Synthesis of enantiopure 1-azaspiro[4.5]decanes by iodoaminocyclization of allylaminocyclohexanes

Article abstract of DOI:10.1002/ejoc.200700056

The 5-endo iodine-promoted ring closure of 4-allyl-4-(alkylamino) cyclohexanone derivatives gives the corresponding 1-azaspiro[4.5]decanes in good yields. The reaction was tested with enantiopure homoallylamines to evaluate the diastereoselectivity of the process and to provide a route for possible intermediates to the natural products embodying this azabicyclic ring. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700056

FULL PAPER
DOI: 10.1002/ejoc.200700056
Synthesis of Enantiopure 1-Azaspiro[4.5]decanes by Iodoaminocyclization of
Allylaminocyclohexanes
Faïza Diaba,[a] Gemma Puigbó,[a] and Josep Bonjoch*[a]
Keywords: Amines / Cyclization / Iodine / Nitrogen heterocycles / Spiro compounds
The 5-endo iodine-promoted ring closure of 4-allyl-4-(alk- sible intermediates to the natural products embodying this
ylamino)cyclohexanone derivatives gives the corresponding
1-azaspiro[4.5]decanes in good yields. The reaction was
tested with enantiopure homoallylamines to evaluate the dia-
stereoselectivity of the process and to provide a route for pos-
azabicyclic ring.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
pound III, which could then be transformed into an
enantiopure advanced intermediate or (b) carry out the
aminocyclization from an enantiopure homoallylamine and
evaluate the stereocontrol induced by the stereogenic center
in the side chain upon the newly formed stereogenic center
at C-3 of the azaspiro derivative.
Introduction
In the course of our studies related to the immuno-
supressant FR901483,[1–4] we introduced a new procedure
for the synthesis of 1-azaspiro[4.5]decanes[5] that is based
on the treatment of homoallylamine
I with iodine
(Scheme 1),[1,6] which promotes the electrophilic cyclofunc-
tionalization of the unsaturated amine to give five-mem-
bered ring II.[7–10]
Results and Discussion
We explored the first possible approach by synthesizing
ketone III (R = Bn), an achiral 1-azaspiro[4.5]decane. Re-
quired homoallylamine 1 was prepared by a one-pot pro-
cedure that involved the formation of an imine from the
monoethylene acetal of 1,4-cyclohexanedione and benzyl-
amine, followed by the addition of allylmagnesium bromide
(Scheme 2).[3,12] Treatment of 1 with iodine promoted the
iodoaminocyclization process to give iodo derivative 2,
which was then oxidized to ketone 3 by using DMSO and
silver tetrafluoroborate.[13] The overall sequence worked
well and we gained access to achiral functionalized azaspir-
ane 3 in 30% overall yield over the four transformations.
The reductive amination of 3 with (S)-α-methylbenzylamine
gave corresponding secondary amines 4a,b, whose configu-
rations at C-3 were not established, in a nearly equimolecu-
lar ratio and a 72% overall yield. Further explorations of
approach (a) (e.g. enantioselective reduction of ketone 3 fol-
lowed by a Fukuyama-Mitsunobu process) were not pur-
sued.
In view of the disappointingly low level of diastereoselec-
tivity observed when the amino group was introduced, we
turned to the alternative strategy outlined in Scheme 1. Ap-
proach (b) required a chiral homoallylamine such as 9 as
the starting material (Scheme 3). Treatment of 1,4-cyclo-
hexanedione monoethylene acetal with (S)-2-amino-3-(4-
methoxyphenyl)propan-1-ol (5a),[14] which was prepared by
direct reduction of O-methyl--tyrosine with LiBH4/TMSCl
Scheme 1.
Extending our previous work on iodoaminocyclizations,
we report here the use of this procedure for the preparation
of enantiopure 1-azaspiro[4.5]decanes, which are potential
building blocks in the synthesis of the aforementioned
FR901483 as well as TAN1251 derivatives.[11] To achieve
this goal, we envisaged two possible approaches: (a) trans-
formation of racemic iodo derivative II into achiral com-
[a] Laboratori de Química Orgànica, Facultat de Farmàcia, Uni-
versitat de Barcelona,
Av. Joan XXIII s/n, 08028 Barcelona, Spain
Fax: +34-934024539
E-mail: josep.bonjoch@ub.edu
3038
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3038–3044

Enantiopure 1-Azaspiro[4.5]decanes by Iodoaminocyclization
FULL PAPER
Scheme 2. Synthesis of enantiopure 3-amino-1-azaspiro[4.5]decan-
8-ones: (i) C6H5CH2NH2, 4 Å molecular sieves, CH2Cl2, room
temp., 5 h; (ii) CH2=CHCH2MgBr, CH2Cl2, room temp., 95% for
the two steps; (iii) I2, NaHCO3, CH2Cl2/H2O, room temp., 12 h,
73%; (iv) AgBF4, DMSO, room temp., 12 h, quantitative; (v) (S)-
1-phenylethylamine, NaCNBH3, THF, room temp., 24 h, 72%.
in 83% yield,[15] gave oxazolidine 6 in excellent yield. As
all our attempts to cleave this cyclic hemiaminal (by using
allylmagnesium bromide, allyltrimethylsilane, allyltributyl-
tin, and allylcerium chloride) to obtain homoallylamine 9
were unsuccessful, we focused our attention on protected
amino alcohol 5b.[16] Condensation of 5b with the afore-
mentioned cyclohexanone produced imine 7, which was
treated with allylmagnesium bromide to give homoallyl-
amine 8 in 72% overall yield. Finally, deprotection of 8 by
cleavage of the silyl ether group by TBAF gave amino
alcohol 9.
Scheme 3. Reagents and conditions: (i) tBuMe2SiCl, imidazole,
DMF, room temp., 12 h, 77%; (ii) from 5a: 1,4-cyclohexanedione
monoethylene acetal, 4 Å molecular sieves, CH2Cl2, room temp.,
2 h, 95%; (iii) from 5b: 1,4-cyclohexanedione monoethylene
acetal, 4 Å molecular sieves, CH2Cl2, room temp., 5 h; (iv)
CH2=CHCH2MgBr, Et2O, room temp., 72% for the two steps; (v)
TBAF, THF, room temp., 1 h, 84%; (vi) I2, NaHCO3, CH2Cl2/
H2O, room temp., 12 h, 62%; (vii) NaBH4, MeOH, room temp.,
2 h, 93%; (viii) Bu3SnH, AIBN, benzene, reflux, 2 h, 70%.
By using the best reaction conditions found for achiral
homoallylic amine 1, we examined the iodine-promoted
cyclization from both amines 8 and 9. Whereas the process
from 8 did not proceed, the less sterically demanding depro-
tected amino alcohol 9 did undergo the aminocyclization
process; although, unexpectedly the isolated end product
was tricyclic oxazolidine 10, which was obtained in 62%
overall yield for the two successive cyclizations. The forma-
tion of 10 probably involved an initial cyclization to afford
azaspiranic ring 11 (or a mixture of diastereomers) followed
by a neighboring hydroxy group oxidation of the amine to
give an iminium intermediate,[17] which was trapped by the
hydroxy group to form the oxazolidine ring.[18] On the basis
of the small coupling constant (J = 2.8 Hz) observed in the
1H NMR spectrum for the methine protons,[19] we have as-
signed the stereochemistry of 10 to that shown in Figure 1
with a trans relationship between the linked heteroatoms at
the pyrrolidine ring. Oxazolidine 10 was reduced
(NaBH4)[20] to azaspirane 11 in good yield and then, for
analytical purposes, to 12 (Bu3SnH, AIBN). Although the
process seems to be diastereoselective as only diastereomer
10 was isolated, the moderate overall yield of the process
(62%) gives room for doubt. The diastereoselectivity could
arise from the initial stereocontrolled formation of the
the hydroxy group on the face opposite to the location of
the iodine atom and antiperiplanar to the electron lone pair
of the nitrogen atom. Alternatively, and more probably, the
nonobservation of other diastereomeric oxazolidines could
simply derive from the fact that after the oxidation step,
other iminium salt intermediates that were formed could
not evolve for steric and/or stereoelectronic reasons and
they decomposed in solution upon work up. Thus, this re-
sult did not clarify if the stereogenic center in the side chain
linked to the nitrogen atom exerted some stereocontrol in
the genesis of the new stereogenic center formed at C-3 in
the azaspiranic ring.
Figure 1. Assignment of the stereochemistry of 10 on the basis of
coupling constants.
We then decided to prepare a new type of azaspiranic
iodonium intermediate and its stereocontrolled ring-open- compound from a homoallylic amine lacking a hydroxy
ing by the amino group. The ring-opening could then be group to prevent the anchimeric process that promotes the
followed by the formation of an iminium ion and attack of oxazolidine ring formation. With this goal in mind, we de-
Eur. J. Org. Chem. 2007, 3038–3044
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3039

F. Diaba, G. Puigbó, J. Bonjoch
FULL PAPER
cided to synthesize vinyl bromide 15 to attempt the iodine-
The aminocyclization of homoallylamine 17 promoted
promoted azaspirodecane ring formation, which would also by iodine proved to have a low stereoselectivity; azaspiranic
allow us to test the diastereoselectivity of the process and derivatives 18 was isolated as a 3:2 mixture of dia-
gain access to a valuable intermediate in the synthetic route stereomers. To gain access to more stable and valuable com-
to FR901683 (Scheme 4).
pounds for the synthesis of FR901483, crude iodides 18
were converted into corresponding amino derivatives 20 by
treatment with sodium azide, followed by reduction of azide
intermediates 19 with triphenylphosphane. At this stage,
both diastereomers at C-3 could be separated, but the abso-
lute configuration was not ascertained. The nearly equimo-
lecular mixture of isolated amines does not reflect the ratio
of initially formed iodides 18. This could be due to the par-
ticipation of the neighboring nitrogen atom at N-1 in the
azide-formation step, which could lead to an aziridinium
ion intermediate during the substitution process to a vari-
able extent depending on the configuration of the starting
iodide.
In summary, the results reported here demonstrate the
utility of iodine-promoted aminocyclization reactions in the
elaboration of the azaspirane ring system found in some
natural products. Concerning the two approaches studied,
we concluded that route (a), which proceeds through achiral
azaspiranic ketone 3, was the most satisfactory as it is
shorter than those using chiral starting materials, and ad-
ditionally, the enantiopure epimeric amino derivatives
formed after the reductive amination can be isolated easily.
Further studies are needed to determine if the stereocontrol
at C-3 can be improved, which would provide a satisfactory
synthetic route to enantiopure building blocks with the 3-
substituted-1-azaspiro[4.5]decane pattern.[27]
Experimental Section
Scheme 4. Reagents and conditions: (i) MeI, NaHCO3, DMF,
room temp., 16 h, 81%; (ii) LiBH4, THF/EtOH, 16 h, 99%; (iii)
TEMPO, NaBr, NaHCO3, NaOCl, CH2Cl2/H2O, 0 °C, 2 h, 91 %;
(iv) (MeO)2P(O)CN2COCH3, K2CO3, MeOH, room temp., 16 h,
74%; (v) 1,4-cyclohexanedione monoethylene acetal, 4 Å molecular
sieves, CH2Cl2, room temp., overnight; (vi) CH2=CHCH2MgBr,
CH2Cl2, room temp., 4 h, 75% for the two steps; (vii) I2, NaHCO3,
CH2Cl2/H2O, room temp., 2 h; (viii) NaN3, DMF, 50 °C, DMSO,
3 h, 58% for the two steps; (ix) Ph3P, THF, 1 d, then H2O, room
temp., 3 d, 95%.
General: All reactions were carried out under an argon atmosphere
with dry, freshly distilled solvents under anhydrous conditions. An-
alytical TLC was performed on SiO2 (silica gel 60 F254, Merck) or
Al2O3 (ALOX N/UV254, Polygram), and the spots were located
with iodoplatinate reagent or 1% aqueous KMnO4. Chromatog-
raphy refers to flash chromatography and was carried out on SiO2
(silica gel 60, SDS, 230–240 mesh ASTM) or Al2O3 (aluminium
oxide 90, Merck). Drying of organic extracts during work up of
reactions was performed over anhydrous Na2SO4. Optical rotations
Commercially available O-methyl-N-(tert-butoxycar- were recorded with a Perkin–Elmer 241 polarimeter. 1H and 13C
NMR spectra were recorded with a Varian Gemini 200 or 300, or
a Varian Mercury 400 instrument. Chemical shifts are reported in
ppm downfield (δ) from Me4Si.
bonyl)--tyrosine (12) was transformed to corresponding al-
dehyde 13 by following a reported procedure.[21] Aldehyde
13 was homologated to alkyne 14 with the use of dimethyl
1-diazo-2-(oxopropyl)phosphonate[22] in a basic methanolic
4-Allyl-4-benzylaminocyclohexanone Ethylene Acetal (1): To a solu-
solution.[23,24] The hydrobromination of alkyne 14 was car- tion of 1,4-cyclohexanedione monoethylene acetal (10 g, 64 mmol)
ried out with gaseous hydrogen bromide,[25] which resulted
in CH2Cl2 (200 mL) were added benzylamine (8.4 mL, 77 mmol)
and 4 Å molecular sieves (20 g). After stirring at room temp. for
in a mixture of regioisomers. Required vinyl bromide 15, in
4 h, the suspension was filtered through Celite, and the filtrate was
which the amine group is deprotected, was isolated in 45%
overall yield. Condensation of primary amine 15 with 1,4-
cyclohexanedione monoethylene acetal was troublesome,
and the conversion of 15 to corresponding imine 16 was
concentrated to give the corresponding imine (see Scheme 2): 13C
NMR (50 MHz, CDCl3): δ = 25.1 (CH2), 34.1 (CH2), 34.8 (CH2),
36.2 (CH2), 54.4 (CH2N), 64.3 (CH2O), 107.8 (C-1), 126.4 (CH),
127.5 (CH), 128.3 (CH), 140.0 (C), 171.7 (CN) ppm. To a solution
of this imine in CH2Cl2 (100 mL) was added dropwise allylmagne-
never complete. Consequently, after treatment with allyl-
magnesium bromide, homoallylamine 17 was formed to-
gether with a small amount of 4-allyl-4-hydroxycyclohexa-
none acetal.[26]
sium bromide (1.28  in Et2O, 100 mL, 128 mmol). The mixture
was stirred at room temp. overnight, poured into saturated aqueous
NH4Cl, and extracted with CH2Cl2. The organic extracts were
3040
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3038–3044

Enantiopure 1-Azaspiro[4.5]decanes by Iodoaminocyclization
FULL PAPER
washed with brine, dried, and concentrated. After chromatography
(Al2O3, hexanes/CH2Cl2, 1:1), amine 2 (18 g, 98%) was obtained.
An analytical sample was obtained by crystallization. M.p. 42–
tracted with CH2Cl2, and the organic extracts were dried, concen-
trated, and purified by chromatography (Al2O3, hexane/CH2Cl2,
1:1). Firstly, amine 4a (247 mg, 38%) was eluted, and secondly,
amine 4b (221 mg, 34%) was isolated. (3R or 3S)-1-Benzyl-3-[(S)-
(1-phenylethyl)amino]-1-azaspiro[4.5]decan-8-one Ethylene Acetal
1
44 °C (hexane). H NMR (300 MHz, CDCl3): δ = 0.90 (br. s, 1 H,
NH), 1.50–1.75 (m, 6 H), 1.90–2.02 (m, 2 H), 2.26 (d, J = 7.4 Hz,
2 H, CH2CH), 3.65 (s, 2 H, CH2Ar), 3.95 (s, 4 H, OCH2), 5.12
(dm, J = 14.7 Hz, 1 H, cis-H), 5.12 (dm, J = 9.3 Hz, 1 H, trans-
H), 5.85 (ddt, J = 14.7, 9.3, 7.4 Hz, 1 H, gem-H), 7.20–7.40 (m, 5
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 30.2 and 32.7 (C-2 and
C-3), 42.0 (CH2CH), 45.7 (CH2Ar), 53.1 (C-4), 64.1 and 64.2
(CH2O), 109.1 (C-1), 117.9 (=CH2), 126.7 (p-Ar), 128.2 (o-Ar and
1
(4a): H NMR (300 MHz, CDCl3): δ = 1.30 (d, J = 6.5 Hz, 3 H,
CH3), 1.32–2.05 (m, 9 H), 2.20 (dd, J = 12.9, 8.3 Hz, 1 H, 4-H),
2.48 (dd, J = 9.4, 5.1 Hz, 1 H, 2-H), 2.68 (dd, J = 9.4, 7.0 Hz, 1
H, 2-H), 3.10 (m, 1 H, 3-H), 3.47 (d, J = 13.1 Hz, 1 H, CH2N),
3.64 (d, J = 13.1 Hz, 1 H, CH2N), 3.73 (q, J = 6.5 Hz, 1 H, CHN),
3.94 (m, 4 H, OCH2), 7.10–7.40 (m, 10 H) ppm. 13C NMR
m-Ar), 134.1 (=CH), 141.3 (ipso-Ar) ppm. IR (neat): ν = 3300, (75 MHz, CDCl3): δ = 23.9 (CH3), 28.8 (CH2), 31.4 (CH2), 32.6
˜
1627 cm–1. C18H25NO2 (287.38): calcd. C 75.23, H 8.77, N 4.87; (CH2), 32.7 (CH2), 42.2 (C-4), 52.0 (CH2N), 52.5 (C-3), 56.0
found C 75.36, H 8.83, N 4.85.
(CHN), 57.1 (C-2), 62.1 (C-5), 64.2 and 64.3 (OCH2), 108.6 (C-8),
126.5 (CH), 126.7 (CH), 126.9 (CH), 128.1 (CH), 128.4 (CH), 140.7
(C), 145.5 (C) ppm. HRMS (ESI-TOF): calcd. for C26H35N2O2 [M
+H] 407.2693; found 407.2692. (3Ror 3S)-1-Benzyl-3-[(S)-N-1-phen-
ylethyl)amino]-1-azaspiro[4.5]decan-8-one Ethylene Acetal (4b): 1H
NMR (300 MHz, CDCl3): δ = 1.26 (d, J = 6.5 Hz, 3 H, CH3),
1.26–2.05 (m, 9 H), 2.14 (dd, J = 12.9, 8.5 Hz, 1 H, 4-H), 2.64 (dd,
J = 9.4, 4.6 Hz, 1 H, 2-H), 2.70 (dd, J = 9.4, 6.4 Hz, 1 H, 2-H),
3.02 (m, 1 H, 3-H), 3.46 (d, J = 13.3 Hz, 1 H, CH2N), 3.64 (d, J
= 13.3 Hz, 1 H, CH2N), 3.73 (q, J = 6.5 Hz, 1 H, CHN), 3.92 (m,
4 H, CH2O), 7.10–7.33 (m, 10 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 24.7 (CH3), 28.1 (CH2), 31.2 (CH2), 32.4 (CH2), 32.7
(CH2), 42.7 (C-4), 51.9 (CH2N), 52.4 (C-3), 56.4 (CHN), 56.5 (C-
2), 61.7 (C-5), 64.1 and 64.2 (CH2O), 108.5 (C-8), 126.5 (CH),
126.6 (CH), 126.8 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH), 140.8
(C), 145.4 (C) ppm. HRMS (ESI-TOF): calcd. for C26H35N2O2 [M
+ H] 407.2693; found 407.2691.
1-Benzyl-3-iodo-1-azaspiro[4.5]decan-8-one Ethylene Acetal (2): To
a solution of amine 1 (0.5 g, 1.7 mmol) in CH2Cl2 (15 mL) and 5%
aqueous NaHCO3 (15 mL) was added dropwise a solution of I2
(0.63 g, 2.5 mmol) in CH2Cl2 (15 mL). After stirring at room temp.
overnight, saturated aqueous sodium thiosulfite (20 mL) was
added. The mixture was extracted with CH2Cl2, and the organic
extracts were concentrated and purified by chromatography (Al2O3,
hexanes/CH2Cl2, 1:1) to give 2 (0.51 g, 71%) as a yellow liquid,
which crystallized on standing. An analytical sample was obtained
by crystallization. M.p. 80–81 °C (Et2O). 1H NMR (500 MHz,
CDCl3, COSY, NOESY, HSQC, HMBC): δ = 1.40 (ddd, J = 13.4,
2.5 Hz, 1 H, 6-Heq), 1.60 (td, J = 13.5, 4.0 Hz, 1 H, 7-Hax), 1.64
(td, J = 14.0, 4.5 Hz, 1 H, 9-Hax), 1.71–1.83 (m, 3 H, 7-Heq, 9-Heq,
and 10-Heq), 1.86 (td, J = 13.5, 4.0 Hz, 1 H, 6-Hax), 1.90 (td, J =
13.5, 4.0 Hz, 1 H, 10-Hax), 2.32 (dd, J = 14.0, 6.5 Hz, 1 H, 4-H),
2.54 (dd, J = 14.0, 8.5 Hz, 1 H, 4-H), 3.01 (dd, J = 10.5, 6.75 Hz,
1 H, 2-H), 3.06 (dd, J = 10.5, 7.0 Hz, 1 H, 2-H), 3.61 (d, J =
13.5 Hz, 1 H, CH2Ar), 3.72 (d, J = 13.5 Hz, 1 H, CH2Ar), 3.94 (s,
4 H, OCH2), 4.19 (dddd, J = 8.5, 7.0, 6.75, 6.5 Hz, 1 H, 3-H), 7.19–
7.33 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.8 (C-
3), 29.7 (C-10), 30.8 (C-6), 32.2 (C-9), 32.6 (C-7), 47.7 (C-4), 51.1
(CH2Ar), 61.5 (C-2), 63.1 (C-5), 64.2 and 64.3 (CH2O), 108.2 (C-
8), 126.7 (p-Ar), 128.1 (o- and m-Ar), 140.0 (ipso-Ar) ppm.
C18H24INO2 (413.28): calcd. C 52.31, H 5.85, N 3.39, I 30.70;
found C 52.29, H 5.70, N 3.40, I 30.65.
(S)-1-[(tert-Butyldimethylsilyl)oxy]-3-(4-methoxyphenyl)-2-propyl-
amine (5b): tBuMe2SiCl (4 g, 26.5 mmol) and imidazole (3.73 g,
54.8 mmol) were added to a solution of (S)-2-amino-3-(4-meth-
oxyphenyl)propanol (5a, 4 g, 22.1 mmol) in DMF (40 mL). The
mixture was stirred at room temp. for 12 h, and H2O and Et2O
were then added. The aqueous phase was extracted with CH2Cl2
(3ϫ50 mL), and all organic extracts were dried, concentrated, and
purified by chromatography (Al2O3, CH2Cl2) to afford silyl ether
5b (5 g, 77%). 1H NMR (300 Hz, CDCl3): δ = 0.06 (s, 6 H, SiCH3),
0.91 (s, 9 H, tBu), 1.40 (br. s, 2 H, NH2), 2.45 (dd, J = 13.5, 8.4 Hz,
1 H, CH2Ar), 2.73 (dd, J = 13.5, 5.4 Hz, 1 H, CH2Ar), 3.05 (m, 1
H, CH), 3.43 (dd, J = 9.7, 6.5 Hz, 1 H, CH2O), 3.57 (dd, J = 9.7,
4.4 Hz, 1 H, CH2O), 3.80 (s, 3 H, OCH3), 6.85 (d, J = 8.6 Hz, 2
H, m-Ar), 7.12 (d, J = 8.6 Hz, 2 H, o-Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = –5.5 (CH3Si), 18.1 (CSi), 25.7 (CH3), 39.3 (CH2Ar),
54.3 (CH), 55.0 (CH3O), 67.3 (CH2O), 113.6 (m-Ar), 130.0 (o-Ar),
131.0 (ipso-Ar), 157.8 (p-Ar) ppm.
1-Benzyl-1-azaspiro[4.5]decan-3,8-dione 8-Monoethylene Acetal (3):
To a solution of AgBF4 (1.26 g, 6.4 mmol) in DMSO (80 mL) was
added dropwise a solution of 2 (2.78 g, 6.7 mmol) in DMSO
(60 mL). After stirring at room temp. overnight, triethylamine
(1.12 mL, 8.0 mmol) was added and the stirring was maintained
for an additional 1 h. The suspension was filtered through Celite,
and the filtrate was partitioned between Et2O and water. The dried
organic extracts yielded crude ketone 3 (2 g) in quantitative yield.
An analytical sample was obtained by crystallization. M.p. 105–
107 °C. 1H NMR (300 MHz, CDCl3): δ = 1.54–1.68 (m, 4 H), 1.78–
1.89 (m, 2 H), 2.01–2.16 (m, 2 H), 2.46 (s, 2 H, 4-H), 3.07 (s, 2 H,
2-H), 3.75 (s, 2 H, CH2Ar), 3.96 (s, 4 H, OCH2), 7.20–7.35 (m, 5
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.8 (C-6 and C-10),
32.5 (C-7 and C-9), 47.9 (C-4), 52.0 (CH2Ar), 58.7 (C-2), 61.9 (C-
5), 64.3 and 64.4 (CH2O), 108.0 (C-8), 127.0 (p-Ar), 128.1 and
128.3 (o- and m-Ar), 139.2 (ipso-Ar), 213.7 (C-3) ppm. IR (neat):
(S)-3-[(4-Methoxyphenyl)methyl]-1,4-oxazaspiro[4.5]decan-8-one
Ethylene Acetal (6): To a solution of 1,4-cyclohexanedione mono-
ethylene acetal (0.86 g, 5.5 mmol) in CH2Cl2 (6 mL) were added
amino alcohol 5a (1 g, 5.5 mmol) and 4 Å molecular sieves (2 g).
After stirring at room temp. for 2 h, the suspension was filtered
through Celite, and the filtrate was concentrated to give 6 (1.8 g,
quantitative). 1H NMR (300 MHz, CDCl3): δ = 1.50–1.90 (m, 9
H), 2.63 (dd, J = 13.6, 7.7 Hz, 1 H, CH2Ar), 2.93 (dd, J = 13.6,
5.9 Hz, 1 H, CH2Ar), 3.38 (t, J = 7.8 Hz, 1 H, 2-H), 3.61 (dddd, J
= 7.8, 7.7, 6.5, 5.9 Hz, 1 H, 3-H), 3.79 (s, 3 H, OMe), 3.84 (dd, J
= 7.8, 6.5 Hz, 1 H, 2-H), 3.94 (s, 4 H, OCH2), 6.84 (d, J = 8.6 Hz, 2
H, m-Ar), 7.12 (d, J = 8.6 Hz, 2 H, o-Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 31.8, 31.9, 32.2, 34.6, 38.7, 55.1, 58.8, 64.1, 69.7, 95.1,
108.3, 113.8, 129.7, 130.1, 158.1 ppm. C18H25NO4·1/2H2O
(328.49): calcd. C 65.83, H 7.98 N 4.27; found C 65.93, H 8.04, N
4.09.
ν = 1753 cm–1.C H NO (301.36): calcd. C 71.74, H 7.69, N 4.65;
˜
18 23
3
found C 71.92, H 7.74, N 4.67.
Reductive Amination of 3: α-(S)-Methylbenzylamine hydrochloride
(0.5 g, 3.2 mmol) and portionwise NaCNBH3 (0.25 g, 3.9 mmol)
were added to a solution of ketone 3 (0.5 g, 1.6 mmol) in THF
(10 mL). After stirring at room temp. for 24 h, water was added,
and the two phases were separated. The aqueous layer was ex-
Eur. J. Org. Chem. 2007, 3038–3044
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3041

F. Diaba, G. Puigbó, J. Bonjoch
(S)-4-Allyl-4-(1-[(tert-butyldimethylsilyl)oxymethyl]-2-(4-methoxy- 8.7 Hz, 2 H, m-Ar), 7.12 (d, J = 8.7 Hz, 2 H, o-Ar) ppm. 13C NMR
FULL PAPER
phenyl)ethylaminocyclohexanone Ethyelene Acetal (8): Following
the above procedure for the preparation of 1 with the use of 1,4-
cyclohexanedione monoethylene acetal (1 g, 6.4 mmol) and (S)-1-
[(tert-butyldimethylsilyl)oxy]-3-(4-methoxyphenyl)-2-propylamine
(75 MHz, CDCl3): δ = 20.7 (CHI), 27.6 (C-2Ј), 32.7 (C-3Ј), 32.9
(C-5Ј), 36.0 (C-6Ј), 40.6 (CH2Ar), 48.2 (C-6), 55.2 (CH3O), 58.0
(C-3), 64.2 i 64.3 (OCH2CH2O), 64.7 (C-5), 70.7 (C-2), 105.6 (C-
7a), 107.7 (C-4Ј), 113.6 (m-Ar), 130.5 (o-Ar), 130.9 (ipso-Ar), 158.1
(5, 2.5 g, 8.3 mmol), corresponding imine 7 was formed. After (p-Ar) ppm. MS (CI): m/z (%) = 486 (23) [M + 1]+, 374 (100).
treatment with allylmagnesium bromide (1  in Et2O, 12.8 mL,
(3S)-1-[(1S)-1-Hydroxymethyl-2-(4-methoxyphenyl)ethyl]3-iodo-1-
12.8 mmol), the crude product was purified by chromatography
azaspiro[4.5]decan-8-one Ethylene Acetal (11): NaBH4 (56 mg,
(CH2Cl2/MeOH, 99.5:0.5) to afford 8 (2.2 g, 72 %). 1H NMR
1.5 mmol) was added to a solution of oxazolidine 10 (240 mg,
(300 MHz, CDCl3): δ = 0.03 (s, 6 H, CH3Si), 0.91 (s, 9 H, tBu),
0.50 mmol) in MeOH (12 mL), and the reaction mixture was stirred
1.30 (br. s, 1 H, NH), 1.40–1.60 (m, 6 H), 1.65 (m, 1 H), 1.75 (m,
at room temp. for 2 h. After quenching with H2O (20 mL), the
1 H), 2.16 (m, 2 H, CH2CH), 2.64 (dd, J = 13.5, 5.8 Hz, 1 H,
solution was extracted with EtOAc (3ϫ30 mL). The dried organic
CH2Ar), 2.76 (dd, J = 13.5, 7.1 Hz, 1 H, CH2Ar), 2.90 (m, 1 H,
extracts furnished 11 (223 mg, 93%). 1H NMR (200 MHz, CDCl3):
CHN), 3.31 (dd, J = 9.8, 5.9 Hz, 1 H, CH2O), 3.45 (dd, J = 9.8,
δ = 1.43–1.99 (m, 8 H), 2.18 (dd, J = 14.0, 8.1 Hz, 1 H, 4-H), 2.40–
4.4 Hz, 1 H, CH2O), 3.79 (s, 3 H, CH3O), 3.92 (s, 4 H, OCH2),
2.68 (m, 3 H, 4-H and CH2Ar), 2.91 (m, 1 H, CHN), 3.12–3.39 (m,
5.02 (dd, J = 16.0, 2.2 Hz, 1 H, cis-H), 5.03 (dd, J = 10.2, 2.2 Hz,
4 H, 2-H and CH2O), 3.79 (s, 3 H, OCH3), 3.94 (m, 4 H, OCH2),
1 H, trans-H), 5.80 (m, 1 H, gem-H), 6.82 (d, J = 8.6 Hz, 2 H, m-
4.32 (m, 1 H, 3-H), 6.83 (d, J = 8.6 Hz, m-Ar), 7.07 (d, J = 8.6 Hz,
Ar), 7.10 (d, J = 8.6 Hz, 2 H, o-Ar) ppm. 13C NMR (75 MHz,
o-Ar) ppm. 13C NMR (50 MHz, CDCl3): δ = 15.7 (C-3), 31.5 and
CDCl3): δ = –5.4 (CH3Si), 18.2 (CMe3), 25.9 (CH3), 30.5 and 30.6
32.0 (C-6 and C-10), 33.0 and 34.8 (C-7 and C-9), 36.3 (CH2Ar),
(C-3 and C-5), 33.1 (C-2 and C-6), 39.4 (CH2Ar), 42.7 (CH2CH),
48.0 (C-4), 54.1 (C-2), 55.2 (OCH3), 56.1 (CHN), 60.5 (CH2OH),
53.6 (C-4), 53.8 (CHN), 55.2 (CH3O), 64.1 (OCH2CH2O), 65.5
63.5 (C-5), 64.1 and 64.3 (OCH2), 108.0 (C-8), 113.8 (m-Ar), 129.6
(CH2O), 108.8 (C-1), 113.6 (m-Ar), 117.3 (=CH2), 130.4 (o-Ar),
(o-Ar), 130.5 (ipso-Ar), 158.0 (p-Ar) ppm. MS (EI): m/z (%) = 456
131.7 (ipso-Ar), 134.8 (=CH), 157.9 (p-Ar) ppm. C27H45NO4Si
(3), 366 (44), 360 (3), 238 (83), 121 (100), 101 (27), 99 (25), 91 (38).
(475.72): calcd. C 68.17, H 9.53, N 2.94; found C 68.08, H 9.74, N
1-[(1S)-1-(Hydroxymethyl)-2-(4-methoxyphenyl)ethyl]-1-azaspiro-
[4.5]decan-8-one (12): To a solution of iodide 11 (88 mg, 0.18 mmol)
in benzene (3 mL) were added AIBN (2 mg, 0.01 mmol) and
Bu3SnH (0.1 mL, 0.38 mmol). The reaction mixture was heated at
reflux for 2 h, cooled, and concentrated. The residue was purified
by chromatography (SiO2, CH2Cl2/MeOH, 100:0 to 96:4), to give
2.93.
(S)-4-Allyl-4-[1-(hydroxymethyl)-2-(4-methoxyphenyl)ethylamino]-
cyclohexanone Ethylene Acetal (9): To a solution of ether 8 (2 g,
4.2 mmol) in THF (10 mL) was added a solution of TBAF (1  in
THF, 12.6 mL, 12.6 mmol). After stirring for 1 h at room temp.,
the reaction was quenched with water and extracted with EtOAc.
The dried organic extract was concentrated and purified by
chromatography (CH2Cl2/MeOH, 100:0 to 97:3) to afford alcohol
9 (1.27 g, 84%). 1H NMR (300 MHz, CDCl3): δ = 1.35–1.75 (m, 8
H), 2.20 (m, 2 H, CH2CH), 2.65 (dd, J = 13.5, 8.3 Hz, 1 H,
CH2Ar), 2.71 (dd, J = 13.5, 6.2 Hz, 1 H, CH2Ar), 3.02 (m, 1 H,
CHN), 3.23 (dd, J = 10.5, 3.3 Hz, 1 H, CH2O), 3.37 (dd, J = 10.5,
4.1 Hz, 1 H, CH2O), 3.79 (s, 3 H, OCH3), 3.92 (s, 4 H, OCH2),
5.07 (dm, J = 16.5 Hz, 1 H, cis-H), 5.09 (dm, J = 10.7 Hz, 1 H,
trans-H), 5.71 (ddt, J = 16.5, 10.7, 7.3 Hz, 1 H, gem-H), 6.84 (d, J
= 8.7 Hz, 2 H, m-Ar), 7.10 (d, J = 8.7 Hz, 2 H, o-Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 30.5 and 30.7 (C-3 and C-5), 32.4
and 33.3 (C-2 and C-6), 39.6 (CH2Ar), 41.8 (CH2CH), 52.9 (CHN),
54.0 (C-4), 55.1 (CH3O), 63.2 (CH2O), 64.0 (OCH2), 108.4 (C-1),
113.8 (m-Ar), 118.1 (=CH2), 130.2 (o-Ar), 130.6 (ipso-Ar), 133.9
(=CH), 158.1 (p-Ar) ppm. C21H31NO4 (361.46): calcd. C 69.78, H
8.64, N 3.87; found C 69.50, H 8.81, N 3.83.
1
12 (46 mg, 70%). H NMR (300 MHz, CDCl3, COSY, HSQC): δ
= 1.60–1.94 (m, 12 H), 2.53 (m, 1 H, CH2Ar), 2.89 (m, 3 H, CH2Ar
and 2-H), 3.22 (m, 2 H, CHN and CH2O), 3.36 (m, 1 H, CH2O),
3.79 (s, 3 H, OCH3), 3.95 (m, 4 H, OCH2), 6.84 (d, J = 8.6 Hz, 2 H,
m-Ar), 7.09 (d, J = 8.6 Hz, 2 H, o-Ar) ppm. 13C NMR (75.5 MHz,
CDCl3): δ = 22.1 (C-3), 30.0 (C-6 and C-10), 32.4 and 33.0 (C-7
and C-9), 34.2 (C-4), 35.9 (CH2Ar), 43.3 (C-2), 55.2 (OCH3), 56.8
(CHN), 60.3 (CH2OH), 64.2 and 64.3 (OCH2), 108.8 (C-8), 113.9
(m-Ar), 129.8 (o-Ar), 130.6 (ipso-Ar), 158.1 (p-Ar) ppm. MS (EI):
m/z (%) = 362 (1), 330 (8), 241 (15), 240 (100), 135 (14), 121 (29),
74 (13), 55 (14). C21H31NO4 (361.46): calcd. C 69.77, H 6.45, N
3.07; found C 69.39, H 6.67, N 2.99.
(2S)-N-(tert-Butoxycarbonyl)-1-(4-methoxyphenyl)but-3-yn-2-amine
(14): Dimethyl 1-diazo-2-oxopropylphosphonate (2.66 g,
13.8 mmol) in MeOH (20 mL) and K2CO3 (2.55 g, 18.4 mmol)
were added in sequence to a solution of aldehyde 13 (2.57 g,
9.2 mmol) in MeOH (20 mL) at 0 °C. The reaction mixture was
stirred at room temp. overnight, then quenched with saturated
aqueous NH4Cl solution (50 mL), and extracted with CH2Cl2
(5 ϫ 50 mL). The dried organic extracts were concentrated and
purified by chromatography (SiO2, CH2Cl2) to give 14 (1.87 g,
7-Iodo-3-[(4-methoxyphenyl)methyl]-2,3,4,5,6,7,7a-hexahydropyr-
rolo[2,1-b]oxazol-5-spirocyclohexanon-4-one Ethylene Acetal (10):
Iodine (1.18 g, 4.6 mmol) in CH2Cl2 (50 mL) was slowly added to
a solution of homoallylamine 9 (0.82 g, 2.27 mmol) in CH2Cl2
(30 mL) and 5% aqueous NaHCO3 solution (30 mL). The mixture
was stirred at room temp. overnight. The reaction mixture was
quenched with saturated aqueous Na2SO3 solution (50 mL), and
the aqueous layer was extracted with CH2Cl2 (2 ϫ80 mL). The
dried organic extracts were concentrated and purified by
chromatography (Al2O3, hexane/EtOAc, 8:2) to yield 10 (0.68 g,
1
74%) as a yellowish solid. H NMR (300 MHz, CDCl3): δ = 1.49
[s, 9 H, C(CH3)3], 2.35 (s, 1 H, ϵCH), 2.94 (m, 2 H, 4-H), 3.81 (s,
3 H, OCH3), 4.68 (m, 1 H, 3-H), 5.07 (m, 1 H, NH), 6.89 (d, J =
8.4 Hz, 2 H, m-Ar), 7.24 (d, J = 8.4 Hz, 2 H, o-Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 28.0 [C(CH3)3], 40.5 (C-4), 43.7 (C-3), 54.8
(OCH3), 71.9 (ϵCH), 79.5 [C(CH3)3], 82.7 (C-2), 113.4 (m-Ar),
128.1 (ipso-Ar), 130.4 (o-Ar), 154.3 (NHCO), 158.2 (p-Ar) ppm.
HRMS: calcd. for C16H21NO3 275.3505; found 275.3521.
1
62%). H NMR (300 MHz, CDCl3): δ = 1.20–1.80 (m, 8 H), 2.15
(dd, J = 12.7, 10.7 Hz, 1 H, 6-H), 2.52 (dd, J = 13.6, 7.4 Hz, 1 H,
CH2Ar), 2.71 (dd, J = 13.6, 7.5 Hz, 1 H, CH2Ar), 2.80 (dd, J =
12.7, 7.5 Hz, 1 H, 6-H), 3.45–3.60 (m, 1 H, 3-H), 3.47 (dd, J = 7.5,
3.4 Hz, 1 H, CH2O), 3.69 (dd, J = 7.5, 6.6 Hz, 1 H, CH2O), 3.79
(2S)-3-Bromo-1-(4-methoxyphenyl)but-3-en-2-amine (15): Hydrogen
bromide gas (900 mg, 11.1 mmol) was bubbled through a solution
(s, 3 H, CH3O), 3.89 (s, 4 H, OCH2), 4.12 (ddd, J = 10.7, 7.7, of Et4NBr (840 mg, 4.0 mmol) in CH2Cl2 (10 mL) at 0 °C. A solu-
2.8 Hz, 1 H, CHI), 5.31 (d, J = 2.8 Hz, 1 H, CHNO), 6.82 (d, J = tion of amine 14 (1 g, 3.6 mmol) in CH2Cl2 (5 mL) was added, and
3042
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3038–3044

Enantiopure 1-Azaspiro[4.5]decanes by Iodoaminocyclization
FULL PAPER
the reaction mixture was stirred for 24 h, basified with aqueous 1 
NaOH solution, and extracted with CHCl3 (4ϫ100 mL). The dried
organic extracts were concentrated and purified by chromatography
(SiO2, CH2Cl2/MeOH, 100:0 to 99.5:0.5) to yield vinyl bromide 15
(420 mg, 45%) and its regioisomer 15Ј –not shown –(159 mg, 17%).
15: [α]D = + 38.9 (c = 0.59, CH3OH). 1H NMR (300 MHz, CDCl3):
NCH), 3.94 (m, 4 H, CH2O), 4.16 (m, 1 H, 3-H), 5.40 (d, J =
1.4 Hz, 1 H, =CH2), 5.58 (d, J = 1.4 Hz, 1 H, =CH2), 6.79 (dm, J
= 8.8 Hz, 2 H, m-Ar), 7.11 (dm, J = 8.8 Hz, 2 H, o-Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 15.3 (C-3), 31.6, 31.9, 32.3, 33.3
(CH2), 38.8 (CH2Ar), 47.9 (C-4), 55.4 (OCH3), 56.7 (C-2), 61.0
(C-5), 62.4 (NCH), 64.5 (CH2O), 107.9 (C-8), 113.7 (m-Ar), 117.5
δ = 1.65 (s, 2 H, NH2), 2.71 and 2.86 (2dd, J = 13.5, 6.8 Hz, 1 H (=CH2), 130.2 (o-Ar), 130.8 (ipso-Ar), 138.4 (C=), 157.9 (p-Ar)
each, CH2), 3.55 (t, J = 6.8 Hz, 1 H, CH), 3.78 (s, 3 H, OMe), 5.41
(d, J = 1.8 Hz, 1 H, =CH2), 5.61 (d, J = 1.8 Hz, 1 H, =CH2), 6.83
(d, J = 8.7 Hz, 2 H, m-Ar), 7.13 (d, J = 8.7 Hz, 2 H, o-Ar) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 41.0 (CH2), 55.1 (OMe), 60.9
(CH), 113.7 (m-Ar), 116.4 (=CH2), 129.8 (ipso-Ar), 130.2 (o-Ar),
ppm.
1-[(S)-3-Bromo-1-(4-methoxyphenyl)but-3-en-2-yl]-3-azido-1-aza-
spiro[4.5]decan-8-one Ethylene Acetal (19): NaN3 (86 mg,
1.32 mmol) was added to a solution of the diastereomeric mixture
of iodides 18 (0.66 mmol) in DMF (15 mL) The mixture was stirred
at 50 °C for 3 h, the solvent was evaporated, and the crude product
was purified by chromatography (SiO2, CH2Cl2) to afford azide
139.9 (=CBr), 158.1 (p-Ar) ppm. IR (NaCl): ν = 3374, 1612, 1512,
˜
1247 cm–1. HRMS: calcd. for C11H14BrNO 256.1452; found
256.1460. (Z)-(2S)-4-Bromo-1-(4-methoxyphenyl)but-3-en-2-amine
1
19 (184 mg, 58% from 17) as a diastereomeric mixture. H NMR
1
(15Ј). H NMR (300 MHz, CDCl3): δ = 1.46 (s, 2 H, NH2), 2.62
(300 MHz, CDCl3): δ = 1.31 (dm, J = 12.2 Hz, 1 H), 1.41 (ddd, J
= 12.6, 6.3, 3.0 Hz, 1 H), 1.51–1.62 (m), 1.66–1.87 (m), 2.06 (dd, J
= 13.5, 7.5 Hz, 1 H), 2.14 (dd, J = 13.5, 7.5 Hz, 1 H), 2.76 (dd, J
= 13.5, 6.6 Hz, 1 H), 2.82 (dd, J = 13.5, 5.7 Hz, 1 H), 2.99 (dd, J
= 13.8, 8.7 Hz, 1 H), 3.02 (dd, J = 14.1, 9.0 Hz, 1 H), 3.12 (dd, J
= 9.6, 5.1 Hz, 1 H), 3.34 (dd, J = 9.6, 4.2 Hz, 1 H), 3.40 (dd, J =
9.6, 5.7 Hz, 1 H), 3.59 (dd, J = 9.6, 6.0 Hz, 1 H), 3.78 (s, 3 H,
OCH3), 3.79 (s, 3 H, OCH3), 3.79 [m, 2 H, N(1)CH], 3.92 (m, 8 H,
(dd, J = 13.5, 8.1 Hz, 1 H, CH2), 2.82 (dd, J = 13.5, 5.1 Hz, 1 H,
CH2), 3.79 (s, 3 H, OMe), 4.06 (ddd, J = 8.1, 7.8, 5.1 Hz, 1 H,
CH), 6.08 (dd, J = 7.8, 6.9 Hz, 1 H, CH=), 6.19 (dd, J = 6.9,
0.9 Hz, 1 H, =CHBr), 6.85 (d, J = 8.4 Hz, 2 H, m-Ar), 7.16 (d, J
= 8.4 Hz, 2 H, o-Ar) ppm. 13C NMR (75.5 MHz, CDCl3): δ = 41.7
(CH2), 52.5 (CH), 55.2 (OCH3), 107.6 (=CHBr), 113.8 (m-Ar),
129.8 (ipso-Ar), 130.3 (o-Ar), 138.6 (CH=), 158.2 (p-Ar) ppm.
4-Allyl-4-{N-[(S)-3-bromo-1-(4-methoxyphenyl)but-3-en-2-yl]- CH2O), 3.93 (m, 2 H, 3-H), 5.39 (d, J = 1.8 Hz, 1 H, =CH2), 5.42
amino}cyclohexanone Ethylene Acetal (17): To a solution of amine (d, J = 1.8 Hz, 1 H, =CH2), 5.51 (d, J = 1.8 Hz, 1 H, =CH2), 5.65
15 (100 mg, 0.39 mmol) in CH2Cl2 (4 mL) were added molecular (d, J = 1.8 Hz, 1 H, =CH2), 6.81 (dm, J = 8.1 Hz, 2 H, m-Ar), 6.82
sieves 4 Å (600 mg) and 1,4-cyclohexanedione monoethylene acetal
(51 mg, 0.33 mmol). The reaction mixture was heated at reflux,
stirred for 4 h, and then filtered through Celite to give a solution
of crude imine 16. To this solution was added allylmagnesium bro-
mide (1  in Et2O, 0.36 mL, 0.36 mmol), and the reaction mixture
was stirred at room temp. for 4 h, quenched with saturated NH4Cl
aqueous solution (15 mL), and extracted with CH2Cl2 (4ϫ15 mL).
The dried organic extracts were concentrated and purified by
(dm, J = 8.4 Hz, 2 H, m-Ar), 7.11 (dm, J = 8.1 Hz, 2 H, o-Ar), 7.14
(dm, J = 8.4 Hz, 2 H, o-Ar) ppm. 13C NMR (75 MHz, CDCl3): δ
= 30.9 (CH2), 31.2 (CH2), 32.8 (CH2), 32.9 (CH2), 33.0 (CH2), 37.6
and 38.0 (CH2Ar), 40.5 (C-4), 50.7 (C-2), 55.2 (OCH3), 58.0 and
58.1 (C-3), 62.6, 62.7 and 62.8 [C-5 and N(1)CH], 64.3 (CH2O),
107.9 (C-8), 113.5 (m-Ar), 117.6 and 117.8 (=CH2), 130.0 and 130.1
(o-Ar), 130.7 and 130.8 (ipso-Ar), 138.0 (C=), 157.9 (p-Ar) ppm.
1-[(S)-3-Bromo-1-(4-methoxyphenyl)but-3-en-2-yl]-3-amino-1-aza-
spiro[4.5]decan-8-one Ethylene Acetal (20): Triphenylphosphane
(23 mg, 0.09 mmol) was added to the diastereomeric mixture of
azides 19 (14 mg, 0.03 mmol) in THF (2 mL), and the reaction mix-
ture was stirred at room temp. for 24 h. H2O (0.1 mL) was added
and the stirring was maintained for 3 d. The reaction mixture was
extracted with 1  HCl (2ϫ5 mL), and the aqueous phase was ba-
sified with K2CO3 and extracted with CH2Cl2 (4ϫ10 mL). The
dried organic extracts were concentrated and purified by
chromatography (SiO2, CH2Cl2/MeOH, 1:0 to 8:2) to yield a mix-
ture of primary amines 20, from which one diastereomer was iso-
lated in a pure form after an additional chromatographic process.
20a: [α]D = + 12.3 (c = 0.46, CHCl3). 1H NMR (400 MHz, CDCl3,
COSY, HSQC, NOESY): δ = 1.08 (dm, J = 12.2 Hz, 1 H), 1.40 (m,
2 H), 1.57 (m 1 H), 1.68 (m, 3 H), 1.78 (m, 2 H), 2.15 (dd, J =
13.0, 7.4 Hz, 1 H, 4-H), 2.84 (dd, J = 14.0, 6.8 Hz, 1 H, CH2Ar),
chromatography (SiO2, CH2Cl2) to give 17 (106 mg, 75%). [α]D
=
1
+ 17.5 (c = 0.23, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.10
(s, 1 H, NH), 1.38–1.70 (m, 7 H), 1.77–1.86 (m, 1 H), 2.16 (d, J =
7.2 Hz, 2 H, CH2C=), 2.66 (dd, J = 13.5, 6.3 Hz, 1 H, CH2Ar),
2.77 (dd, J = 13.5, 7.5 Hz, 1 H, CH2Ar), 3.42 (dd, J = 7.5, 6.3 Hz,
1 H, CHN), 3.78 (s, 3 H, OMe), 3.90 (s, 4 H, OCH2), 5.01 (dm, J
= 18.9 Hz, 1 H, cis-H), 5.03 (dm, J = 9.3 Hz, 1 H, trans-H), 5.35
and 5.53 (2d, J = 1.7 Hz, 1 H each, CBr=CH2), 5.64–5.78 (m, 1 H,
gem-H), 6.81 (d, J = 8.7 Hz, 2 H, m-Ar), 7.09 (d, J = 8.7 Hz, 2 H,
o-Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.3 and 30.7 (C-3
and C-5), 32.9 and 33.1 (C-2 and C-6), 42.1 and 42.8 (CH2C = and
CH2Ar), 54.3 (C-4), 55.2 (OCH3), 61.2 (CHN), 64.1 (OCH2), 108.7
(C-1), 113.6 (m-Ar), 116.9 (=CH2), 117.4 (=CH2), 130.1 (ipso-Ar),
130.3 (o-Ar), 134.6 (=CH), 141.8 (=CBr), 158.1 (p-Ar) ppm.
HRMS: calcd. for C22H30BrN2O 435.1409; found 435.1418.
1-[(S)-3-Bromo-1-(4-methoxyphenyl)but-3-en-2-yl]-3-iodo-1-aza- 2.87 (m, 1 H, 2-H), 3.00 (dd, J = 14.0, 7.6 Hz, 1 H, CH2Ar), 3.39
spiro[4.5]decan-8-one Ethylene Acetal (18): A solution of I2
(252 mg, 0.99 mmol) in CH2Cl2 (7.5 mL) was added dropwise to a
solution of amine 17 (289 mg, 0.66 mmol) in CH2Cl2 (2.5 mL) and
5 % aqueous NaHCO3 (7.5 mL). After stirring for 2 h at room
temp., 10% aqueous Na2S2O3 (20 mL) was added. The mixture was
extracted with CH2Cl2 (4ϫ20 mL), and the organic extracts were
concentrated to give a diastereomeric mixture of iodides 18, which
was used in the next step without further purification. 1H NMR
(400 MHz, CDCl3, COSY, HSQC): δ = 1.43–1.61 (m, 3 H), 1.76
(m, 1 H, 3-H), 3.46 (dd, J = 8.4, 5.6 Hz, 1 H, 2-H), 3.78 (s, 3 H,
OCH3), 3.80 [m, 1 H, N(1)CH], 3.91 (m, 4 H, OCH2), 5.42 (d, J =
1.8 Hz, 1 H, =CH2), 5.59 (d, J = 1.8 Hz, 1 H, =CH2), 6.82 (dm, J
= 8.4 Hz, 2 H, m-Ar), 7.15 (dm, J = 8.4 Hz, 2 H, o-Ar) ppm. 13C
NMR (100 MHz, CDCl3): δ = 32.5 (CH2), 32.7 (CH2), 32.8 (CH2),
32.9 (CH2), 38.1 (CH2Ar), 44.7 (C-4), 49.3 (C-3), 54.2 (C-2), 55.2
(OCH3), 62.6 and 62.7 (C-5 and N(1)CH), 64.3 (CH2O), 108.1 (C-
8), 113.6 (m-Ar), 117.5 (=CH2), 130.1 (o-Ar), 131.1 (ipso-Ar), 138.8
(C=), 158.0 (ipso-Ar) ppm. HRMS: calcd. for C22H31BrN2O3
(m, 4 H), 1.99 (m, 1 H), 2.05 (m, 1 H, 4-H), 2.50 (m, 1 H, 4-H), 451.4071; found 451.4058. 20b (from a mixture): 1H NMR
2.85 (dd, J = 14.0, 3.6 Hz, 1 H, CH2Ar), 3.04 (dd, J = 14.0, 8.8 Hz,
1 H, CH2Ar), 3.28 (dd, J = 10.2, 3.2 Hz, 1 H, 2-H), 3.52 (dd, J =
8.8, 3.2 Hz, 1 H, 2-H), 3.78 (s, 3 H, OCH3), 3.80 (masked, 1 H,
(400 MHz, CDCl3, COSY, HSQC, NOESY): δ = 1.20 (m, 1 H),
1.48 (m, 1 H), 1.60 (m, 1 H, 4-H), 1.66 (m), 1.92 (td, J = 13.6,
4.0 Hz, 1 H), 2.14 (dd, J = 12.8, 7.6 Hz, 1 H, 4-H), 2.41 (br. s, 2
Eur. J. Org. Chem. 2007, 3038–3044
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3043

F. Diaba, G. Puigbó, J. Bonjoch
FULL PAPER
M. Song, A. Augustine, J. Org. Chem. 2006, 71, 2779–2786; f)
M. C. Marcotullio, V. Campagna, S. Sternativo, F. Costantino,
M. Curini, Synthesis 2006, 2760–2766.
H, NH2), 2.81 (dd, J = 14.0, 5.6 Hz, 1 H, CH2Ar), 2.92 (dd, J =
14.0, 9.2 Hz, 1 H, CH2Ar), 3.09 (dd, J = 8.8, 3.6 Hz, 1 H, 2-H),
3.26 (dd, J = 8.8, 5.2 Hz, 1 H, 2-H), 3.36 (m, 1 H, 3-H), 3.76 [m,
1 H, N(1)CH], 3.79 (s, 3 H, OCH3), 3.92 (m, 4 H, OCH2), 5.36 (d,
J = 2.0 Hz, 1 H, =CH2), 5.52 (d, J = 2.0 Hz, 1 H, =CH2), 6.81
(dm, J = 8.6 Hz, 2 H, m-Ar), 7.11 (dm, J = 8.6 Hz, 2 H, o-Ar)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 30.2 (CH2), 32.6 (CH2),
33.2 (CH2), 35.1 (CH2), 37.5 (CH2Ar), 44.6 (C-4), 49.5 (C-3), 54.0
(C-2), 55.4 (OCH3), 62.7 [C-5 and N(1)CH], 64.5 (CH2O), 108.3
(C-8), 113.8 (m-Ar), 117.5 (=CH2), 130.3 (o-Ar), 131.1 (ipso-Ar),
139.0 (C=), 158.2 (ipso-Ar) ppm.
[11] For a review on the synthesis of FR901483 and TAN1251 de-
rivatives, see: J. Bonjoch, F. Diaba, Stud. Nat. Prod. Chem.
2005, 32, 3–60.
[12] J. E. Kropf, I. C. Meigh, W. P. Bebbington, S. M. Weinreb, J.
Org. Chem. 2006, 71, 2046–2055.
[13] D. M. Lemal, A. J. Fry, J. Org. Chem. 1964, 29, 1673–1676.
[14] M. Ousmer, N. A. Braun, C. Bavoux, M. Perrin, M. A. Ciufol-
ini, J. Am. Chem. Soc. 2001, 123, 7534–7538.
[15] For similar procedures reducing the corresponding N-protected
methyl ester, see: a) M. K. Gurjar, S. Karmakar, D. K. Mo-
hapatra, U. D. Phalgune, Tetrahedron Lett. 2002, 43, 1897–
1900; b) M. P. Bosch, F. Campos, I. Niubó, G. Rosell, J. L.
Díaz, J. Brea, M. I. Loza, A. Guerrero, J. Med. Chem. 2004,
47, 4041–4053.
Acknowledgments
This research was supported by the MEC (Spain)-FEDER through
project CTQ2004-04701/BQU. Thanks are also due to the DURSI
(Catalonia) for Grant 2005SGR-00442.
[16] For a recent example of the allylation reaction using phenylgly-
cinol-based oxazolidines or imine, see: G. Chaume, M.-C.
Van Severen, S. Marinkovic, T. Brigaud, Org. Lett. 2006, 8,
6123–6126.
[17] A possible interpretation of this generation could be that a
primary alkoxyl radical was initially formed by iodine, which
then evolved through an intramolecular 1,5-hydrogen abstrac-
tion to an α-aminoalkyl radical that was easily oxidized in the
reaction medium to the iminium salt.
[18] For processes in which N-(2-hydroxyethyl)pyrrolidines undergo
an oxidative cyclization to the corresponding oxazolidines, see:
a) J. T. Yli-Kauhaluoma, C. W. Harwig, P. Wentworth Jr, K. D.
Janda, Tetrahedron Lett. 1998, 39, 2269–2272; b) A. J. Pearson,
Y. Kwak, Tetrahedron Lett. 2005, 46, 3407–3410.
[19] M. G. Constantino, G. V. J. da Silva, Tetrahedron 1998, 54,
11363–11374.
[1] J. Bonjoch, F. Diaba, G. Puigbó, D. Solé, V. Segarra, L. Santa-
maría, J. Beleta, H. Ryder, J.-M. Palacios, Bioorg. Med. Chem.
1999, 7, 2891–2897.
[2] G. Puigbó, F. Diaba, J. Bonjoch, Tetrahedron 2003, 59, 2657–
2665.
[3] J. Bonjoch, F. Diaba, G. Puigbó, E. Peidró, D. Solé, Tetrahe-
dron Lett. 2003, 44, 8387–8390.
[4] F. Diaba, E. Ricou, D. Solé, E. Teixidó, N. Valls, J. Bonjoch,
ARKIVOC 2007, iv, 320–330.
[5] For a review on the synthesis of 1-azaspiro[4.5]decanes, see: G.
Dake, Tetrahedron 2006, 62, 3467–3492.
[6] For synthetic uses of molecular iodine in organic synthesis, see:
H. Togo, S. Iida, Synlett 2006, 2159–2175.
[20] a) L. Belvisi, C. Gennari, G. Poli, C. Scolastico, B. Salom, Tet-
rahedron: Asymmetry 1993, 4, 273–280; b) V. I. Tararov, R. Ka-
dyrov, T. H. Riermeier, A. Börner, Synthesis 2002, 3, 375–380.
[21] J. Jurczak, D. Gryko, E. Kobrzycka, H. Gruza, P. Prokopowicz,
Tetrahedron 1998, 54, 6051–6064.
[22] P. Callant, L. D’Haenens, M. Vandewalle, Synth. Commun.
1984, 14, 155-161. For a recent alternative procedure to synthe-
size this reagent, see:J. Pietruska, A. Witt, Synthesis 2006,
4266–4268.
[7] For the use of iodine as a promoter in homoallylamine cycliza-
tions through a 5-endo-trig process, see: a) ref.[1]; b) K.-T.
Chang, K. C. Jang, H.-Y. Park, Y.-K. Kim, K. H. Park, W. S.
Lee, Heterocycles 2001, 55, 1173–1179; c) J. H. Kim, M. J. C.
Long, J. Y. Kim, K. H. Park, Org. Lett. 2004, 6, 2273–2276.
[8] For iodine-promoted cyclization of other aminoalkenes, see: a)
S. R. Wilson, R. A. Sawicki, J. Org. Chem. 1979, 44, 287–291;
b) D. Tanner, M. Sellén, J.-E. Bäckvall, J. Org. Chem. 1989, 54,
3374–3378; c) H. M. Hügel, A. B. Hugues, K. Khalil, Aust. J.
Chem. 1998, 51, 1149–1155; d) H. M. C. Ferraz, F. L. C. Per-
eira, F. S. Leite, M. R. S. Nunes, M. E. Payret-Arrúa, Tetrahe-
dron 1999, 55, 10915–10924; e) C. Fiorelli, C. Marchioro, G.
Martelli, M. Monari, D. Savoia, Eur. J. Org. Chem. 2005, 3987–
3993.
[23] a) S. Ohira, Synth. Commun. 1989, 19, 561–564; b) G. J. Roth,
B. Liepold, S. G. Müller, H. J. Bestmann, Synthesis 2004, 59–
62.
[24] For other procedures applied to N-Boc-α-aminoaldehydes, see:
G. Reginato, A. Mordini, F. Messina, A. Degl’Innocenti, G.
Poli, Tetrahedron 1996, 52, 10985–10996.
[25] J. Cousseau, Synthesis 1980, 805–806.
[9] For iodoaminocyclization of tertiary amines, see: S. G. Davies,
R. L. Nicholson, P. D. Price, P. M. Roberts, A. D. Smith, Syn-
lett 2004, 901–903.
[26] 1H NMR (200 MHz, CDCl3): δ = 1.52–1.73 (m, 5 H), 1.75–
2.02 (m, 3 H), 2.24 (d, J = 7.8 Hz, 2 H, CH2C=), 3.95 (m, 4
H, CH2O), 5.15 (dm, J = 17.0 Hz, 1 H, cis-H), 5.17 (dm, J =
8.2 Hz, 1 H, trans-H), 5.88 (m, 1 H, gem-H) ppm. MS (CI):
m/z (%) = 198 (1), 181 (28), 157 (32), 113 (15), 100 (85), 99
(100), 95 (51), 86 (46), 71 (21), 67 (21), 57 (22), 56 (14), 55 (48),
53 (11).
[10] For pyrrolidine ring formation through iodine-promoted cycli-
zation of homoallylic amides or carbamates, see inter alia: a)
A. D. Jones, D. W. Knight, D. E. Hibbs, J. Chem. Soc., Perkin
Trans. 1 2001, 1182–1203; b) D. W. Knight, A. L. Redfern, J.
Gilmore, J. Chem. Soc., Perkin Trans. 1 2001, 2874–2883; c) T.
Hashihayata, H. Sakoh, Y. Goto, K. Yamada, H. Morishima,
Chem. Pharm. Bull. 2002, 50, 423–425; d) M. Amjad, D. W.
Knight, Tetrahedron Lett. 2006, 47, 2825–2828; e) F. A. Davis,
[27] For related studies about 5-endo-trig cyclizations of homoal-
lylic amines in the field of FR901483 synthesis, see ref.[12]
Received: January 22, 2007
Published Online: April 30, 2007
3044
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3038–3044