Synthesis of enantiopure 1-azaspiro[4.5]dec-6-en-8-ones from l-proline derivatives

Article abstract of DOI:10.1016/j.tetasy.2006.05.002

An enantioselective synthesis of protected 1-azaspiro[4.5]dec-6-en-8-one derivatives was achieved using an alkylidene carbene 1,5-CH insertion reaction as the key step.

Full text of DOI:10.1016/j.tetasy.2006.05.002

Tetrahedron: Asymmetry 17 (2006) 1437–1443
Synthesis of enantiopure 1-azaspiro[4.5]dec-6-en-8-ones
from L-proline derivatives
Faıza Diaba, Eva Ricou and Josep Bonjoch*
¨
` `
Laboratori de Quı´mica Organica, Facultat de Farmacia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
Received 24 April 2006; accepted 1 May 2006
Abstract—An enantioselective synthesis of protected 1-azaspiro[4.5]dec-6-en-8-one derivatives was achieved using an alkylidene carbene
1,5-CH insertion reaction as the key step.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
sis of undescribed enantiopure 1-azaspiro[4.5]dec-6-en-8-
one8 derivatives 1 and 2, which could be considered as
building blocks for the enantioselective construction of
the azatricyclic ring of some of the aforementioned alka-
loids. The synthetic approach follows the methodology
recently reported by Hayes,9 based on the alkylidene carbene
1,5-CH insertion in proline derivatives, which he has also
used in a formal synthesis of TAN1251A (see Scheme 1).10
The 1-azaspiro[4.5]decane1 skeleton is found in several nat-
ural products, such as TAN1251 derivatives, FR901483,2,3
cylindricines,4 lepadiformines5 and lapidilectine B (Fig. 1).6
OMe
Me
N
HO
O
N
N
H
NHMe
R
R
R
O
O
N
Boc
(HO)2P
O
TAN1251D
FR901483
N
CO2Me
N
Boc
Boc
O
O
N
N
1, R = N(CO2Me)Me
2, R = H
HO
HO
Lepadiformine
C6H13
C6H13
Scheme 1.
Cylindricine C
O
N
O
2. Results and discussion
N
CO2Me
Lapidilectine B
The synthetic studies were first devoted to the synthesis of 1
using proline 3 as the starting material. Alcohol 3 was con-
verted to the protected 4-methylamino derivative 7a
through a four-step sequence involving a Mitsunobu pro-
cess11 to give azide 4,12 which was reduced to the primary
amine 5,13 undergoing subsequent methoxycarbonylation
and methylation to give carbamate 7a (Scheme 2). The
methoxycarbonyl group at C-2 of proline 7a was trans-
formed into the required 3-oxobutyl side chain by an initial
Figure 1.
Following our studies in the FR901483 series starting from
1-azaspiro[4.5]decan-8-ones,7 we herein report the synthe-
*
Corresponding author. Tel.: +34 934 024 540; fax: +34 934 024 539;
e-mail: josep.bonjoch@ub.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.05.002

1438
F. Diaba et al. / Tetrahedron: Asymmetry 17 (2006) 1437–1443
After these results, we revisited Hayes’ synthesis9 of azas-
HO
R
piranic compound 12b for two reasons: (i) in order to gain
access to an advanced intermediate in the pathway towards
target 2, following the chemistry used in the preparation of
1, and (ii) to check the level of stereocontrol in the 1,5-CH
insertion reaction (11b!12b), since in the reported process
the authors were unable to determine the enantiomeric
excess of the synthesized 12b.
DPPA, DEAD, PPh3
THF
CO2Me
N
Boc
CO2Me
N
Boc
R
3
4
5
6
N3
NH2
i
iii
iii
NHCO2Me
7a
N(CO2Me)Me
The required cyclization precursor 11b18 was prepared as
outlined in Scheme 3 starting from proline 7b, which was
sequentially reduced to alcohol 8b, oxidized to aldehyde
9b and submitted to a chain extension sequence through
a Wittig process followed by hydrogenation.
Scheme 2. Reagents and conditions: (i) H2 (500 psi), Pd/C, MeOH, rt
overnight; (ii) ClCO2Me, K2CO3, CH3CN; (iii) NaH, MeI, DMF.
conversion to aldehyde 9a (TEMPO, NaOCl, NaBr)14
through alcohol 8a, followed by a Wittig olefination and
hydrogenation of the resulting enone 10a (Scheme 3).
Ketone 11b was added over a period of 30 min instead of
15 min9a to lithium(trimethylsilyl)diazomethane solution
at ꢀ78 ꢁC, prepared by the addition of BuLi to a solution
of TMSCHN2 in THF at ꢀ78 ꢁC. After column chroma-
tography, 12b was obtained in 63% yield and its specific
rotation was ꢀ104.8 instead of ꢀ78, as reported by Hayes.
The time over which the ketone was added to the carbene
solution seemed to determine the reaction’s stereocontrol,
since quick addition of the ketone gave optically inactive
cyclopentene 12b. The latter was used to synthesize the
same cyclohexene 2 in a racemic manner to provide refer-
ence samples for an enantiomeric excess determination.
As occurred in series a, the ring enlargement (12b!2)
was carried out by an initial ring cleavage of 12b, leading
to ketoaldehyde 14b. This underwent the recyclization pro-
cess by an aldol condensation, which after treatment with
MsCl gave target 2 from 12b in 68% overall yield. Like
Hayes, we were initially unable to determine the % ee of
At this point, the critical construction of the stereogenic
quaternary spirocentre was undertaken following the Ohira
protocol.15 Ketone 11a was added to a preformed solution
of lithium(trimethylsilyl)diazomethane at ꢀ78 ꢁC to form
the corresponding alkylidene carbene and, after the CH
insertion,16 the cyclized azaspiranic compound 12a was iso-
lated in 54% yield, with the process being stereocontrolled.
Cyclopentene 12a was oxidatively cleaved by a two-step
protocol. Treatment with K2OsO4 in the presence of
NMO provided the dihydroxy derivative 13a as a single
diastereomer with the hydroxy groups being delivered
opposite to the bulky Boc-protecting group. Oxidation of
13a using NaIO4 provided ketoaldehyde 14a, which was ex-
posed to alkaline conditions and then treated with MsCl17
to give target compound 1 in 70% overall yield from 14a.
R
R
R
R
Ph3P=CHCOCH3
CH2Cl2
H2, Pd/C
AcOEt
TEMPO, NaClO
CH2Cl2, H2O
LiBH4
THF
CO2Me
CH2OH
CHO
N
Boc
N
Boc
N
Boc
N
Boc
O
9a (77%)
9b (99%)
8a (98%)
8b (97%)
10a (71%)
10b (62%)
7a
7b
R
R
R
R
OH
OH
TMSCHN2, BuLi
THF
K2OsO4.2H2O, NMO
t-BuOH
NaIO4, buffer 7
THF
CHO
N
Boc
N
Boc
N
Boc
N
Boc
O
O
12a (54%)
12b (63%)
13a
14a (76% from 12a)
14b (90%)
11a (96%)
13b (96%)
11b (100%)
R
1- KOH, EtOH
2- MsCl, Et3N
N
Boc
Series
a
b
R = N(CO2Me)Me
R = H
O
1 (70%)
2 (79%)
Scheme 3. Preparation of 1 and 2.

F. Diaba et al. / Tetrahedron: Asymmetry 17 (2006) 1437–1443
1439
12b using either chiral GC or HPLC. Fortunately, in a later
stage of the synthesis, 2 was resolved using a chiral HPLC
(Chiracel OD, 2% isopropanol in hexane) and was found to
have an enantiomeric excess of 90%.
was then filtered on a Celite pad and concentrated to yield
513 in a quantitative yield and was pure enough to be used
in the next step without further purification. To a solution
of primary amine 5 (8.83, 36.1 mmol) in CH3CN were
added successively methyl chloroformate (5.6 mL,
72.3 mmol) and K2CO3 (10.1 g, 72.3 mmol). The mixture
was stirred at rt for 4 h, concentrated, and the residue
diluted with CH2Cl2 and washed with concentrated
NaHCO3. The organic layer was dried and concentrated
3. Conclusion
Enantiomerically pure 1-azaspiro[4.5]dec-6-en-8-ones were
synthesized from L-proline derivatives using a stereocon-
trolled 1,5-CH insertion as a key step. These intermediates
are suitable precursors of FR901483, cylindricines or
lepadiformine.
to yield carbamate 6 as a colourless oil (9.6 g, 88%).
23
½aꢁD ¼ ꢀ23:7 ðc 0:85; CHCl3Þ; IR (NaCl, neat): 3333,
2978, 1700 cmꢀ1 1H NMR (CDCl3, 200 MHz) d 1.41
;
and 1.46 (2s, 9H, CH3), 1.95 (br s, 1H, H-3), 2.48 (m,
1H, H-3), 3.51 (m, 1H, H-5), 3.66 (m, 1H, H-5), 3.66 (s,
3H, CH3O), 3.77 (s, 3H, CH3O), 4.28 (m, 1H, H-2), 4.36
(br s, 1H, NH), 5.83 (br s, 1H, H-4); 13C NMR (CDCl3,
50.3 MHz) d 28.2 and 28.3 (CH3), 35.7 and 36.7 (C-3),
49.5 and 50.5 (CH), 52.1 (CH3O), 52.3 and 52.5 (CH3O),
52.8 and 53.4 (C-5), 57.5 and 57.7 (CH), 80.4 (C), 153.2
and 154.0 (CO), 156.2 (CO), 174.3 (CO). To a solution of
6 (5.4 g, 17.9 mmol) in DMF (250 mL) at 0 ꢁC were added
NaH (0.86 g, 19.7 mmol) portionwise and then MeI
(3.71 mL, 59 mmol). The mixture was stirred overnight at
rt and quenched by adding a saturated solution of NH4Cl.
The aqueous phase was extracted with ether and the organ-
ics dried and concentrated to yield compound 7a (4.6 g,
4. Experimental
1H and 13C NMR spectra were recorded in CDCl3 solution
at 200, 300, or 400 MHz, and 50.3, 75.4 or 100 MHz,
respectively. In addition, chemical shifts are reported as d
values (ppm) relative to internal Me4Si. Infrared spectra
were recorded on a Nicolet 205 FT-IR spectrophotometer.
Optical rotations were taken on a Perkin–Elmer 241 polar-
imeter with a 1 mL (L = 1 dm) cell. TLC was performed on
SiO2 (silica gel 60 F254, Merck). The spots were located by
UV light and a 1% KMnO4 solution. Chromatography
refers to flash chromatography and carried out on SiO2
(silica gel 60, SDS, 230–400 mesh). HPLC analyses for
the determination of enantiomeric excess were carried out
using a daicel Chiralcel OD-H column (250 · 4.6 mm
I.D., 5 lm; J. T. Baker) on a Waters model 2487 Dual
Absorbance Detector and set at the wavelength of
220 nm. The chromatographic resolution of compound 2
was achieved using 2:98 2-propanol/hexane as the mobile
phase in an isocratic run. All reactions were carried out un-
der an argon atmosphere with dry, freshly distilled solvents
under anhydrous conditions. Drying of the organic extracts
during the work-up of reactions was performed over
anhydrous Na2SO4. Melting points were determined in a
82%). An analytical sample was obtained by chromatogra-
23
phy eluting with CH2Cl2. ½aꢁD ¼ ꢀ44:7 ðc 1; CHCl3Þ; IR
1
(NaCl, neat): 3019, 1748, 1692 cmꢀ1; H NMR (CDCl3,
200 MHz) d 1.41 and 1.45 (2s, 9H, CH3), 1.98 (m, 1H,
H-3), 2.42 (td, 1H, J = 12.4, 7.6 Hz, H-3), 2.83 (s, 3H,
CH3N), 3.33 (m, 1H, H-5), 3.71 (m, 1H, H-5), 3.72 (s,
3H, CH3O), 3.76 (s, 3H, CH3O), 4.24 (m, 1H, H-2), 4.79
(br s, 1H, H-4); 13C NMR (CDCl3, 50.3 MHz) d 28.2 and
28.3 (CH3), 28.8 (CH3N), 31.6 and 32.6 (C-3), 46.2 and
46.6 (C-5), 52.1 and 52.3 (CH3O), 52.6 and 53.2 (CH),
52.9 (CH3O), 57.1 and 57.5 (CH), 80.5 (C), 153.4 and
154.1 (CO), 156.7 (CO), 173.1 (CO). Anal. Calcd for
C14H24N2O6: C, 53.15; H, 7.65; N, 8.86. Found: C, 53.23;
H, 7.64; N, 8.62.
capillary tube on a Buchi apparatus. L-Proline and trans-
¨
4-hydroxy-L-proline were used as chiral starting materials
purchased from Panreac and Fluka, respectively.
4.2. tert-Butyl (2S,4S)-2-(hydroxymethyl)-4-[(N-methoxy-
carbonyl)-N-methylamino]pyrrolidine-1-carboxylate 8a
4.1. tert-Butyl 2-methyl (2S,4S)-4-[(N-methoxycarbonyl)-N-
methylamino]pyrrolidine-1,2-dicarboxylate 7a
To a solution of 7a (5.18 g, 16.37 mmol) in THF (75 mL) at
0 ꢁC was added LiBH4 (0.75 g, 32.75 mmol) portionwise
and the mixture stirred overnight at rt. The reaction was
quenched by the addition of water and the resulting clear
solution extracted with ether (5 · 250 mL). The combined
organic phase was washed with saturated aqueous NaH-
CO3 (200 mL), then with brine (200 mL) and dried. Re-
moval of the solvent provided alcohol 8a as a viscous
Starting from alcohol 3 (22.6 g, 112.4 mmol), azide 4 was
prepared according to the protocol reported by Silver-
man.11 After chromatography (hexane–hexane/EtOAc
60:40), 412 was obtained as a viscous yellow oil in a quan-
23
titative yield. ½aꢁD ¼ ꢀ40:3 ðc 1; CHCl3Þ; IR (NaCl, neat):
2977, 2105, 1755, 1704 cmꢀ1; 1H NMR (CDCl3, 200 MHz)
d 1.42 and 1.47 (2s, 9H, CH3), 2.17 (2t, 1H, J = 4.4 Hz, H-
3), 2.47 (m, 1H, H-3), 3.48 (m, 1H, H-5), 3.72 (m, 1H, H-5),
3.76 (s, 3H, CH3O), 4.16 (m, 1H, H-4), 4.33 and 4.43 (2dd,
1H, J = 8.8, 4.6 Hz, H-2); 13C NMR (CDCl3, 50.3 MHz) d
28.2 and 28.3 (CH3), 35.0 and 36.0 (C-3), 50.7 and 51.2
(C-5), 52.2 and 52.4 (CH3O), 57.3 and 57.6 (CH), 58.2
and 59.2 (CH), 80.5 (CH3), 153.3 and 153.8 (CO), 171.8
and 172.1 (CO). A suspension of 4 (5.31 g, 19.6 mmol)
and Pd/C (0.53 g, 10%) in MeOH (60 mL) was stirred over-
night at rt under hydrogen pressure (500 psi). The mixture
colourless oil (4.61 g, 98%), which was used in the next step
23
without further purification. ½aꢁD ¼ ꢀ43:7 ðc 1; CHCl3Þ;
IR (NaCl, neat): 3444, 2977, 1693 cmꢀ1; 1H NMR (CDCl3,
500 MHz) d 1.46 (s, 9H, CH3), 1.66 (br s, 1H, H-3), 2.12
(td, 1H, J = 12.0, 7.5 Hz, H-3), 2.81 (s, 3H, CH3N), 3.12
(t, 1H, J = 10.5 Hz, H-5), 3.61 (dd, 1H, J = 11.5, 6.5 Hz,
CH2OH), 3.71 (s, 3H, CH3O), 3.71 (m, 1H, H-5), 3.74
(br t, 1H, J = 11.5 Hz, CH2OH), 3.94 (br s, 1H, H-2),
4.63 (br s, 1H, H-4); 13C NMR (CDCl3, 50.3 MHz) d
28.1 (CH3), 28.6 (CH3N), 30.1 (C-3), 47.2 (C-5), 52.2

1440
F. Diaba et al. / Tetrahedron: Asymmetry 17 (2006) 1437–1443
(C-4), 52.5 (CH3O), 58.7 (C-2), 66.1 (CH2OH), 80.3 (C),
156.0 (CO), 156.5 (CO).
1H, J = 16, 7.2 Hz, @CH); 13C NMR (CDCl3, 50.3 MHz)
d 27.3 (CH3), 28.3 (CH3)3, 29.0 (CH3N), 34.5 (C-3), 46.6
(C-5), 52.8 (C-4), 52.8 (CH3O), 56.7 (C-2), 80.3 (C), 129.4
(@CH), 147.5 (@CH), 154.1 (CO), 156.7 (CO), 198.0
(CO). Anal. Calcd for C16H26N2O5Æ1/4 H2O: C, 58.08; H,
8.07; N, 8.47. Found: C, 57.98; H, 7.97; N, 8.33.
4.3. tert-Butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carb-
oxylate 8b
Operating as above, from ester 7b (10.3 g, 47.8 mmol) and
LiBH4 (2.19 g, 95.6 mmol) in THF (350 mL), 8b19 (8.74 g,
97%) was isolated.
4.7. tert-Butyl (S)-2-[(1E)-3-oxobut-1-enyl]pyrrolidine-1-
carboxylate 10b
4.4. tert-Butyl (2S,4S)-2-formyl-4-[(N-methoxycarbonyl)-N-
methylamino]pyrrolidine-1-carboxylate 9a
Operating as above, from aldehyde 9b (10.3 g, 51.83 mmol)
and 1-triphenylphosphoranylidene-2-propanone (25 g,
77.7 mmol) in CH2Cl2 (300 mL), after chromatography
To a solution of alcohol 8a (3.14 g, 10.88 mmol) in CH2Cl2
(50 mL) at 0 ꢁC were added successively under vigourous
stirring TEMPO (0.035 g, 0.022 mmol) and NaBr (0.13 g,
10.88 mmol). To the resulting mixture was added a solution
of NaHCO3 (2.12 g, 25.02 mmol) and 10% NaClO in active
chlorine (20.65 mL, 16.64 mmol) in water (50 mL) and the
mixture rapidly extracted with ether (4 · 100 mL). The
combined organic phase was first washed with a solution
of NaHSO4 (10%) and KI (4%), then with brine and dried.
After removal of all volatiles in vacuum, aldehyde 9a
(2.40 g, 77%) was obtained as a colourless oil, which was
used in the next step without further purification. An ana-
(hexane–hexane/EtOAc 60:40), 10b was isolated as a viscous
23
colourless oil (7.6 g, 62%). ½aꢁD ¼ ꢀ86:9 ðc 1:1; CHCl3Þ;
1
IR (NaCl, neat): 3018, 2979, 1686, 1630 cmꢀ1; H NMR
(CDCl3, 200 MHz) d 1.43 and 1.47 (2s, 9H, CH3), 1.70–
1.93 (m, 3H), 2.11 (m, 1H), 2.26 (s, 3H, CH3), 3.44 (br s,
2H, CH2-5), 4.41 (br s, 1H, H-2), 6.07 (dd, 1H,
J = 15.6 Hz, 1.6, @CH), 6.67 (dd, 1H, J = 15.4, 5.4 Hz,
@CH); 13C NMR (CDCl3, 50.3 MHz) d 22.8 and 23.3
(C-4), 26.9 (CH3), 28.1 (CH3), 30.6 and 31.6 (C-3), 46.1
and 46.3 (C-5), 57.3 and 57.7 (C-2), 79.3 (C), 129.1
(@CH), 147.2 (@CH), 153.9 (CO), 197.9 (CO). Anal. Calcd
for C13H21NO3Æ0.2H2O: C, 64.52; H, 8.87; N, 5.79. Found:
C, 64.57; H, 8.74; N, 5.76.
lytical sample was obtained by chromatography (hexane/
23
EtOAc 50:50). ½aꢁD ¼ ꢀ70:7 ðc 1; CHCl3Þ; IR (NaCl,
neat): 3017, 2980, 1736, 1691 cmꢀ1
;
1H NMR (CDCl3,
4.8. tert-Butyl (2R,4S)-2-(3-oxobutyl)-4-[(N-methoxycarb-
onyl)-N-methylamino]pyrrolidine-1-carboxylate (11a)
200 MHz) d 1.43 and 1.47 (2s, 9H, CH3), 1.97 (td, 1H,
J = 11.8, 10.6 Hz, H-3), 2.24 (m, 1H, H-3), 2.84 (s, 3H,
CH3N), 3.31 (td, 1H, J = 9.6, 9.2 Hz, H-5), 3.72 (s, 3H,
CH3O), 3.75 (m, 1H, H-5), 4.13 (m, 1H, H-2), 4.76 (br s,
1H, H-4); 13C NMR (CDCl3, 50.3 MHz) d 26.9 and 27.0
(CH3), 28.1 (CH3N), 28.3 (C-3), 45.4 and 45.7 (C-5), 51.6
(CH3O), 51.9 and 52.6 (C-4), 61.7 and 62.0 (C-2), 79.4
and 79.8 (C), 152.2 and 153.4 (CO), 155.3 (CO), 197.5
and 197.8 (CO). Anal. Calcd for C13H22N2O5Æ2/3H2O: C,
52.33; H, 7.88; N, 9.39. Found: C, 52.56; H, 8.05; N, 8.90.
A suspension of enone 10a (1.73 g, 5.30 mmol) and Pd/C
(0.18 g, 10%) in ethyl acetate (70 mL) was stirred overnight
under hydrogen pressure (500 psi). The mixture was filtered
on a Celite pad and concentrated to yield 11a (1.68 g, 96%).
This compound was pure enough for the next step. An ana-
lytical sample was obtained by chromatography (hexane–
23
hexane/EtOAc 40:60). ½aꢁD ¼ ꢀ47:3 ðc 1; CHCl3Þ; IR
(NaCl, neat): 2974, 1697 cmꢀ1
;
1H NMR (CDCl3,
200 MHz) d 1.46 (s, 9H, CH3), 1.50–1.90 (m, 2H), 2.02–
2.32 (m, 2H), 2.17 (s, 3H, CH3), 2.45 (t, 2H, J = 7.2 Hz),
2.83 (s, 3H, CH3N), 3.08 (t, 1H, J = 10.6 Hz), 3.63–3.90
(m, 2H), 3.71 (s, 3H, CH3O), 4.55 (br s, 1H, H-4); 13C
NMR (CDCl3, 50.3 MHz) d 28.2 (CH3), 29.0 (CH3N),
29.0 (CH2), 29.6 (CH3), 33.2 (CH2), 39.6 (CH2), 46.3 (C-
5), 52.6 (CH3O), 52.8 (CH), 54.9 (CH), 79.5 (C), 154.3
(CO), 156.6 (CO), 207.8 (CO).
4.5. tert-Butyl (S)-2-formylpyrrolidine-1-carboxylate 9b
Operating as above, from alcohol 8b (23.8 g, 118.5 mmol),
TEMPO (0.38 g, 2.37 mmol) and NaBr (12.31 g, 118.5 mmol)
in CH2Cl2 (550 mL) and then a solution of NaHCO3
(23.12 g, 272.5 mmol) and NaClO (225 mL, 181.3 mmol)
in water (550 mL), 9b20 (23.3 g, 99%) was isolated.
4.6. tert-Butyl (2S,4S)-2-[(1E)-3-oxobut-1-enyl]-4-[(N-meth-
oxycarbonyl)-N-methylamino]pyrrolidine-1-carboxylate 10a
4.9. tert-Butyl (S)-2-(3-oxobutyl)pyrrolidine-1-carboxylate
11b
A solution of aldehyde 9a (1.06 g, 3.71 mmol) and 1-triphen-
ylphosphoranylidene-2-propanone (1.79 g, 5.57 mmol) in
CH2Cl2 (30 mL) was stirred overnight at rt. The mixture
was concentrated and purified by chromatography, eluting
Operating as above, from enone 10b (3.7 g, 15.47 mmol)
and Pd/C (0.37 g, 10%) in ethyl acetate (70 mL), 11b was
isolated in a quantitative yield (3.7 g). An analytical sample
was obtained by chromatography (hexane–hexane/EtOAc
23
with ethyl acetate, to give enone 10a (0.86 g, 71%) as a
40:60). ½aꢁD ¼ ꢀ51:8 ðc 1; CHCl3Þ; IR (NaCl, neat):
23
viscous colourless oil. ½aꢁD ¼ ꢀ31:8 ðc 1; CHCl3Þ; IR
3019, 2976, 1711, 1681 cmꢀ1
;
1H NMR (CDCl3,
(NaCl, neat): 3017, 2980, 1686, 1630 cmꢀ1; 1H NMR (CDCl3,
200 MHz) d 1.42 (s, 9H, CH3), 1.84 (m, 1H, H-3), 2.28
(s, 3H, CH3), 2.29 (m, 1H, H-3), 2.83 (s, 3H, CH3N),
3.22 (t, 1H, J = 10.2 Hz, H-5), 3.72 (s, 3H, CH3O), 3.77
(br t, 1H, J = 10.2 Hz, H-5), 4.37 (br s, 1H, H-2), 4.70
(br s, 1H, H-4), 6.13 (d, 1H, J = 16 Hz, @CH), 6.70 (dd,
300 MHz) d 1.46 (s, 9H, CH3), 1.55–1.73 (m, 2H), 1.75–
1.99 (m, 4H), 2.15 (s, 3H, CH3), 2.46 (br s, 2H), 3.30 (br
s, 1H), 3.42 (br s, 1H), 3.81 (br s, 1H); 13C NMR (CDCl3,
75.5 MHz) d 23.1 and 23.7 (CH2), 28.5 (CH3), 28.7 (CH2),
29.8 (CH3), 30.3 and 30.7 (CH2), 40.7 (CH2), 46.3 (CH2),
56.5 (C-2), 79.3 (br s, C), 154.8 (CO), 208.3 and 208.7 (CO).

F. Diaba et al. / Tetrahedron: Asymmetry 17 (2006) 1437–1443
1441
4.10. tert-Butyl (5R)-4-[(N-methoxycarbonyl)-N-methyl-
amino]-7-methyl-1-azaspiro[4.4]non-6-ene-1-carboxylate 12a
K2OsO4Æ2H2O (0.15 g, 5%) and a solution of 12a (3 g,
9.25 mmol) in acetone (30 mL). The mixture was stirred
overnight at rt, extracted with CH2Cl2 (5 · 100 mL) and
dried. The crude was pure enough to be used in the next
step without further purification (3.3 g, 100%). An analy-
To a solution of trimethylsilyldiazomethane (2 M in diethyl
ether, 2.48 mL, 4.96 mmol) in dry THF (30 mL) at ꢀ78 ꢁC
was added BuLi (1.6 M in hexanes, 3.10 mL, 4.96 mmol)
and the mixture stirred at this temperature for 30 min. A
solution of ketone 11a (1.09 g, 3.31 mmol) in THF
(25 mL) was then added and the mixture stirred at this tem-
perature for 5 h. The reaction was then quenched with
water and extracted with ether (5 · 100 mL). The organics
were washed with brine, dried and concentrated to yield a
yellow oil, which was purified by chromatography (hexane/
tical sample of 13a was obtained by column chromatogra-
23
phy (CH2Cl2–CH2Cl2/MeOH 90:10). ½aꢁD ¼ þ11:8 ðc 1;
CHCl3Þ, IR (NaCl, neat): 3422, 2972, 1685 cmꢀ1
;
1H
NMR (CDCl3, 300 MHz) d 1.32 (s, 3H, CH3-7), 1.44 and
1.48 (2s, 9H, (CH3)3C), 1.60–1.98 (m, 3H), 2.08 (m, 1H),
2.30 and 2.46 (2m, 1H), 2.66 (m, 1H), 2.80 (s, 3H,
CH3N), 3.13 and 3.23 (2t, 1H, J = 9.9 Hz, H-2), 3.61 (m,
1H, H-2), 3.70 (s, 3H, CH3O), 4.10 and 4.27 (2d, 1H,
J = 7.8 Hz, H-6), 4.86 (br s, 1H, H-3); 13C NMR (CDCl3,
75.5 MHz) d 26.1 and 26.4 (CH3-7), 28.6 (CH3), 28.7
(CH3N), 33.7 and 34.7 (CH2), 35.6 and 35.7 (CH2), 39.1
and 40.5 (CH2), 47.5 (CH2), 50.9 and 51.5 (C-3), 52.8
(CH3O), 70.1 and 70.3 (C-5), 77.9 (C-7), 79.2 and 80.3
(C), 80.0 and 81.3 (C-6), 153.3 and 153.7 (CO), 157.2 (CO).
CH2Cl2 50:50–100). Compound 12a was obtained as a col-
23
ourless oil (0.58 g, 54%). ½aꢁD ¼ ꢀ78:3 ðc 1; CHCl3Þ; IR
1
(NaCl, neat): 2973, 2931, 1701 cmꢀ1; H NMR (CDCl3,
500 MHz) d 1.39 (s, 9H, CH3), 1.71 (s, 3H, CH3-7), 1.80–
2.75 (m, 6H), 2.81 (s, 3H, CH3N), 3.23 (br s, 1H), 3.59
(br s, 1H), 3.70 (s, 3H, CH3O), 4.62 (br s, 1H, H-3), 5.19
(s, 1H, H-6); 13C NMR (CDCl3, 75.5 MHz) d 16.5 (CH3-
7), 28.5 (CH3), 28.8 (CH3N), 35.7 (CH2), 35.7 and 37.0
(CH2), 43.7 and 45.3 (CH2), 48.1 (CH2), 51.3 (C-3), 52.7
(CH3O), 73.9 (C-5), 79.2 (C), 127.0 and 128.4 (C-6),
141.2 and 142.7 (C-7), 153.0 and 154.5 (CO), 157.0 (CO).
Anal. Calcd for C17H28N2O4Æ1/2H2O: C, 61.24; H, 8.77;
N, 8.40. Found: C, 61.47; H, 9.01; N, 8.60.
4.13. tert-Butyl (5S,6R,7S)-6,7-dihydroxy-7-methyl-1-aza-
spiro[4.4]nonane-1-carboxylate 13b
Compound 13b was prepared from 12b following the same
procedure for 13a with some modifications. Compound
12b (0.69 g, 2.9 mmol), NMO (2.28 g, 18.85 mmol),
K2OsO4Æ2H2O (0.017 g, 2.5%), BuOH (5 mL), water
(5 mL) and acetone (5 mL). After extraction with CH2Cl2,
the organics were placed on a silica gel pad and eluted first
with CH2Cl2 to eliminate the impurities and then with ethyl
4.11. tert-Butyl (5R)-7-methyl-1-azaspiro[4.4]non-6-ene-1-
carboxylate 12b
To a solution of trimethylsilyldiazomethane (2 M in diethyl
ether, 2 mL) in dry THF (20 mL) at ꢀ78 ꢁC was added
BuLi (1.6 M in hexanes, 2.5 mL) and the mixture was stir-
red at this temperature for 1 h. A solution of ketone 11b
(0.80 g, 3.33 mmol) in THF (20 mL) was added over
30 min using a syringe pump. After the addition the reac-
tion mixture was stirred at ꢀ78 ꢁC for a further 1 h and
then it was allowed to reach 0ꢁ over another 1 h. The reac-
tion mixture was quenched with water at 0ꢁ and extracted
with ether (5 · 50 mL). The combined organic extracts
were dried and concentrated to yield a yellow liquid, which
was purified by chromatography (hexane–hexane/EtOAc
acetate to provide the desired compound 13b (0.76 g, 96%)
23
as
a
white
solid.
Mp:
130–131 ꢁC;
½aꢁD ¼
þ40:5 ðc 1:05; CHCl3Þ, IR (NaCl, neat): 3421, 2972,
2874, 1688, 1665 cmꢀ1 1H NMR (CDCl3, 300 MHz) d
;
1.32 (s, 3H, CH3-7), 1.45 and 1.48 (2s, 9H, CH3), 1.56–
2.70 (m, 8H), 3.34 (br s, 2H, CH2-2), 4.32 and 4.58 (2br
s, 1H, H-6); 13C NMR (CDCl3, 75.5 MHz) d 22.7 and
22.9 (C-3), 26.9 (CH3-7), 28.6 (CH3), 32.4 and 34.1
(CH2), 35.1 and 36.9 (CH2), 35.4 (CH2), 47.9 and 48.0
(CH2), 70.9 and 71.1 (C-5), 77.0 (C-7), 77.9 and 79.5
(C-6), 78.7 and 79.9 (C), 153.6 and 154.0 (CO). Anal. Calcd
for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C,
61.65; H, 9.37; N, 5.03.
90:10). Compound 12b was obtained as a colourless oil
23
(0.471 g, 63%). ½aꢁD ¼ ꢀ104:8 ðc 1; CHCl3Þ; IR (NaCl,
neat): 2970, 2931, 1687 cmꢀ1
;
1H NMR (CDCl3,
4.14. tert-Butyl (2R,4S)-2-formyl-4-[(N-methoxycarbonyl)-
N-methylamino]-2-(3-oxobutyl)pyrrolidine-1-carboxylate
14a
300 MHz) d 1.40 (s, 9H, (CH3)), 1.71 (s, 3H, CH3-7),
1.67–1.89 (m, 5H), 2.09–2.52 (m, 3H), 3.34 and 3.48 (2br
s, 2H, CH2-2), 5.10 and 5.20 (2br s, 1H, H-6); 13C NMR
(CDCl3, 75.5 MHz) d 16.4 (CH3-7), 22.4 (CH2), 28.4
(CH3), 35.3 (CH2), 36.8 (CH2), 41.0 (CH2), 47.4 (CH2),
74.5 (C-5), 78.2 (C), 129.6 and 130.2 (C-6), 138.9 (C-7),
154.5 (CO). Anal. Calcd for C14H23NO2Æ1/5H2O: C,
69.79; H, 9.79; N, 5.81. Found: C, 69.79; H, 9.84; N,
5.81. HRMS calcd for C14H23NO2: 237.1729; found:
237.1614.
To a deoxygenated solution of 13a (3.3 g, 9.2 mmol) in
THF (40 mL) and pH 7 buffer (20 mL) was added NaIO4
(9.21 g, 43.1 mmol) and the mixture stirred at rt for 4 h.
Water was then added till all the solid was dissolved and
the mixture extracted with CH2Cl2 (5 · 100 mL). The com-
bined organic phase was dried and concentrated to yield
23
ketoaldehyde 14a (2.49 g, 76%). ½aꢁD ¼ þ12:5 ðc 1;
CHCl3Þ; IR (NaCl, neat): 2974, 1695 cmꢀ1
;
1H NMR
4.12. tert-Butyl (3S,5R,6R,7S)-6,7-dihydroxy-4-[(N-meth-
oxycarbonyl)-N-methylamino]-7-methyl-1-azaspiro[4.4]non-
ane-1-carboxylate 13a
(CDCl3, 300 MHz) d 1.43 and 1.45 (2s, 9H, CH3), 1.90–
2.70 (m, 6H), 2.16 and 2.17 (2s, 3H, CH3), 2.82 (m, 1H),
2.85 (s, 3H, CH3N), 3.29 (q, 1H, J = 10.5 Hz), 3.70 (s,
3H, CH3O), 3.82 and 3.94 (2t, 1H, J = 9.0 Hz), 4.52 (m,
1H, H-4), 9.56 and 9.62 (2s, 1H, CHO); 13C NMR (CDCl3,
75.5 MHz) d 26.8 (CH2), 28.2 (CH3), 28.4 (CH3N), 29.7
To a solution of NMO (10 g, 82.35 mmol) in tert-BuOH
(30 mL) and water (30 mL) were successively added at rt

1442
F. Diaba et al. / Tetrahedron: Asymmetry 17 (2006) 1437–1443
and 30.0 (CH3), 34.6 and 35.4 (CH2), 37.6 and 38.2 (CH2),
47.8 (C-5), 52.0 (br s, C-4), 52.8 (CH3O), 69.3 and 69.7 (C-
2), 80.9 and 81.6 (C), 153.1 and 154.0 (CO), 156.6 (CO),
199.1 and 199.7 (CHO), 207.0, 207.7 (CO).
(m, 2H), 2.65 and 2.85 (2dt, 1H, J = 13.5, 5.4 Hz), 3.34–
3.68 (m, 2H), 5.87 and 5.94 (2d, 1H, J = 10.2 Hz, H-7),
6.74 and 6.86 (2d, 1H, J = 10.2 Hz, H-6); 13C NMR
(CDCl3, 75.5 MHz) d 22.3 and 23.0 (C-3), 28.3 (CH3),
30.1 and 31.4 (CH2), 34.7 and 35.3 (CH2), 35.6 and 35.7
(CH2), 47.2 (C-2), 61.6 and 61.8 (C-5), 79.7 and 80.4 (C),
126.4 and 126.9 (C-7), 153.4 (CO), 157.3 and 157.4 (C-6),
197.9 and 198.2 (CO). Anal. Calcd for C14H21NO3Æ
1/5H2O: C, 65.96; H, 8.46; N, 5.49. Found: C, 65.99; H,
8.50; N, 5.37. HRMS calcd for C14H21NO3: 251.1521;
found: 251.1423.
4.15. tert-Butyl (2S)-2-formyl-2-(3-oxobutyl)pyrrolidine-1-
carboxylate 14b
Operating as above, from diol 13b (0.7 g, 2.58 mmol) and
NaIO4 (1.65 g, 7.74 mmol) in THF (9 mL) and pH 7 buffer
(4.5 mL), keto aldehyde 14b (0.7 g, 90%) was isolated.
23
½aꢁD ¼ þ11:9 ðc 1:1; CHCl3Þ; IR (NaCl, neat): 2976,
1
1692 cmꢀ1; H NMR (CDCl3, 300 MHz) d 1.43 and 1.45
(2s, 9H, CH3), 1.57–2.31 (m, 6H), 2.13 and 2.17 (2s, 3H,
CH3), 2.39–2.74 (m, 2H), 3.37–3.77 (m, 2H, CH2-5), 9.35
and 9.38 (2s, 1H, CHO); 13C NMR (CDCl3, 75.5 MHz) d
22.7 and 23.5 (C-4), 26.6 and 26.6 (CH2), 28.2 and 28.3
(CH3), 29.8 and 29.9 (CH3), 33.2 and 33.7 (CH2), 38.5
and 38.8 (CH2), 47.7 and 48.1 (C-5), 70.2 and 70.6 (C-2),
80.3 and 81.4 (C), 153.3 and 154.4 (CO), 198.6 and 198.7
(CHO), 207.6, 208.5 (CO). Anal. Calcd for C14H23NO4:
C, 62.43; H, 8.61; N, 5.20. Found: C, 62.52; H, 8.74; N,
5.13.
Acknowledgements
This work was supported by the MEC (Spain) FEDER
(Project CTQ2004-04701). Thanks are also due to the
DURSI, Catalonia, for Grant 2005SGR-00442.
References
1. For a review on the synthesis of 1-azaspiro[4.5]decanes, see:
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4.16. tert-Butyl (3S,5R)-4-[(N-methoxycarbonyl)-N-meth-
ylamino]-8-oxo-1-azaspiro[4.5]dec-6-ene-1-carboxylate 1
To a solution of 14a (0.66 g, 1.86 mmol) in ethanol (50 mL)
was added KOH (0.61 g, 9.3 mmol) at 0 ꢁC and the mixture
stirred at rt for 2 h. The reaction was then quenched with a
saturated aqueous NH4Cl. Ethanol was then removed
under reduced pressure and the mixture extracted with ether
(3 · 50 mL). The combined organic extracts were dried,
and the solvent was removed. To a stirred solution of the
above azaspiro aldol in CH2Cl2 (7 mL) were added MsCl
(0.97 mL, 12.27 mmol) and Et3N (2.1 mL, 15.1 mmol).
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was extracted with CH2Cl2. The organics were dried,
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concentrated and purified by chromatography (CH2Cl2–
23
CH2Cl2/MeOH 99:1) providing 1 (0.45 g, 70%). ½aꢁD
¼
´
´
7. (a) Bonjoch, J.; Diaba, F.; Puigbo, G.; Sole; Segarra, V.;
´
ꢀ18:3 ðc 1:05; CHCl3Þ; IR (NaCl, neat): 2974, 1686
Santamarıa, L.; Beleta, J.; Ryder, H.; Palacios, J.-M. Bioorg.
cmꢀ1; H NMR (CDCl3, 300 MHz) d 1.43 (s, 9H, CH3),
1
´
Med. Chem. 1999, 7, 2891–2897; (b) Puigbo, G.; Diaba, F.;
Bonjoch, J. Tetrahedron 2003, 59, 2657–2665; (c) Bonjoch, J.;
1.92 (br s, 1H), 2.24–2.65 (m, 4H), 2.86 (s, 3H, CH3N),
3.34 (br s, 1H), 3.73 (s, 3H, CH3O), 3.85 (br s, 1H), 4.72
(br s, 1H, H-3), 5.88 (br d, 1H, H-7), 6.92 (br s, 1H,
H-6); 13C NMR (CDCl3, 75.5 MHz) d 28.3 (CH3), 29.2
(CH3N), 34.0 (CH2), 35.5 (CH2), 40.8 and 41.6 (CH2),
47.4 (C-2), 51.8 (C-3), 52.8 (CH3O), 61.0 (C-5), 80.4 and
81.0 (C), 126.6 and 127.4 (C-7), 153.4 (CO), 156.7 (C-6),
197.4 (CO). Anal. Calcd for C17H26N2O5Æ4/5CH2Cl2: C,
56.12; H, 7.25; N, 7.52. Found: C, 56.19; H, 7.34; N, 7.48.
´
´
´
Diaba, F.; Puigbo, G.; Peidro, E.; Sole, D. Tetrahedron Lett.
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4.17. tert-Butyl (5S)-8-oxo-1-azaspiro[4.5]dec-6-ene-1-carb-
oxylate 2
Operating as above, from 14b (0.5 g), gave enone 2 (0.4 g,
79%). 2 was isolated as a colourless viscous liquid, which
23
crystallized on standing: mp: 101–103 ꢁC; ½aꢁD
¼
ꢀ111:5 ðc 0:95; CHCl3Þ; IR (NaCl, neat): 2972, 2878,
1685 cmꢀ1; H NMR (CDCl3, 300 MHz) d 1.41 and 1.45
1
(2s, 9H, CH3), 1.75–2.02 (m, 4H), 2.22 (m, 1H), 2.36–2.58

F. Diaba et al. / Tetrahedron: Asymmetry 17 (2006) 1437–1443
1443
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