH2O),
4.72 (dd, J¼13.5, 3.8 Hz, 1H, H-6ax), 6.78 (d, J¼8.7 Hz,
2H, m-ArOMe), 7.12 (d, J¼8.7 Hz, 2H, o-ArOMe), 7.26–
7.42 (m, 10H, Ar).
3.1.12. Cyclization of 8 promoted by TBCO. To a solution
of 8 (50 mg, 0.10 mmol) in CH2Cl2 (2 mL) was added
2,4,4,6-tetrabromo-2,5-cyclohexadienone
(82 mg,
0.20 mmol) and the reaction mixture was stirred at room
temperature overnight. CH2Cl2 (8 mL) was added and the
organic layer was washed with saturated aqueous Na2CO3
(2£10 mL). The dried organic extracts were concentrated
and purified by chromatography (Al2O3, hexane to EtOAc)
to give a partially separable mixture of 6-bromoazaspiro
derivatives 12b (30 mg, 30%) and 12b0 (22 mg, 22%) and
the oxazinone 13b (12 mg, 13%). (3S,5R,6S)-6-Bromo-3-
(N-tert-butoxycarbonyl-N-methylamino)-1-[(1S)-1-(meth-
oxycarbonyl)-2-(4-methoxyphenyl)ethyl]-1-azaspiro
[4.5]decan-8-one ethylene acetal (12b): 1H NMR
(500 MHz, CDCl3, COSY, HMQC) 1.47 (s, 9H, C(CH3)3),
1.53–1.60 (m, 2H, H-10), 1.66 (m, 2H, H-9), 2.05 (m, 3H,
H-7ax, H-4), 2.33 (dm, J¼11.1 Hz, 1H, H-7eq), 2.85 (s, 3H,
NCH3), 3.05 (m, 2H, CH2Ar), 3.17 (m, 1H, H-2), 3.46 (m,
1H, H-2), 3.53 (s, 3H, CO2CH3), 3.61 (m, 1H, CHCO), 3.78
(s, 3H, OCH3), 3.91 (m, 4H, CH2O), 4.51 (dd, J¼13.2,
3.6 Hz, 1H, H-6), 4.84 (m, 1H, H-3), 6.81 (dm, J¼8.7 Hz,
2H, m-Ar), 7.12 (dm, J¼8.7 Hz, 2H, o-Ar); 13C NMR, see
Table 1. Anal. calcd for C28H41BrN2O7: C 56.28, H 6.92, N
4.69. Found: C 56.07, H 7.05, N 4.36.
In some runs, 4-methylene-3(S)-[(1S)-1-(methoxycarbon-
yl)-2-(4-methophenyl)ethylamino]cyclohexanone ethylene
acetal (11) was also isolated (,10% yield): 1H NMR
(500 MHz, CDCl3, COSY, HSQC, HMBC, NOESY) 1.53
(t, J¼6.5 Hz, 2H, H-6), 1.76 (dd, J¼13, 5.5 Hz, 1H, H-2),
1.84 (m, 2H, H-2, H-5), 1.96 (dt, J¼12, 6.5 Hz, 1H, H-5),
2.76 (dd, J¼13.5, 9 Hz, 1H, CH2Ar), 2.98 (dd, J¼13.5,
5.5 Hz, 1H, CH2Ar), 3.23 (t, J¼5.5 Hz, 1H, H-3), 3.43 (dd,
J¼9, 5.5 Hz, 1H, CHN), 3.68 (s, 3H, CO2CH3), 3.80 (s, 3H,
OCH3), 3.89 (m, 4H, CH2O), 4.61 and 4.76 (2 brs, 1H each,
vCH2), 6.81 (d, J¼8.5 Hz, 2H, m-Ar), 7.11 (d, J¼8.5 Hz,
2H, o-Ar); 13C NMR (50.3 MHz, CDCl3) 28.4 (C-5), 36.1
(C-6), 38.8 (CH2Ar), 41.0 (C-2), 51.8 (CO2CH3), 55.2
(OCH3), 57.1 (C-3), 60.2 (CHN), 64.1/64.3 (CH2O), 108.3
(C-1), 109.9 (vCH2), 113.7 (m-Ar), 126.9 (ipso-Ar), 130.2
(o-Ar), 146.5 (C-4), 158.3 (p-Ar), 174.8 (CO2Me).
3.1.13. Cyclization of 8 through its N-chloroamine. To a
solution of 8 (125 mg, 0.24 mmol) in CH2Cl2 (6 mL) was
added N-chlorosuccinimide (34 mg, 0.26 mmol) at 08C. The
reaction mixture was stirred at room temperature for 24 h
3.1.11. Cyclization of 8 promoted by iodine. Operating as
above, starting from 8 (100 mg, 0.19 mmol), using 74 mg

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G. Puigbo et al. / Tetrahedron 59 (2003) 2657–2665
2664
Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M.
J. Antibiot. 1996, 49, 37–44.
and concentrated to give the corresponding N-chloroamine.
To cooled (2788C) solution of this compound
a
6. (a) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121,
7778–7786. (b) Snider, B. B.; Lin, H. Org. Lett. 2000, 2,
643–646.
(0.24 mmol) in degassed CH2Cl2 (5 mL) and under argon
atmosphere were added TiCl3 (48 mg, 0.31 mmol) and
BF3·Et2O (33 mL, 0.27 mmol). After being stirred for 3 h at
this temperature, the reaction mixture was basified with
saturated aqueous Na2CO3 and extracted with CH2Cl2
(5£15 mL). The dried organic extracts were concentrated to
give a residue which was purified by chromatography
(Al2O3, hexane to EtOAc), to give 83 mg (70%) of
(4S,6S,7R)-7-chloro-3-methyl-4-[(3S)-3-(methoxycarbonyl)-
4-(4-methoxyphenyl)-2-azabutyl]-1-oxa-3-azaspiro[5.5]un-
7. Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem. Int. Ed.
2000, 39, 4593–4596.
8. (a) Ousmer, M.; Braun, N. A.; Ciufolini, M. A. Org. Lett.
2001, 3, 765–767. (b) Ousmer, M.; Braun, N. A.; Bavoux, C.;
Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123,
7534–7538.
9. Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3, 1053–1056.
10. Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Tetrahedron
Lett. 2002, 43, 2411–2414.
1
decan-2,9-dione (13c): H NMR (300 MHz, CDCl3) 1.48
(m, 1H), 1.56 (m, 1H), 1.75–1.81 (m, 1H), 1.86–2.00 (m,
1H), 2.02 (m, 1H), 2.28 (dq, J¼13.8, 2.2 Hz, 1H. H-8eq),
2.44–2.54 (m, 2H), 2.95 (s, 3H, NCH3), 2.98 (m, CH2N),
3.36 (m, 2H), 3.70 (s, 3H, CO2CH3), 3.78 (s, 3H, OCH3),
3.96 (m, 4H, CH2O), 4.24 (dd, J¼11.4, 4.5 Hz, 1H, H-7),
6.82 (dm, J¼8.7 Hz, 2H), 7.11 (dm, J¼8.7 Hz, 2H); 13C
NMR, see Table 2. HRMS calculated from C24H33ClN2O7
496.1976, found 496.1979.
11. For the racemic synthesis of 3-amino-1-azaspiro[4.5]decan-8-
´
´
ones, see: Bonjoch, J.; Diaba, F.; Puigbo, G.; Sole, D.; Segarra,
V.; Santamaria, L.; Beleta, J.; Ryder, H.; Palacios, J.-M.
Bioorg. Med. Chem. 1999, 7, 2891–2897, See also Ref. 3.
12. From carbamates: (a) Terao, K.; Toshimitsu, A.; Uemura, S.
J. Chem. Soc., Perkin Trans 1 1986, 1837–1845. (b) Tamaru,
Y.; Kawamura, S.; Bando, T.; Tanaka, K.; Hojo, M.; Yoshida,
Z. J. Org. Chem. 1988, 53, 5491–5501. From imidates:
(c) Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53,
4006–4014. (d) Takahata, H.; Takamatsu, T.; Mozumi, M.;
Chen, T.-S.; Yamazaki, T.; Aoe, K. J. Chem. Soc., Chem.
Commun. 1987, 1627–1628. (e) Takano, S.; Iwabuchi, Y.;
Ogasawara, K. From amides: Heterocycles 1989, 29,
1861–1864. (f) Hashihayata, T.; Sakoh, H.; Goto, Y.;
Yamada, K.; Morishima, H. Chem. Pharm. Bull. 2002, 50,
423–425. From sulfonamides: (g) Jones, A. D.; Knight, D. W.;
Hibbs, D. E. J. Chem. Soc., Perkin Trans 1 2001, 1182–1203.
13. Wilson, S. R.; Sawicki, R. A.; Huffman, J. C. J. Org. Chem.
1981, 46, 3887–3891.
3.1.14. (4S)-3-Methyl-4-[(3S)-3-(methoxycarbonyl)-4-(4-
methoxyphenyl)-2-azabutyl]-1-oxa-3-azaspiro[5.5]unde-
can-2,9-dione (18). To a solution of AIBN (3 mg,
0.015 mmol) in benzene (1 mL) was added Bu3SnH
(21 mL, 0.077 mmol) and heated to reflux temperature. A
solution of 17 (17 mg, 0.031 mmol) in benzene (1 mL) was
added and the reaction mixture was maintained at this
temperature for 2.5 h, and concentrated. The residue was
purified by chromatography (SiO2, hexane–CH2Cl2 1:1 to
1
CH2Cl2–MeOH 95:5) to give 18 (8 mg, 54%); H NMR
(400 MHz, CDCl3) 1.54–1.73 (m, 6H), 1.88–1.92 (m, 2H),
1.96 (dd, J¼14, 11 Hz, 1H, H-5), 2.06 (qd, J¼13, 4.5 Hz,
1H, H-7eq), 2.45 (dd, J¼12, 3 Hz, 1H, CH2N), 2.79 (dd,
J¼14, 7.5 Hz, 1H, CH2Ar), 2.88 (m, 1H, CH2Ar), 2.89 (dd,
J¼12, 5.5 Hz, 1H, CH2N), 2.94 (s, 3H, NCH3), 3.35 (m, 2H,
H-4, CHCO), 3.68 (s, 3H, CO2CH3), 3.79 (s, 3H, OCH3),
3.94 (m, 4H, CH2O), 6.82 (d, J¼8.5 Hz, 2H, m-Ar), 7.07 (d,
J¼8.5 Hz, 2H, o-Ar).
14. For the two examples of a 6-exo cyclisation of d-aminocyclo-
hexenes to give 1-azaspiro[5.5]undecanes, see: (a) Tanner, D.;
Somfai, P. Tetrahedron 1986, 42, 5657–5664. (b) Tanner, D.;
´
¨
Sellen, M.; Backwall, J. E. J. Org. Chem. 1989, 54,
3374–3378, For the application to the synthesis of
1-azaspiro[4.5]decanes through a 5-endo process, see Ref. 11.
15. For the chemistry of N,N-dibenzyl a-aminoaldehydes, see
Reetz, M. T. Chem. Rev. 1999, 99, 1121–1162.
16. For electrophilic additions to cyclohexenes with neighbouring
groups, see: Kocovsky, P.; Pour, M. J. Org. Chem. 1990, 55,
5580–5589, and references therein.
Acknowledgements
17. For a related process in which a diastereoselective construc-
tion of a quaternary carbon adjacent to nitrogen was done, see:
Itoh, T.; Watanabe, M.; Fukuyama, T. Synlett 2002,
1323–1325.
This work was supported by the MCYT, Spain (project
BQU2001-3551). Thanks are also due to the DURSI,
Catalonia, for Grant 2001SGR-00083. G. P. is a recipient
of a fellowship (MCYT, Spain).
18. For a related ring closure through an epoxide, see: Fujimoto,
R. A.; Boxer, J.; Jackson, R. H.; Simke, J. P.; Neales, R. F.;
Snowhill, E. W.; Barbaz, B. J.; Williams, M.; Sills, M. A.
J. Med. Chem. 1989, 32, 1259–1265.
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