A β,β′-ketoaminoester as a valuable tool for the asymmetric construction of substituted homopipecolic esters: Application to a formal synthesis of (+)-Calvine

Article abstract of DOI:10.1016/j.tetasy.2004.04.008

A highly diastereoselective 1,4-addition involving Davies' lithium amide is employed as the key reaction to prepare, in five steps from ethyl acetoacetate, an enantiomerically pure keto protected β,β^′- ketoaminoester. This latter was reacted with aldehydes in an intramolecular Mannich process and furnished a direct and stereoselective access to substituted homopipecolates. The validity of this approach was achieved through a new formal asymmetric synthesis of alkaloid (+)-Calvine.

Full text of DOI:10.1016/j.tetasy.2004.04.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1561–1567
A b,b0-ketoaminoester as a valuable tool for the asymmetric
construction of substituted homopipecolic esters: application to a
formal synthesis of (+)-Calvine
Sophie Rougnon-Glasson, Christophe Tratrat, Jean-Louis Canet, Pierre Chalard
and Yves Troin*
Laboratoire de Chimie des Hꢀetꢀerocycles et des Glucides, EA 987, Ecole Nationale Supꢀerieure de Chimie de Clermont-Ferrand,
Universitꢀe Blaise Pascal, BP 187, 63174 Aubiꢁere cedex, France
Received 27 February 2004; accepted 5 April 2004
Abstract—A highly diastereoselective 1,4-addition involving Davies’ lithium amide is employed as the key reaction to prepare, in five
steps from ethyl acetoacetate, an enantiomerically pure keto protected b,b0-ketoaminoester. This latter was reacted with aldehydes in
an intramolecular Mannich process and furnished a direct and stereoselective access to substituted homopipecolates. The validity of
this approach was achieved through a new formal asymmetric synthesis of alkaloid (þ)-Calvine.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
on a preparative scale, and gives variable diastereo-
selectivities depending on the nature of the a-amino sub-
stituent. As illustrated in Scheme 1, an alkyl group in 1a
furnishes the cis-2,6 adducts almost exclusively,2 while
the use of a-aminoacid derivative 1b is accompanied by
an obvious loss of selectivity.5 Such results prompted us
to focus our attention on chiral b-aminoester 2, which
according to our synthetic scheme, should permit highly
stereoselective access to cis-2,6-disubstituted homo-
pipecolic esters2 3 (Scheme 2).
In previous work1;2 we have described an efficient and
stereoselective pathway to polysubstituted piperidine
systems. Our approach, summarized in Scheme 1, rests
on the use of an aldehyde involved in a Mannich-type
reaction with an a-chiral ketoprotected 1,3-aminoketone
and gives a selective access to the corresponding cis-2,6-
disubstituted piperidines. Although having proven its
efficiency through the concise total asymmetric synthesis
of 2,6-disubstituted3 and 2,4,6-trisubstituted4 piperidine
alkaloids, this strategy has found some limits in terms of
generality.
Homopipecolic acid derivatives may be considered as
attractive target compounds. Effectively, these ring
constrained b-aminoacids have been incorporated in
peptides of pharmaceutical interest6 in order to increase
their bioactivity. Furthermore, they were described as
valuable synthons for the stereoselective synthesis of
alkaloids7 as well as piperidine intermediates of bicyclic
b-lactams8 (carbacephams) of biological interest. Pos-
sessing different convertible functional groups allowing
Indeed, it implies the systematic enantioselective prep-
aration of amines 1, which remains sometimes difficult
H
R
N
R1
R1
O
O
H
+
RCHO
O
O
H2N
H
R
N
1a R1 = Me
1b R1 = CO2Me
de > 95%
CO2Me
de : 30-50%
NH2
O
O
H
RCHO
+
CO2Me
O
O
Scheme 1. Synthesis of piperidines.
2
3
* Corresponding author. Tel.: +33-473407139; fax: +33-473407008;
e-mail: troin@chimtp.univ-bpclermont.fr
Scheme 2. Synthesis of cis-2,6-disubstituted homopipecolic esters 3.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.008

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S. Rougnon-Glasson et al. / Tetrahedron: Asymmetry 15 (2004) 1561–1567
a wide range of selective transformations, we thought
that compounds 3 exhibit a certain potential particularly
in the field of the asymmetric synthesis of piperidine-
containing structures. Thus, the preparation of homo-
chiral b-aminoester 2 was studied.
ref. 16
O
O
O
O
CHO
CO2Et
10
11
Ph
O
N
Ph
CO2Et
i
ii
NH2
O
O
CO2Me
2. Results and discussion
O
Among the various synthetic strategies9 permitting
stereoselective access to b-aminoacids and esters, two
were explored. The first one used as the key step the
diastereoselective reduction of b-aminoester 4 bearing a
chiral amino group, which was prepared as follows
(Scheme 3). In situ treatment of acylchloride 5, conve-
niently obtained in three steps from ethyl acetoacetate as
described,10 using triethylamine and methyl triphenyl-
phosphoranylidene acetate at 20 ꢁC in dichloromethane
gave the reactive ketene intermediate 6, then the desired
Wittig adduct 7 (65% overall yield from acid 8). This
conjugated allenic ester 7 was then submitted to nucleo-
philic attack by (þ)-(R)-a-methylbenzylamine in toluene
under reflux. These conditions provided an inseparable
3:1 mixture of chiral enaminoesters 4a and 4b in 88%
yield. As expected for such an addition of primary
amine on allenic ester,11;12 the Z stereoisomer 4a, stabi-
lized by an intramolecular H-bond, formed predomi-
nantly. Next was the reduction of the olefinic bond.
Classical catalytic hydrogenation using 10% Pd/C13 gave
no reaction while treatment of the 3:1 4a and b mixture
with sodium borohydride at room temperature in di-
chloromethane in the presence of zinc iodide14 furnished
the desired aminoesters 9a and 9b (3:1), albeit in mod-
erate yield (42%). The optimal results were then
obtained using in situ prepared sodium acetoxy-
borohydride, at 0 ꢁC in AcOH/MeCN.15 By this way,
reduction of the 3:1 4a and b b-enaminoesters mixture
yielded (81%) reduced analogues 9a and 9b (3:1, NMR
of the crude), which were nicely separated by column
chromatography (DRf ꢀ 0:1 in AcOEt). At this stage,
the relative configurations of 9a and b (Scheme 4) are
given arbitrarily and will be confirmed later (vide infra).
Finally, separated hydrogenolysis of 9a and 9b using
methanolic ammonium formate in the presence of 10%
(-)-2
(+)-12
de > 95%
Scheme 4. Reagents and conditions: (i) nBuLi, (R)-N-benzylphenyl-
ethylamine, THF, ꢂ78 ꢁC, 2 h, 91%; (ii) HCO2NH4, Pd(OH)2/C,
MeOH, reflux, 5 h, 94%.
Pd/C led to target b-aminoesters (þ)-2 f½aꢁ ¼ 12:8g
D
and (ꢂ)-2 f½aꢁ ¼ ꢂ13:0g in nearly quantitative yields.
D
However, this synthesis was not satisfactory enough in
regard to the restrained (50%) diastereoisomeric excess
observed for 9a and b. Accordingly, a second pathway
to homochiral 2 was studied, involving as the key step
the asymmetric Davies’ lithium amide 1,4-addition on
the required unsaturated ester 10 (Scheme 4). Thus, ester
10 was easily prepared, as reported,16 by Wittig
homologation of aldehyde 11, which is readily available
from ethyl acetoacetate after keto-protection then DI-
BAL-H reduction.17 Treatment of 10 with lithium (R)-
(ꢂ)-N-benzylphenylethylamide, at low temperature in
THF, afforded b-aminoester (þ)-12 as almost a single
isomer (91%, de >95%, from NMR datas).
The (R)-configuration of the created stereogenic center
was given in respect with stereochemical behaviour of
Davies’ process.18 Finally, hydrogenolysis of the benzyl
groups, realized with ammonium formate in the pres-
ence of Pearlman’s catalyst in refluxing methanol, gave
completely transesterified b-aminoester (R)-(ꢂ)-2 in 95%
yield. The specific rotation of (ꢂ)-2 f½aꢁ ¼ ꢂ13:0g was
D
in perfect agreement with those obtained previously
(vide supra). A further part of our program consisted of
the valuation of compound 2 for the asymmetric prep-
aration of cis-2,6-disubstituted-4-piperidones using our
O
i
O
O
ref. 10
ref. 10
O
O
CO2Me
CO2Me
O
O
O
O
CO2Et
CO2H
COCl
•
•
O
( )-7
8
5
6
NH2
HN
Ph
CO2Me
iv
iv
O
O
O
O
O
O
CO2Me
MeO2C
3
9a
(+)-2
Ph
Ph
ii
iii
N
H
N
H
:
+
+
O
O
O
1
NH2
O
HN
Ph
4a
4b
O
O
CO2Me
CO2Me
(-)-2
9b
Scheme 3. Reagents and conditions: (i) NEt3, Ph3PCHCO2Me, CH2Cl2, rt, 2 h, 65% from 8; (ii) (þ)-(R)-a-methylbenzylamine, toluene, reflux, 24 h,
88%; (iii) NaHB(OAc)3, AcOH/MeCN, 0 ꢁC, 4 h, 81%; (iv) HCO2NH4, Pd/C, MeOH, reflux, 5 h, 94%.

S. Rougnon-Glasson et al. / Tetrahedron: Asymmetry 15 (2004) 1561–1567
1563
CO2Me
CO2Me
or
O
CO2Me
H
N
H
N
O
H
N
R
R
N
RCHO
O
O
O
O
(+)-17
(+)-18
from (-)-2
CO2Me
from (+)-2
CO2Me
H
N
i
ii
CO2Me
(+)-15
H
N
(+)-18
H
N
Ar
S
S
O
O
O
O
(+)-19
(+)-13a Ar = phenyl
( )-13b Ar = 4-fluorophenyl
14
Scheme 6. Reagents and conditions: (i) ethanedithiol, BF3ÆEt2O,
CH2Cl2, rt, 85%; (ii) Raney Ni, MeOH, D, 88%.
CO2Me
CO2Me
H
N
H
N
shown in Scheme 6, we have considered that (þ)-18, of
already known absolute configurations, should be easily
prepared by simple deoxygenation then olefinic reduc-
tion of piperidine (þ)-15. Accordingly, (þ)-15 treated
with ethanedithiol in the presence of BF3ÆEt2O in excess
at room temperature in dichloromethane furnished the
parent dithiolane derivative (þ)-19, which when sub-
mitted to W2 Raney nickel22 in methanol under reflux,
gave the expected piperidine (þ)-18 [72% yield from (þ)-
S
S
O
(+)-15
O
(-)-16
Scheme 5. Diastereoselective synthesis of methyl homopipecolates
derivatives.
15]. The specific rotation of (þ)-18 f½aꢁ ¼ 23:3, (c 0.53
D
in CHCl3)} was in agreement with those reported {lit.20
strategy2 (Scheme 2). Thus, reaction of benzaldehyde, 4-
fluorobenzaldehyde, crotonaldehyde and 2-hexenal with
amine (þ)-2 or (ꢂ)-2 in refluxing dichloromethane in the
presence of magnesium sulfate as drying agent led (TLC
monitoring), in approximatively 2 h, to the corre-
sponding imines. These unstable intermediates were di-
rectly treated for 3 h with 1.3 equiv of p-toluene sulfonic
acid (previously dried under Dean–Stark conditions) at
70 ꢁC in toluene. Under these conditions, functionalized
piperidones (þ)-13a (65%), ( )-13b [80% from ( )-2], 14
and (þ)-15 (62%) were obtained (Scheme 5). Crude
compound 14, accompanied with a non negligible
amount of the parent keto deprotected product was di-
rectly transformed into (ꢂ)-16 under classical dithioke-
talization conditions (59% yield from (ꢂ)-2). In all cases,
as observed with amine bearing an a-methyl group and
contrarily with the use of an a-aminoester (Scheme 1),
the cis-2,6-diastereoisomer was exclusively formed.
Relative configurations of compounds 13, 15 and 16
were unambigously established from 1H NMR data,
particularly with the signals corresponding to axial H-3
and axial H-5, showing typical coupling constants for a
2,6-diequatorial disubstitution in a chair conformation.
The last points to be verified were the enantiomeric ex-
cesses of these new methyl homopipecolates together
with the confirmation of the presumed absolute config-
urations. This was achieved through a formal synthesis
of alkaloid (þ)-Calvine 17.
½aꢁ ¼ 23:0, (c 0.52 in CHCl3)}, as spectroscopic data.
D
This confirmed that we were able to prepare homochiral
(þ)-(2S,6S)-18 from the (þ)-2 synthon. Thus, we can
assume that no racemization, due to retro-Michael nor
retro-Mannich process occurred during the sequence,
and consequently that our synthetic b-aminoesters (þ)-2
and (ꢂ)-2 were enantiopure compounds of (S)- and (R)-
configuration, respectively.
3. Conclusion
We have reported herein a short and efficient23 asym-
metric preparation of the ketoprotected b,b0-ketoami-
noester 2 in five steps from ethyl acetoacetate. Through,
notably, a new formal synthesis of alkaloid (þ)-Calvine
17, we could demonstrate that this synthon constitutes a
valuable tool for the stereoselective synthesis of 2,4,6-
functionalized homopipecolic esters, compounds of high
synthetic potential. Exploitation of this strategy, in the
field of enantioselective synthesis of piperidine-contain-
ing alkaloids as well as the asymmetric preparation of
polysubstituted bicyclic b-lactams (carbacephams) of
biological interest is currently in progress.
4. Experimental
4.1. General
Piperidinic lactone (þ)-Calvine 17 has recently been
isolated19 from the ladybird beetles of Genus Calvia
(Coccinellidae) and fully characterized20 by Braeck-
mann et al. who were able propose the first two unique
enantioselective syntheses of 17.20 Their efficient strat-
egy, based on the CN (R,S) methodology,21 used am-
inoester (þ)-18 as the key intermediate (Scheme 6). As
Unless otherwise specified, reagents were obtained from
commercial suppliers. Solvents were dried and freshly
distilled following the usual procedures. Organic prod-
uct solutions were dried over sodium sulfate prior to
evaporation of the solvents under reduced pressure on a

1564
S. Rougnon-Glasson et al. / Tetrahedron: Asymmetry 15 (2004) 1561–1567
rotatory evaporator. Thin layer chomatography was
performed on TLC precoated aluminium backed silica
plates and spots visualized using UV light (254 nm) be-
fore using ethanolic phosphomolybdic acid solution
(heating). Column chromatography was carried out on
silica gel (70–230 mesh). 1H and 13C NMR spectra were
measured at 400.13 and 100.61 MHz, respectively.
Chemicals shifts are reported in ppm relative to SiMe4.
Signals are quoted as s (singlet), d (doublet), t (triplet), q
(quartet), p (pentet), m (multiplet), br (broad) and
coupling constant (J) values given in Hz. Infrared
spectra were recorded on a FTIR spectrophotometer.
Electron Impact Hight Resolution Mass Spectra (EI-
4.1.3. Methyl 5,5-ethylenedioxy-3-(10-methylbenzyl-
amino)-hexanoate 9. Sodium borohydride (0.555 g,
14.7 mmol) was placed by small portions in 8.5 mL of
acetic acid at room temperature under stirring. At the
end of gaseous evolution, acetonitrile (8.5 mL) was
added and the resulting solution cooled at 0 ꢁC before
addition of the 3:1 mixture of enaminoesters 4a and b
(1.5 g, 4.92 mmol) previously obtained. After 4 h of
stirring at 0 ꢁC, the solvents were evaporated and residue
diluted with saturated aqueous solution of Na2CO3
(10 mL), dried, filtrated then concentrated. Column
chromatography (EtOAc/cyclohexane, 1:1) gave 916 mg
(61%) and 305 mg (20%) of respectively b-aminoesters
9a and 9b as colourless oil.
ꢀ
HRMS) were obtained from the Centre Regional de
Mesures Physiques de l’Ouest, Universitede Rennes I,
ꢀ
20
D
France. Optical rotations were measured at 589 nm and
specific rotations are given in units of 10ꢂ1deg cm2 gꢂ1
(þ)-(10R,3S)-9a: ½aꢁ ¼ þ14:1 (c 1.06, CHCl3); 1H
.
NMR (400 MHz, CDCl3): d 7.35–7.19 (5H, m), 3.94–
3.80 (5H, m), 3.60 (3H, s), 3.01 (1H, m), 2.50 (1H, dd,
J ¼ 15:5 and 5.5 Hz), 2.27 (1H, br s), 1.96 (1H, dd,
J ¼ 14:5 and 5.5 Hz), 1.77 (1H, dd, J ¼ 14:5 and
7.0 Hz), 1.33 (3H, d, J ¼ 6:5 Hz), 1.27 (3H, s); 13C NMR
(100 MHz, CDCl3): d 173.0, 146.1, 128.3, 126.8, 109.6,
64.4, 64.3, 55.7, 51.3, 49.4, 42.5, 40.8, 24.7, 24.2;
IR (neat) 3339, 1738, 1256, 1054, 892, 764,
703 cmꢂ1; HRMS calcd for C17H25NO4, 307.1783, found
307.1784.
4.1.1. ( )-Methyl 5,5-ethylenedioxy-hexa-2,3-dienoate 7.
To a cold (0 ꢁC) stirred solution of crude ketoprotected
ketoacid
8 (1.5 g, 10.3 mmol) in dichloromethane
(20 mL) was added, under argon, 6.2 mL of a 2 M ox-
alylchloride solution in dichloromethane (12.4 mmol).
The resulting mixture was stirred at room temperature
for 3 h then transferred via cannula to a solution of
triethylamine (2.86 mL, 20.6 mmol) and methyltriphe-
nylphosphoranylidene acetate (3.44 g, 10.3 mmol) in di-
chloromethane (100 mL). After 2 h of stirring, the
solvent was evaporated and the residue directly purified
by column chromatography (ethyl acetate/cyclohexane,
1:5) to give 1.23 g (65%) of allenic ester ( )-7 as a col-
20
D
(þ)-(10R,3R)-9b: ½aꢁ ¼ þ44:7 (c 1.06, CHCl3); 1H
NMR (400 MHz, CDCl3): d 7.37–7.20 (5H, m), 3.95-
3.75 (5H, m), 3.66 (3H, s), 2.97 (1H, m), 2.56–2.42 (2H,
m), 2.15 (1H, br s), 1.86–1.75 (2H, m), 1.36 (3H, d,
J ¼ 6:5 Hz), 1.11 (3H, s); 13C NMR (100 MHz, CDCl3):
d 171.2, 145.9, 128.5, 126.4, 109.5, 64.4, 64.3, 55.9, 51.1,
49.4, 42.7, 40.5, 24.5, 24.1; IR (neat) 3339, 1738, 1256,
1054, 892, 764, 703 cmꢂ1; HRMS calcd for C17H25NO4,
307.1783, found 307.1784.
1
ourless oil. H NMR (400 MHz, CDCl3): d 5.76 (1H, d,
J ¼ 6:0 Hz), 5.62 (1H, d, J ¼ 6:0 Hz), 4.09-3.95 (4H, m),
3.75 (3H, s), 1.59 (3H, s); 13C NMR (100 MHz, CDCl3):
d 210.9, 165.7, 106.3, 99.0, 90.6, 65.0, 64.5, 52.1, 25.3; IR
(neat) 1965, 1720, 1376, 1268, 1034, 870, 803 cmꢂ1
.
4.1.2. Methyl 5,5-ethylenedioxy-3-(10-methylbenzyl-
amino)-hex-2-enoate 4. To a stirred solution of allenic
compound 7 (3.0 g, 16 mmol) in toluene (100 mL) under
argon was added a solution of (þ)-(R)-a-methylbenzyl-
amine (1.88 mL, 14.7 mmol) in toluene (30 mL). The
resulting mixture was refluxed for 24 h. After cooling at
room temperature, the solvent was eliminated in vacuo.
Column chromatography (diethyl ether/cyclohexane,
1:3) afforded 4.39 g of an 3:1 unseparable mixture of
enaminoesters 4a and 4b as a yellow oil (88%). 1H NMR
(400 MHz, CDCl3): d 9.05 (0.75H, br d, J ¼ 7:0 Hz),
7.38–7.20 (5H, m), 5.62 (0.25H, br s), 4.94 (0.75H, p,
J ¼ 7:0 Hz), 4.64 (0.75H, s), 4.55 (0.25H, s), 4.40 (0.25H,
p, J ¼ 7:0 Hz), 4.05–3.92 (4H, m), 3.68 (3 · 0.75H s),
3.55 (3 · 0.25H, s), 3.45 (0.25H, d, J ¼ 14:0 Hz), 3.34
(0.25H, d, J ¼ 14:0 Hz), 2.54 (0.75H, d, J ¼ 14:0 Hz),
2.30 (0.75H, d, J ¼ 14:0 Hz), 1.50 (3 · 0.75H, d,
J ¼ 7:0 Hz), 1.47 (3 · 0.25H, d, J ¼ 7:0 Hz), 1.35 (3H, s);
13C NMR (100 MHz, CDCl3): d 171.0, 169.1, 160.1,
156.9, 145.3, 145.2, 128.8, 127.3, 127.0, 125.7, 125.6,
109.8, 109.0, 86.0, 85.3, 65.1, 64.8, 64.6, 64.5, 52.8, 52.6,
50.1, 42.0, 38.2, 25.3, 24.9, 23.9, 23.2; IR (neat) 3392,
4.1.4. (+)-(3S)-Methyl 3-amino-5,5-ethylenedioxyhex-
anoate 2. To a stirred suspension of 10% Pd/C
(261 mg) in anhydrous methanol (20 mL) was added a
solution of aminoester (þ)-9a (1.00 g, 3.26 mmol) in
methanol (30 mL) then ammonium formate (1.02 g,
16.30 mmol). The resulting mixture was heated at reflux
for 5 h. After cooling at room temperature, the catalyst
was removed by filtration on celiteꢂ. The residue ob-
tained after evaporation of the solvent was diluted with
30 mL of dichloromethane. This organic phase was
washed with a saturated aqueous solution of NaHCO3
(10 mL). The aqueous phase was extracted with dichlo-
romethane (3 · 30 mL) and the combined organic ex-
tracts dried, filtrated and then concentrated to afford
622 mg (94%) of pure enaminoester (þ)-2 as pale yellow
20
D
1
oil. ½aꢁ ¼ þ12:3 (c 1.04, CHCl3); H NMR (400 MHz,
CDCl3): d 3.98–3.90 (4H, m), 3.67 (3H, s), 3.52–3.48
(1H, m), 2.49 (1H, dd, J ¼ 16:0 and 5.0 Hz), 2.34 (1H,
dd, J ¼ 16:0 and 8.0 Hz), 1.83 (1H, br s), 1.77–1.73 (2H,
m), 1.35 (1H, s); 13C NMR (100 MHz, CDCl3): d 172.9,
109.7, 64.6, 64.3, 51.5, 45.4, 4 4.6, 42.9, 24.6; IR (neat)
3377, 1735, 1438, 1379, 1255, 1042, 949, 816 cmꢂ1
;
3275, 1691, 1654, 1608, 1376, 1262, 1048, 786, 701 cmꢂ1
HRMS calcd for C17H23NO4, 305.1627, found 305.1615.
;
HRMS calcd for C7H12NO3 (MꢂC2H5O), 158.0817,
found 158.0797.

S. Rougnon-Glasson et al. / Tetrahedron: Asymmetry 15 (2004) 1561–1567
1565
4.1.5. (+)-(10R,3S)-Ethyl-3-(N-benzyl-N-10-ethylbenzyl-
amino)-5,5-ethylenedioxyhexanoate 12. To a cold (0 ꢁC)
solution of (þ)-(R)-N-benzyl-N-a-methyl benzylamine
(3.37 g, 16.0 mmol) in dry THF (50 mL) was added
slowly under argon 6.4 mL of a 1.6 M n-butyllithium
solution in hexanes (15 mmol). The resultant pink
solution of lithium amide was stirred for 15 min and
then cooled at ꢂ78 ꢁC before dropwise addition of a
solution of conjugated ester 10 (2.00 g, 10 mmol) in
20 mL of dry THF. After 3 h stirring at ꢂ78 ꢁC, a sat-
urated aqueous solution of NH4Cl (30 mL) was added
dropwise and the resulting solution allowed to warm to
room temperature. Aminoester 12 was then extracted
with diethylether (4·30 mL). The combined organic ex-
tracts were dried, filtered and evaporated. Column
chromatography using ethyl acetate:cyclohexane 1:7 as
eluent furnished 3.73 g (91%) of (þ)-12 as a colourless
(ꢂ)-2 (203 mg) afforded cyclic b-aminoester (þ)-13a as a
20
yellow oil (189 mg, 65%). ½aꢁ ¼ þ28:0 (c 0.85, CHCl3);
D
1H NMR (400 MHz, C6D6): d 7.47 (2H, d, J ¼ 8:0 Hz),
7.20 (3H, m), 4.22 (1H, dd, J ¼ 11:5 and 3.0 Hz), 3.64
(5H, m), 3.34 (3H, s), 2.37 (1H, dd, J ¼ 16:0 and
8.0 Hz), 2.32 (1H, dd, J ¼ 16:0 and 5.0 Hz), 2.04 (1H, dt,
J ¼ 12:0 and 3.0 Hz), 2.00 (1H, br s), 1.96 (1H, t,
J ¼ 12:5 Hz), 1.87 (1H, dt, J ¼ 12:5 and 2.5 Hz), 1.69
(1H, t, J ¼ 12:0 Hz); 13C NMR (100 MHz, C6D6): d
172.5, 143.8, 128.5, 127.3, 126.9, 107.8, 64.5, 64.3, 58.6,
51.6, 51.0, 43.0, 41.0, 40.8; IR (neat) 3323, 1732, 1313,
1263, 1178, 1058, 760, 700 cmꢂ1; HRMS calcd for
C16H21NO4 291.1471, found 291.1480.
4.2.2. ( )-(2S*,6R*)-1-Aza-2-(40-fluoro)phenyl-6-(meth-
oxycarbonyl) methyl-10,30-dioxaspiro[5,4]decane 13b. Fol-
lowing the cyclization procedure, 4-fluorobenzaldehyde
(137 mg) and amine ( )-2 (203 mg) afforded cyclic
b-aminoester ( )-13b as a colourless oil (247 mg, 80%).
1H NMR (400 MHz, CHCl3): d 7.34 (2H, m), 7.00 (2H,
tt, J ¼ 9:0 and 2 Hz), 3.96 (5H, m), 3.67 (3H, s), 3.36
(1H, m), 2.45 (2H, d, J ¼ 6:5 Hz), 2.23 (1H, br. s),
1.82 (1H, dt, J ¼ 12:0 and 2.5 Hz), 1.72 (1H, dt, J ¼ 12:0
and 2.5 Hz), 1.68 (1H, t, J ¼ 12:0 Hz), 1.51 (1H, t,
J ¼ 12:0 Hz); 13C NMR (100 MHz, CHCl3): d 172.5,
162.0 (JC–F ¼ 245 Hz), 139.6, 128.3, 115.2 (JC–F ¼ 20 Hz),
107.7, 64.5, 64.3, 57.8, 50.9, 50.2, 43.2, 40.9, 40.6; IR
(neat) 3321, 1739, 1605, 1509, 1315, 1224, 1061,
836 cmꢂ1; EI-MS (70 eV) 309 (Mþ, 4), 264 (32), 236 (20),
208 (42), 150 (100), 122 (40), 87 (56).
20
1
oil. ½aꢁ ¼ þ8:2 (c 0.55, CHCl3); H NMR (400 MHz,
D
CDCl3): d 7.40–7.00 (10H, m), 3.98-3.68 (7H, m), 3.64
(1H, d, J ¼ 14:5 Hz), 3.55 (1H, d, J ¼ 14:5 Hz), 3.42
(1H), m), 2.40 (1H, dd, J ¼ 14:0 and 5.0 Hz), 2.26 (1H,
dd, J ¼ 14:0 and 8.5 Hz),
2.04 (1H, dd,
J ¼ 14:5; 2:0 Hz), 1.61 (1H, dd, J ¼ 14:5 and 9.0 Hz),
1.29 (3H, d, J ¼ 7:0 Hz), 1.21 (3H, s), 1.02 (3H, t,
J ¼ 7:0 Hz); 13C NMR (100 MHz, CDCl3): d 172.5,
144.1, 141.4, 128.7, 128.3, 128.1, 127.8, 126.6, 109.8,
64.8, 64.5, 60.0, 57.5, 50.6, 50.1, 41.7, 39.8, 26.9, 25.0,
16.3, 14.1; IR (neat) 1732, 1373, 1046, 749, 700 cmꢂ1
EI-MS (70 eV) 411 (Mþ, 3), 396 (12), 324 (35), 310 (24),
206 (32), 105 (53), 87 (100).
;
4.1.6. ())-(3R)-Methyl-3-amino-5,5-ethylenedioxyhex-
anoate 2. Following the procedure described for syn-
4.2.3. ())-(2S,6S)-1-Aza-6-(methoxycarbonyl)methyl-2-
prop-100-enyl-10,30-dithiaspiro[5,4]decane 16. Following
the cyclization procedure, crotonaldehyde (150 mg) and
amine (ꢂ)-2 (406 mg) afforded crude cyclic b-aminoester
14 accompanied with the parent ketodeprotected com-
pound. This mixture was directly submitted to di-
thioketalization conditions as follows. To a stirred
solution of the mixture obtained in dichloromethane
(20 mL) was added dropwise at room temperature, eth-
ane dithiol (900 lL, 10 mmol) then BF3ÆOEt2 (1.32 mL,
10 mmol). After 24 h of stirring, 20 mL of dichlorome-
thane then 20 mL of 1 M aqueous NaOH were added
before extraction with dichloromethane (4 · 20 mL). The
combined organic phases were dried, filtered and evap-
orated. Purification by column chromatography
thesis of (þ)-2 from (þ)-9a, using 20% Pd(OH)2/C in
20
place of 10% Pd/C, hydrogenolysis of (þ)-12 (2.05 g)
afforded 954 mg (94%) of pure (ꢂ)-2. ½aꢁ ¼ ꢂ13:0 (c
D
1.50, CHCl3). Other data were identical with those given
for its enantiomer (vide supra).
4.2. Typical procedure for intramolecular Mannich-type
cyclization
To a stirred solution of aldehyde (1.1 mmol) in dichloro-
methane (10 mL) was added MgSO4 (ca 1 g) followed by
a solution of aminoester (þ) or (ꢂ)-2 (1 mmol) in
dichloromethane (5 mL). The resulting solution was
heated at reflux until disappearance (TLC monitoring)
of the amine (3-4 h) and then cooled to room tempera-
ture and transferred via a cannula to a solution of dry
p-TsOH (1.3 mmol) in toluene (30 mL). The resulting
mixture was heated at 70 ꢁC for 3-4 h. After being cooled
to room temperature, a saturated aqueous solution of
NaHCO3 (8 mL) was added and the ketoprotected pip-
eridone extracted with ethylacetate (4 · 20 mL). The
combined organic extracts were dried, filtered and
evaporated. The residue was purified by column chro-
matography.
(EtOAc/cyclohexane, 1:1) led to 339 mg (59%) of di-
20
thioderivative (ꢂ)-16 as yellow oil. ½aꢁ ¼ ꢂ17:2 (c 1.45,
CHCl3); 1H NMR (400 MHz, C6D6) dD5.55 (2H, m), 3.59
(1H, m), 3.49 (1H, m), 3.35 (3H, s), 2.88 (4H, s), 2.40–
2.10 (5H, m), 2.02 (1H, dd, J ¼ 12:5 and 11.0 Hz), 1.85
(1H, dd, J ¼ 12:5 and 11.5 Hz), 1.57 (3H, d, J ¼ 7:0 Hz);
13C NMR (100 MHz, C6D6): d 172.4, 133.1, 126.5, 66.1,
57.9, 52.0, 51.6, 48.2, 47.8, 40.5, 39.2, 37.8, 17.8; IR
(neat) 3328, 1733, 1672, 1436, 1200, 1174, 968 cmꢂ1
;
HRMS calcd for C13H21NO2S2 287.1014, found
287.1019.
4.2.1. (+)-(2S,6R)-1-Aza-6-(methoxycarbonyl)methyl-2-
phenyl-10,30-dioxaspiro[5,4]decane 13a. Following the
cyclization procedure, benzaldehyde (117 mg) and amine
4.2.4. (+)-(2R,6S)-1-Aza-6-(methoxycarbonyl)methyl-2-
pent-100-enyl-10,30-dioxaspiro[5,4]decane 15. Following
the cyclization procedure, hex-2-enal (162 mg) and

1566
S. Rougnon-Glasson et al. / Tetrahedron: Asymmetry 15 (2004) 1561–1567
ꢁ
Ministere de la Jeunesse, de l’Education Nationale
et de la Recherche for financial support.
amine (þ)-2 (300 mg) afforded b-aminoester (þ)-15 as a
20
yellow oil (236 mg, 62%). ½aꢁ ¼ þ13:6 (c 1.06, CHCl3);
D
1H NMR (400 MHz, CDCl3): d 5.66–5.57 (1H, m), 5.37
(1H, dd, J ¼ 15:5 and 7.0 Hz), 3.95 (4H, s), 3.68 (3H, s),
3.39–3.32 (1H, m), 3.28–3.20 (1H, m), 2.42 (2H, m), 2.07
(1H, br s), 2.00–1.65 (2H, m), 1.72–1.58 (2H, m), 1.43
(1H, t, J ¼ 12:0 Hz), 0.88 (3H, t, J ¼ 7:0 Hz); 13C NMR
(100 MHz, CDCl3): d 172.5, 132.2, 131.4, 107.6, 64.4,
64.2, 56.1, 51.6, 50.3, 41.3, 40.9, 40.7, 34.4, 22.3, 13.6; IR
(neat) 3328, 1736, 1437, 1317, 1277, 1198, 1173,
970 cmꢂ1; HRMS calcd for C15H25NO4, 283.1769 found
283.1784.
References and notes
1. Rougnon-Glasson, S.; Canet, J.-L.; Troin, Y. Tetrahedron
Lett. 2000, 41, 9797–9798.
2. Ciblat, S.; Besse, P.; Canet, J.-L.; Troin, Y.; Veschambre,
H.; Gelas, J. Tetrahedron: Asymmetry 1999, 10, 2225–
2235.
3. Ciblat, S.; Besse, P.; Papastergiou, V.; Veschambre, H.;
Canet, J.-L.; Troin, Y. Tetrahedron: Asymmetry 2000, 11,
2221–2229.
4.2.5. (+)-(2R,6R)-1-Aza-6-(methoxycarbonyl)methyl-2-
pent-100-enyl-10,30-dithiospiro[5,4]decane 19. To a stirred
solution of cyclic aminoester (þ)-15 (200 mg, 0.71 mmol)
in 10 mL of anhydrous dichloromethane was added
dropwise at room temperature 300 lL (3.53 mmol) of
ethanedithiol and 440 lL (3.53 mmol) of BF3ÆOEt2. The
resulting mixture was stirred for 24 h then diluted with
dichloromethane (10 mL) before addition of 1 M aque-
ous NaOH (10 mL) then extraction with dichlorome-
thane (3 · 15 mL). The combined organic extracts were
dried, filtered and evaporated. Purification by column
chromatography (ethylacetate/cyclohexane, 1:1) afford-
ed dithioketal compound (þ)-19 as pale yellow oil
4. Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem.
Soc., Perkin Trans. 1 2000, 353–357.
5. Carbonnel, S.; Troin, Y. Heterocycles 2002, 57, 1807–1830.
6. (a) Sielecki, T. M.; Wityak, J.; Liu, J.; Mousa, S. A.;
Thoolen, M.; Wexler, R. R.; Olson, R. E. Bioorg. Med.
Chem. Lett. 2000, 10, 449–452; (b) Muller, G.; Albers, M.;
Fisher, R.; Hessler, G.; Lehman, T. E.; Okigami, H.;
€
Tajimi, M.; Bacon, K.; Rolle, T. Bioorg. Med. Chem. Lett.
2001, 11, 3019–3021.
7. For examples of stereoselective preparation of homopipe-
colates and applications in alkaloids synthesis see: (a)
Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin,
R. M.; Smethurst, C. A. P.; Smith, A. D.; Rodriguez-
Solla, H. Tetrahedron 2003, 59, 3253–3265; (b) Back, T.
G.; Hamilton, M. D. Org. Lett. 2002, 4, 1779–1781; (c)
Sengupta, S.; Mondal, S. Tetrahedron 2002, 58, 7983–
7986; (d) O’Brien, P.; Porter, D. W.; Smith, N. Synlett
2000, 1336–1338, and references cited therein; (e) Herdeis,
C.; Schiffer, T. Tetrahedron 1999, 55, 1043–1056; (f)
25
D
1
(189 mg, 85%). ½aꢁ ¼ þ15:6 (c 1.09, CHCl3); H NMR
(400 MHz, CDCl3): d 5.61 (1H, m), 5.35 (1H, dd,
J ¼ 15:5 and 7.0 Hz), 3.66 (3H, s), 3.36–3.25 (5H, m),
3.19 (1H, m), 2.40 (2H, m), 2.07 (1H, br s), 2.05–1.90
(4H, m), 1.78 (1H, t, J ¼ 12:0 Hz), 1.73 (1H, t,
J ¼ 12:0 Hz), 1.41–1.29 (2H, m), 0.86 (3H, t,
J ¼ 7:5 Hz); 13C NMR (100 MHz, CDCl3): d 172.4,
131.9, 131.8, 66.1, 58.0, 52.1, 51.7, 48.3, 47.8, 40.5, 39.2,
37.9, 34.4, 22.2, 13.7; IR (neat) 3328, 1736, 1437, 1317,
ꢀ
Ledoux, S.; Celerier, J.-P.; Lhommet, G. Tetrahedron
Lett. 1999, 40, 9019–9020; (g) Banwell, M. G.; Bisset, B.
D.; Bui, C. T.; Pham, H. T. T.; Simpson, G. W. Aust. J.
Chem. 1998, 51, 9–18; (h) Enders, D.; Wiedmann, J.
Liebigs Ann./Recueil 1997, 699–706; (i) Munchhof, M. J.;
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Momose, T.; Toyooka, N.; Hirai, Y. Chem. Lett. 1990,
1319–1322.
1277,
C15H25NO2S2315.1315, found 315.1327.
1173,
970 cmꢂ1
;
HRMS
calcd
for
8. (a) Maison, W.; Kosten, M.; Charpy, A.; Kintscher-
€
4.2.6. (+)-(2S,6S)-2-(Methoxycarbonyl)methyl-6-pentyl-
piperidine 18. To a stirred solution of dithioketal (þ)-
19 (140 mg, 0.44 mmol) in absolute methanol (5 mL) was
added freshly prepared W2 Raney nickel (ca 1 g). The
resulting suspension was heated at reflux for 2 h then
cooled to room temperature. The suspension was then
filtered through celiteꢂ and the filtrate concentrated
under reduced pressure. The residue was dissolved in
1 M aqueous NaOH and the piperidine extracted with
dichloromethane (4 · 10 mL). The combined organic
extracts were washed with brine and dried. Evaporation
of the solvent followed by column chromatography
Langenhagen, J.; Schlemminger, I.; Lutzen, A.; Wester-
hoff, O.; Martens, J. Eur. J. Org. Chem. 1999, 2433–2441;
(b) Avenova, A.; Busto, J. H.; Cativiela, C.; Corzana, F.;
Peregrina, J. M.; Zurbano, M. M. J. Org. Chem. 2002, 67,
598–601, and references cited therein; (c) Folmer, J. J.;
Acero, C.; Thai, D. L.; Rapoport, H. J. Org. Chem. 1998,
63, 8170–8182; (d) Berrien, J. M.; Billion, M. A.; Husson,
H.-P.; Royer, J. J. Org. Chem. 1995, 60, 2922–2924.
9. For a recent review see: Liu, M.; Sibi, M. P. Tetrahedron
2002, 58, 7991–8035.
10. Deslongchamp, P.; Belanger, A.; Berney, D. J. F.;
Borshberg, H. J.; Brousseau, R.; Doutheau, A.; Durand,
R.; Katayama, H.; Lapalme, R.; Letruc, D. M.; Liao, C.
C.; MacLachlan, F. N.; Maffrand, J. P.; Marazza, F.;
Lartino, R.; Moreau, C.; Ruest, L.; Saint-Laurent, L.;
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11. Nixon, N. S.; Scheinmann, F.; Suschitzky, J. L. J. Chem.
Res. (M) 1984, 3401–3448.
(ethyl acetate/methanol, 9:1) gave piperidine (þ)-18
20
(89 mg, 88%) as colourless oil. ½aꢁ ¼ þ23:3 (c 0.53,
D
20
D
CHCl3), lit.20 ½aꢁ ¼ þ23:0 (c 0.52, CHCl3); Spectral
data are identical with those reported.20
12. Sugita, T.; Eida, M.; Ito, H.; Komatsu, N.; Abe, K.;
Suama, M. J. Org. Chem. 1987, 52, 3789–3793.
13. David, O.; Blot, J.; Bellec, C.; Fargeau-Bellasoued, M. C.;
Acknowledgements
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We thank Matthieu Beauperin, Nicolas Dailly and Ar-
naud Denecheau, ENSCCF undergraduate students,
who reproduced some experiments.23 We thank the

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23. The efficiency of our method has been checked by
undergraduate students of the ENSCCF: Beauperin, M.;
Dailly, N.; Denecheau, A. who did reproduce in extenso
synthesis of piperidine ( )-13b during their practical
sessions.
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