A new asymmetric synthesis of 2,6-cis-disubstituted 4-methylenepiperidines: Total synthesis of (+)-alkaloid 241D and (+)-isosolenopsin A

Article abstract of DOI:10.1016/j.tetasy.2005.01.018

A highly diastereoselective synthesis of 2,6-cis-disubstituted-4- methylenepiperidines based on a Mannich type intramolecular cyclization of an allylsilane on an iminium ion is described. The synthetic potential of this methodology is demonstrated by the

Full text of DOI:10.1016/j.tetasy.2005.01.018

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1025–1034
A new asymmetric synthesis of 2,6-cis-disubstituted
4-methylenepiperidines: total synthesis of (+)-alkaloid 241D
and (+)-isosolenopsin A
*
´ ´
Jeremy Monfray, Yvonne Gelas-Mialhe, Jean-Claude Gramain and Roland Remuson
´ `
UMR 6504, CNRS, Universite Blaise Pascal (Clermont-Ferrand), 63177 Aubiere cedex, France
Received 2 December 2004; accepted 6 January 2005
Abstract—A highly diastereoselective synthesis of 2,6-cis-disubstituted-4-methylenepiperidines based on a Mannich type intramo-
lecular cyclization of an allylsilane on an iminium ion is described. The synthetic potential of this methodology is demonstrated
by the enantioselective synthesis of two natural piperidine alkaloids: (+)-alkaloid 241D and (+)-isosolenopsin A.
Ó 2005 Elsevier Ltd. All rights reserved.
R2
R2
1. Introduction
NH2
*
HN
R1
6
HN
Many natural biologically active compounds contain the
piperidine ring system as a common structural element.
Among the numerous piperidines, cis- and trans-2,6-
dialkylpiperidines represent an important class of alka-
loids isolated from insects, amphibians or plants.1 For
instance, dihydropinidine 1 was found in the Mexican
beetle Epilachna varivestis.2 Solenopsins 2 and isosole-
nopsins 3 are extracted from the fire antsꢀ venom of
the genus Solenopsis,3 while alkaloid 241D 4 was iso-
lated from the poison frog Dendrobates4 (Fig. 1).
SiMe3
R1
SiMe3
2
4
*
R1
*
*
5
Scheme 1. Formation of the piperidine ring by intramolecular addition
of an allylsilane on an iminium ion.
this strategy to the synthesis of these compounds. In this
case, the piperidine ring would be formed by a Mannich
type intramolecular cyclization reaction starting from
substituted aminoallylsilanes 5 (Scheme 1).
The stereoselective synthesis of piperidines, and notably
2,6-cis-disubstituted piperidines, has received consider-
able attention5,6 due to the broad range of their biolog-
ical activity.7 As part of our programme to expand the
synthetic utility of allylsilyl-functionalized substrates
for the synthesis of natural products,8 we have applied
2. Results and discussion
Previously,9 we have described the enantioselective syn-
thesis of substrates 5. They were prepared from a,b-eth-
ylenic esters 6 in four steps in 21–67% overall yields and
80–84% enantiomeric excesses (Scheme 2).
OH
2.1. Synthesis of 2,6-disubstituted-4-methylenepiperidines
Me
N
H
Me
n
Since numerous natural piperidines are substituted by a
methyl group at the 2 position, we have chosen to pre-
pare piperidines 17–22 by condensation of methyl
substituted aminoallylsilane (R)-5a on carbonyl com-
pounds 11–16 (Scheme 3).
N
H
Me
n-C9H19
N
H
Me
n = 8, 10, 12, 14
1
2 (trans); 3 (cis)
4
Figure 1. Examples of natural piperidines.
*
Reaction of aminoallylsilane (R)-5a (ee = 82%) with
aldehydes 11–15 in the presence of trifluoroacetic acid
Corresponding author. Tel.: +33 (0)4 73 40 76 45; fax: +33 (0)4 73 40
77 17; e-mail: remuson@chimie.univ-bpclermont.fr
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.018

1026
J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
Me Ph
*
Me Ph
O
*
Me Ph
Ph
N
O
Ph
N
OH
a
b
*
R1
SiMe3
+
OEt
*
*
Ph
N
H
R1
OEt
R1
7
6
8
9
SiMe3
NH2
*
NH2 OH
*
c
d
SiMe3
SiMe3
SiMe3
R1
R1
10
5
Scheme 2. Reagents and conditions: (a) n-BuLi, THF, 0 °C; (b) Me3SiMgCl then CeCl3, THF, rt, 3 days; (c) Pd(OH)2, H2, MeOH, H2O, THF,
AcOH, 24 h; (d) HCl 1 M, diethyl ether, 1–24 h.
observed previously by other authors10 during the addi-
tion of vinyl and allylsilanes on iminium salts.
R2
HN
Me
In order to improve yields and minimize racemization
during the cyclization step, we studied the preparation
of piperidines 17–22 from b-aminohydroxysilanes 10,
precursors of b-aminoallylsilanes 5 (Scheme 5).
17a - 21a
NH2
CF3COOH
(cis)
2
SiMe3
+
R CHO
+
R2
Me
H20/THF 1:1
rt, 24 h
(R)-5a
11-15
HN
Me
Reaction of b-aminohydroxysilanes 10 with carbonyl
derivatives 11, 13–16 and 23 in the presence of trifluoro-
acetic acid (10 equiv) in a mixture of water–THF (1:1) at
room temperature for 3 days led to a mixture of cis- and
trans-4-methylenepiperidines. The results are summa-
rized in Table 2.
17b - 21b
(trans)
O
NH2
CF3COOH
SiMe3
HN
+
Me
H2O/THF 1:1
rt, 24 h
Me
As in the preceding results, in all cases, the cis-diaste-
reoisomers were predominant. Comparison of these re-
sults with those mentioned in Table 1 shows that
diastereoselectivity is about the same but enantioselec-
tivity is significantly increased when the piperidine ring
is achieved from aminohydroxysilanes.
(R)-5a
16
22
Scheme 3. Synthesis of 4-methylenepiperidines from aminoallylsilane
(R)-5a.
in a mixture of water–THF (1:1) at room temperature
for 24 h led to a mixture of cis- and trans-4-methylenepi-
peridines. The results are summarized in Table 1. In all
cases, the cis-diastereomers were predominant. The dia-
stereoisomeric excesses, which were found to be better
A mechanism that could account for the formation of 4-
methylenepiperidines from b-aminohydroxysilanes 10 is
depicted in Scheme 6. Cyclization might proceed by the
following sequence: after formation of 1,3-oxazinane 24
and its protonation, iminium ion 25 is generated. Pro-
tonation of the oxygen atom leads to allylsilane 26
and finally cyclization affords the expected piperidine.
In this case, the allylsilane moiety is generated in situ
and reacts instantaneously with the iminium ion previ-
ously formed.
1
than 82%, were determined by H NMR spectroscopy
on the signals corresponding to the methylene protons.
The relative configuration of the cis-diastereoisomers
17a–21a was established unambiguously by H NMR
1
1
spectroscopy. For instance, the H NMR spectrum of
21a showed triplets for H-3ax and H-5ax with
J = 12.8 Hz and J = 12.9 Hz corresponding, respec-
tively, to geminal and trans-diaxial couplings indicative
of a cis-stereochemistry for the 2,6-disubstituted piperi-
dine ring. These results were confirmed by NOE experi-
ments on isomers 21a and 21b (Fig. 2).
The intermediate 1,3-oxazinanes 24 were unambigu-
ously displayed by isolation of 24a (R1 = Me, R2 = n-
C9H19) and 24b (R1 = Me, R2 = Ph) from, respectively,
condensation of decanal 13 and benzaldehyde 15 with
b-aminohydroxysilane (R)-10a without adding trifluoro-
acetic acid. Furthermore, treatment of 24a with trifluo-
roacetic acid led to piperidine 19a.
To explain such a diastereoselectivity, we considered the
transition states A and B (Scheme 4). It appears that the
transition state B leading to the 2,6-trans isomer is disfa-
voured due to a 1,3-diaxial interaction compared to the
transition state A leading to the 2,6-cis isomer.
2.2. Total synthesis of piperidine alkaloids
The preceding results have shown that the best way to
access to 4-methylenepiperidines is from b-aminohydr-
oxysilanes 10. We have used this strategy for the total
synthesis of piperidine alkaloids (+)-alkaloid 241D 4
and (+)-isosolenopsin A 3a.
The enantiomeric purity of piperidines 18a–21a and 22
was determined using two different techniques: GC–
MS with Mosherꢀs acid derivatives and H NMR with
(R)-mandelic acid derivatives. The results (Table 1) have
shown that a partial racemization occurred during the
cyclization step. This racemization can be explained by
an aza-Cope type rearrangement. It has already been
1
2.2.1. Synthesis of (+)-alkaloid 241D 4. Racemic alka-
loid 241D was shown to have interesting biological activ-

J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
Table 1. Preparation of 4-methylenepiperidines from aminoallylsilane 5a
1027
Carbonyl compound
Major product
Dea (%)
Yieldb (%)
Eeb (%)
21
n.d. (½aꢀD ¼ ꢁ4)
84
49
n-C3H7CHO
11
n-C3H7
N
H
CH3
CH3
CH3
17a
CH3CH@CHCHO
12
n.d.
84
32
49
78c
N
H
18a
n-C9H19CHO
13
28d
n-C9H19
n-C11H23
Ph
N
H
19a
n-C11H23CHO
14
82
58
38d
N
H
CH3
20a
PhCHO
15
86
86
70
46
76d
N
H
CH3
CH3
21a
24c
O
N
H
16
22
a Determined by 1H NMR on the crude product.
b Determined on the major isolated piperidine.
c Determined by 1H NMR of the (R)-mandelic acid ammonium salt.
d Determined by GC–MS of the Mosherꢀs acid derivative.
4.3 %
R2
*
no effects
NH2 OH
*
NH2
*
2
R CHO
HN
SiMe3
SiMe3
R1
*
R1
H
+
H
H
R1
Ph
H
H
3.3 %
4.3 %
SiMe3
10
5
Ph
N
H
Me
N
H
Me
Scheme 5. Synthesis of 4-methylenepiperidines from b-aminohydroxy-
allylsilanes 10.
no effects
2.9 %
21b (trans)
21a (cis)
complex.11 Also it is a potent inhibitor of binding of [3H]-
perhydrohistrionicotoxin to nicotinic receptor channels
of electroplax membranes.12 Various asymmetric synthe-
sis of (+)-alkaloid 241D have been described.13 We have
used methylenepiperidine 19a to prepare this alkaloid
Figure 2. NOE effects on cis- and trans-piperidines 21.
ities: for example, it stops the action of acetylcholine by a
noncompetitive blocker of the nicotinic receptor channel
SiMe3
R2
R2
H
H3C
NH
CH3
NH
HN
H
HN
H3C
HN
Si face
Re face
SiMe3
R2
R2
Me3Si
H3C
H
H
CH3
cis-piperidine
trans-piperidine
R2
A
B
Scheme 4. Explanation of diastereoselectivity.

1028
J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
Table 2. Preparation of 4-methylenepiperidines from b-aminohydroxysilanes 10
Aminoalcohol
Carbonyl compound
Major product
Dea (%)
82
Yieldb (%)
53
Eeb (%)
NH2 OH
1
21
n.d. (½aꢀD ¼ ꢁ5:5)
n-C3H7CHO
11
SiMe3
Me
n-C3H7
n-C3H7
n-C9H19
n-C9H19
N
H
17a
CH3
CH3
CH3
CH3
SiMe3
(R)-10a
NH2 OH
21
n.d. (½aꢀD ¼ ꢁ5:5)
SiMe3
2
3
4
CH3CHO
23
82
84
78
32
73
53
n-C3H7
N
H
17a
SiMe3
(S)-10b
NH2 OH
n-C9H19CHO
13
74d
SiMe3
Me
N
H
19a
SiMe3
(R)-10a
NH2 OH
76d
SiMe3
CH3CHO
23
n-C9H19
N
H
SiMe3
(S)-10c
19a
NH2 OH
5
n-C11H23CHO
14
84
70
64d
SiMe3
Me
n-C11H23
N
CH3
SiMe3
(R)-10a
H
20a
NH2 OH
6
7
PhCHO
15
90
90
70
25
84d
SiMe3
SiMe3
Me
Me
Ph
N
H
21a
CH3
CH3
SiMe3
(R)-10a
NH2 OH
14c
O
N
H
22
SiMe3
(R)-10a
16
a Determined by 1H NMR on the crude product.
b Determined on the major isolated piperidine.
c Determined by 1H NMR of the (R)-mandelic acid ammonium salt.
d Determined by GC–MS of the Mosherꢀs acid derivative.
R2
R2
+
N
+
O
NH2 OH
H
H
R1
2
H
R CHO
SiMe3
SiMe3
CF CO H
3 2
HN
R1
O
R1
SiMe3
SiMe3
SiMe3
SiMe3
water/THF
rt, 24 h
1
2
10
24a R = Me, R = C H
9
19
1
2
24b R = Me, R = Ph
R2
R2
R2
R2
H
O
+
HN
+
H
H
O
N
HN
HN
+
SiMe3
SiMe3
SiMe3
SiMe3
SiMe3
R1
R1
R1
R1
25
26
Scheme 6. Mechanism of the formation of 4-methylenepiperidines from aminohydroxysilanes 10.
according to the sequence outlined in Scheme 7. Oxida-
tion of 4-methylenepiperidine 19a with osmium tetroxide
in the presence of Na3H3IO6 in acetic acid led to piperi-
din-4-one 25 in 68% yield. The stereoselective reduction

J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
1029
O
OH
OH
NaBH
OsO , Na H IO
6
4
4
3
3
+
n-C9H19
N
H
Me
n-C9H19
N
H
Me
MeOH
n-C9H19
N
H
Me
n-C9H19
N
H
Me
AcOH 80%
10°C, 24 h
68%
4
19a
25
26
83
:
17
e.e. = 74 %
Scheme 7. Synthesis of (+)-alkaloid 241D 4.
O
S
S
OsO , Na HIO
6
SH SH
BF .Et O
H
4
3
2
Raney Ni
3
2
AcOH 80%
10°C, 24 h
n-C11H23
N
H
Me
n-C11H23
N
H
Me
n-C11H23
N
H
Me
n-C11H23
2
N
Me
EtOH, reflux
CH Cl
2
H
20a
e.e. = 64%
27
28
3a
Scheme 8. Synthesis of the (+)-isosolenopsin A hydrochloride 3a.
of 25 with sodium borohydride afforded (+)-alkaloid
241D 4 and its C-4 epimer 26 in a ratio of 83:17. The nat-
ural product was isolated in a 66% yield. Consequently,
(+)-alkaloid 241D was obtained in six steps from methyl
4. Experimental
4.1. General
crotonate in an overall yield of 23% and an enantiomeric
Commercially available materials were used without fur-
ther purification. THF used for moisture sensitive oper-
ations were distilled from potassium/benzophenone
under an argon atmosphere. All moisture sensitive reac-
tions were carried out in flame-dried glassware under an
argon atmosphere. Analytical thin layer chromatogra-
phy (TLC) was performed on Merck silica gel 60F254
plates. Visualization on TLC was achieved by use of
UV light (254 nm), iodide, ninhydrin or vanillin fol-
lowed by heating. Flash chromatography was per-
formed using Merck silica gel 40–60 lm.
25
D
excess of 74% {½aꢀ ¼ þ5:5 (c 1.04, MeOH), lit.13a
25
½aꢀ ¼ þ6:5 (c 2, MeOH)}.
D
2.2.2. Synthesis of (+)-isosolenopsin A 3a. (+)-Isosole-
nopsin A has been shown to have numerous biological
activities such as antibacterian, antifongic, insecticide
and phytocid. According to a similar sequence, (+)-iso-
solenopsin A14 was prepared from 4-methylenepiperi-
dine 20a. (Scheme 8). Oxidation of 20a with osmium
tetroxide and Na3H3IO6 led to piperidin-4-one 27 in
67% yield. Treatment of 27 with an excess of ethane dith-
iol in the presence of BF3ÆEt2O gave the dithiolane deriv-
ative 28 in 82% yield. Finally, 28 was converted into (+)-
isosolenopsin A 3a (isolated as its hydrochloride salt) in
43% yield using Raney nickel in reflux ethanol.
Infrared spectra were recorded on a Perkin–Elmer 881
(spectra in solution) or on a Perkin–Elmer FTIR Spec-
trometer Paragon 500 (film). Only selected absorbances
are reported. Optical rotations were measured on a Jas-
co DIP-370 polarimeter at 589 nm (Na D-line).
(+)-Isosolenopsin A (HCl) was obtained in seven steps
from ethyl crotonate in 11% overall yield and 64% enan-
Nuclear magnetic resonance (NMR) spectra were reco-
rded on a Bruker Avance 400 spectrometer at operating
frequencies of 400 MHz (1H NMR) or 100 MHz (13C
NMR). Chemical shifts (d) are given in ppm relative
25
D
tiomeric excess. {½aꢀ ¼ þ5:5 (c 1.00, CHCl3), lit.14c
[a]D = þ10.0 (c 1.17, CHCl3)}.
1
to CDCl3 (d = 7.27 ppm for H, d = 77.1 ppm for 13C)
3. Conclusion
and coupling constants (J) in hertz. Multiplicity is tabu-
lated as s for singlet, d for doublet, t for triplet, q for
quadruplet, m for multiplet; the prefix br is used for a
broad signal.
We have described a new approach for the enantioselec-
tive synthesis of 2,6-cis-disubstituted-4-methylenepiperi-
dines. The key step of the sequence is an intramolecular
allylsilane–iminium cyclization. Piperidines were ob-
tained with good yields and excellent diastereoselectiv-
ity. Moderate enantiomeric excesses were measured
when a b-aminoallylsilane was used as starting material,
a better enantioselectivity was observed when we started
from b-aminohydroxysilanes. This methodology was
applied to the synthesis of (+)-alkaloid 241D and (+)-
isosolenopsin A.
Mass spectra (MS) in electronic ionization mode (EI)
were recorded on an Agilent 6890N mass spectrometer
(GC/MS). Other spectra were performed on a Hew-
lett–Packard 5989B spectrometer. High-resolution mass
´
spectra (HRMS) were recorded at the Centre Regional
de Mesures Physique de lꢀOuest (CRMPO, University
of Rennes I, France) on a Varian Mat 311 spectrometer
(EI) or on
a
Micromass ZABSpecTOF (ESI).

1030
J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
25
D
1
Microanalysis were carried out at the Laboratoire Cen-
tral de Microanalyse du CNRS (Vernaison, France).
½aꢀ ¼ ꢁ11 (c 1.10, CHCl3); IR (CCl4): m (cmꢁ1
)
1722; H NMR d major diastereoisomer 0.95 (t, 3H,
J = 6.9 Hz), 1.23 (t, 3H,J = 7.2 Hz), 1.25–1.36 (m,
14H), 1.39 (d, 3H, J = 6.8 Hz), 1.51–1.65 (m, 1H, H-
4), 2.08 (AB part of ABX system, 2H, H-2, Dm = 21 Hz,
dA = 2.10 (dd, 1H, JAB = 14.4 Hz, JAX = 4.1 Hz),
dB = 2.05 (dd, 1H, JAB = 14.4 Hz, JBX = 8.7 Hz)), 3.36
(m, 1H), 3.72 (AB system, 2H, Dm = 99 Hz, dA = 3.84
4.2. General procedure for preparation of 8
To a solution of (R)- or (S)-N-benzyl-N0-a-methylbenz-
ylamine 7 (1.1 equiv, 0.25–0.32 mol Lꢁ1) in dry THF
was added dropwise at 0 °C a solution of n-butyllithium
(1.2 equiv) in hexane (c = 1.6 mol Lꢁ1). After stirring for
15 min, a solution of the a,b-ethylenic ester 6 (23–35
mmol, 1.1–1.6 mol Lꢁ1) in dry THF was added at 0 °C.
After stirring for 1 h, the mixture was hydrolyzed with
a saturated solution of ammonium chloride. The layers
were separated and the aqueous layer extracted with
diethyl ether. The combined organic layers were dried
over MgSO4 and concentrated. The crude product was
purified by flash chromatography (cyclohexane/AcOEt
95:5). A mixture of two diastereoisomers was obtained.
(d,
1H,
JAB = 15.0 Hz),
dB = 3.60
(d,
1H,
JAB = 15.0 Hz)), 3.89 (q, 1H, J = 7.0 Hz), 4.0–4.13 (m,
2H), 7.25–7.50 (m, 10H); 13C NMR d major diastereo-
isomer 14.3, 19.7 (CH3), 22.7, 27.0, 29.5, 29.6, 32.0,
33.6, 36.9, 50.0 (CH2), 54.1, 56.9 (CH), 60.1 (CH2),
126.8, 126.9, 128.1, 128.7 (CH), 141.8, 143.3, 172.9
(C); MS for C29H43NO2: m/z 465. Anal. Calcd for
C29H43NO2: C, 79.59; H, 9.90; N, 3.20. Found: C,
79.76; H, 10.13; N, 3.10.
4.3. General procedure for the preparation of 9
4.2.1. Ethyl (3R,30R)-3-(N-a-methylbenzyl-N0-benzyl-
amino)-butanoate 8a. Pale yellow oil; yield: 83%;
TLC: Rf = 0.37 (cyclohexane/AcOEt, 95:5); de = 82%;
Powdered CeCl3Æ7H2O (4.5–4.6 equiv) was dried under
vacuum (0.5 mmHg) for 3 days at 120–130 °C while stir-
ring. The flask was flushed with argon, then dry THF
(7 mL/g of CeCl3Æ7H2O) added. The white suspension
was stirred at room temperature for an additional 2 h.
This slurry was cooled to ꢁ78 °C and trimethylsilyl
methylmagnesium chloride (4.6 equiv; freshly prepared
from trimethylsilylmethyl chloride and magnesium) in
dry THF (30 mL) was added dropwise over a period
of 1–2 h. The cold mixture was stirred for 1 h and ester
8 (7–10 mmol) in dry THF (10 mL) was added dropwise
over 30 min. The resulting mixture was allowed to warm
to room temperature and stirred for 3 days. The reaction
mixture was then cooled to ꢁ10 °C and hydrolyzed by
the dropwise addition of 1 M hydrochloric acid. The
layers were separated and the aqueous layer extracted
with diethyl ether. The combined organic layers were
dried over MgSO4 and concentrated. The crude product
was purified by flash chromatography (cyclohexane/
AcOEt 95:5).
25
½aꢀ ¼ þ3 (c 1.12, CHCl3); IR (CCl4): m (cmꢁ1) 1730;
D
1H NMR d major diastereoisomer 1.20 (d, 3H,
J = 6.7 Hz), 1.22 (t, 3H, J = 7.1 Hz), 1.41 (d, 3H,
J = 6.9 Hz), 2.29 (AB part of ABX system, 2H,
Dm = 100 Hz), dA = 2.42 (dd, 1H, JAB = 14.1 Hz,
JAX = 6.0 Hz, dB = 2.17 (dd, 1H, JAB = 14.1 Hz,
JBX = 8.0 Hz)), 3.51 (X part of ABX system, m, 1H,
JAX = 6.0 Hz, JBX = 8.0 Hz), 3.77 (AB system, 2H,
Dm = 20 Hz, dA = 3.79 (d, 1H, JAB = 14.7 Hz), dB = 3.75
(d, 1H, JAB = 14.7 Hz)), 3.92–4.11 (m, 3H), 7.24–7.49
(m, 10H); 13C NMR d major diastereoisomer 14.2,
18.0, 18.6 (CH3), 39.9, 49.7 (CH2), 50.1, 57.9 (CH), 60.2
(CH2), 126.6, 126.7, 127.8, 128.0, 128.1, 128.2, 128.4
(CH), 141.7, 144.3, 172.5 (C); MS for C21H27NO2: m/z
325. Anal. Calcd for C21H27NO2: C, 77.50; H, 8.36; N,
4.30. Found: C, 77.92; H, 8.45; N, 4.07.
4.2.2. Ethyl (3S,30S)-3-(N-a-methylbenzyl-N0-benzyl-
amino)-hexanoate 8b. Yellow oil; yield: 70%; TLC:
Rf = 0.33 (cyclohexane/AcOEt, 95:5); de = 82%;
4.3.1. (30R,4R)-4-(N-a-Methylbenzyl-N0-benzylamino)-
25
½aꢀ ¼ ꢁ20 (c 1.31, CHCl3); IR (CCl4): m (cmꢁ1) 1735;
1-trimethylsilyl-2-trimethylsilylmethylpentan-2-ol
Colourless oil; yield: 90%; TLC: Rf = 0.52 (cyclohex-
9a.
D
1H NMR
d
major diastereoisomer 0.78 (t, 3H,
25
J = 7.2 Hz), 1.08 (t, 3H, J = 7.2 Hz), 1.12–1.22 (m, 2H),
1.25 (d, 3H, J = 6.8 Hz), 1.36–1.57 (m, 2H), 1.93 (AB part
of ABX system, 2H, Dm = 20 Hz, dA = 1.95 (dd, 1H,
JAB = 14.5 Hz, JAX = 4.2 Hz), dB = 1.90 (dd, 1H,
JAB = 14.6 Hz, JBX = 8.9 Hz)), 3.24 (X part of ABX sys-
tem, m, 1H, JAX = 4.2 Hz, JBX = 8.9 Hz), 3.57 (AB sys-
tem, 2H, Dm = 99 Hz, dA = 3.70 (d, 1H, JAB = 14.9 Hz),
dB = 3.45 (d, 1H, JAB = 14.9 Hz)), 3.74 (q, 1H,
J = 7.0 Hz), 3.85–3.99 (m, 2H), 7.10–7.35 (m, 10H); 13C
NMR d major diastereoisomer 14.2, 14.3, 19.8 (CH3),
20.3, 35.9, 36.9, 50.0 (CH2), 53.8, 58.0 (CH), 60.1
(CH2), 126.6, 126.8, 126.9, 127, 128.0, 128.1, 128.2,
128.3 (CH), 143.2, 141.9, 173.0 (C); MS for
C23H31NO2: m/z 353. Anal. Calcd for C23H31NO2: C,
78.15; H, 8.84; N, 3.96. Found: C, 78.10; H, 8.65; N, 3.87.
ane/AcOEt 95:5); de = 82% ½aꢀ ¼ þ24 (c 1.12, CHCl3);
D
1
IR (CCl4): m (cmꢁ1) 3240; H NMR d major diastereo-
isomer ꢁ0.21 (s, 9H), 0.00 (s, 9H), 0.05 (AB system,
2H, Dm = 235 Hz, dA = 0.35 (d, 1H, JAB = 14.6 Hz),
dB = ꢁ0.24 (d, 1H, JAB = 14.6 Hz)), 0.77 (AB system,
2H, Dm = 44 Hz, dA = 0.82 (d, 1H, JAB = 14.8 Hz),
dB = 0.72 (d, 1H, JAB = 14.8 Hz)), 1.07 (d, 3H,
J = 6.4 Hz), 1.35 (d, 3H, J = 7.2 Hz), 1.48 (AB part of
ABX system, 2H, H-3, Dm = 385 Hz, dA = 1.96 (t,
J = 13.2 Hz,
JAX = 1.6 Hz),
dB = 1.00
(dd,
JAB = 14.4 Hz, JBX = 2.0 Hz)), 3.23–3.32 (X part of
ABX system, m, 1H), 3.73 (AB system, 2H,
Dm = 187 Hz, dA = 3.97 (d, 1H, JAB = 12.8 Hz),
dB = 3.50 (d, 1H, JAB = 12.8 Hz)), 3.90 (q, 1H,
J = 6.8 Hz), 6.29 (s, 1H), 7.10–7.42 (m, 10H); 13C
NMR d major diastereoisomer 0.4, 1.1, 13.6, 18.6
(CH3), 33.1, 34.9, 45.8 (CH2), 48.9 (CH), 49.0 (CH2),
56.2 (CH), 75.8 (C), 127.4, 128.4, 128.7, 129.1, 129.8
(CH), 139.2, 142.6 (C). Anal. Calcd for C27H45NOSi2:
4.2.3.
Ethyl
(3S,30S)-3-(N-methylbenzyl-N0-benzyl-
amino)-dodecanoate 8c. Yellow oil; yield: 69%; TLC:
Rf = 0.48 (cyclohexane/AcOEt, 95:5); de = 80%;

J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
1031
C, 71.14; H, 9.95; N, 3.07. Found: C, 71.57; H, 10.08; N,
3.10.
on Kugelrohr: 172 °C/0.5 mmHg; yield: 92%; TLC:
25
Rf = 0.18 (AcOEt); ½aꢀ ¼ þ1 (c 1.18, CHCl3);
D
1
IR (CCl4): m (cmꢁ1) 3260; H NMR 0.03 (s, 1H), 0.06
(s, 1H), 1.01 (AB system, 2H, Dm = 42 Hz, dA = 1.06
4.3.2. (30S,4S)-4-(N-a-Methylbenzyl-N0-benzylamino)-
1-trimethylsilyl-2-trimethylsilylmethylheptan-2-ol
9b
Yellow oil; yield: 72%; TLC: Rf = 0.38 (cyclohexane/
(d,
1H,
JAB = 15.0 Hz),
dB = 0.96
(d,
1H,
JAB = 15.0 Hz)), 1.10 (d, 3H, J = 6.4 Hz), 1.17 (AB sys-
tem, 2H, Dm = 73 Hz, dA = 1.26 (d, 1H, JAB = 14.3 Hz),
dB = 1.08 (d, 1H, JAB = 14.3 Hz)), 1.47 (AB part of
ABX system, 2H, Dm = 24 Hz, dA = 1.50 (dd,
25
AcOEt, 95:5); ½aꢀ ¼ ꢁ5 (c 1.04, CHCl3); IR (CCl4): m
D
1
(cmꢁ1) 3260; H NMR d major diastereoisomer ꢁ0.15
(s, 9H), 0.00 (s, 9H), 0.19 (AB system, 2H, Dm = 158 Hz,
dA = 0.38 (d, 1H, JAB = 14.6 Hz), dB = ꢁ0.01 (d, 1H,
JAB = 14.6 Hz)), 0.86 (AB system, 2H, Dm = 32 Hz,
dA = 0.90 (d, 1H, JAB = 14.6 Hz), dB = 0.82 (d, 1H,
JAB = 14.6 Hz)), 0.92 (t, 3H, J = 7.0 Hz), 1.13–1.32 (m,
2 H), 1.35 (d, 3H, J = 6.8 Hz), 1.51 (AB part of ABX
system, 2H, Dm = 228 Hz, dA = 1.80 (dd, 1H,
JAB = 14.5 Hz, JAX = 11.4 Hz), dB = 1.23 (dd, 1H,
JAB = 14.5 Hz, JBX = 2.4 Hz)), 1.65–1.73 (m, 2H, H-5),
3.09 (X part of ABX system, t, 1H, J = 10.4 Hz), 3.75
(AB system, 2H, Dm = 158 Hz, dA = 3.95 (d, 1H,
JAB = 13.1 Hz), dB = 3.55 (d, 1H, JAB = 13.1 Hz)), 3.91
(q, 1H, J = 6.8 Hz), 6.36 (br s, 1H), 7.11–7.40 (m,
10H, H aromatics); 13C NMR d major diastereoisomer
0.9, 1.0, 14.7 (CH3), 21.1, 32.0, 34.9, 35.0, 43.4, 49.5
(CH2), 54.3, 57.2 (CH), 75.9 (C), 127.3, 128.3, 128.5,
128.6, 128.9, 129.6 (CH), 139.5, 142.7 (C); MS (CI,
methane) for C29H49NOSi2 + H: m/z 484 (M+H+).
Anal. Calcd for C29H49NOSi2: C, 71.98; H, 10.21; N,
2.89. Found: C, 72.25; H, 10.30; N, 3.38.
JAB = 14.3 Hz,
JAX = 2.6 Hz),
dB = 1.44
(dd,
JAB = 14.3 Hz, JBX = 10.9 Hz)), 3.15 (X part of ABX
system, m, 1H); 13C NMR d (ppm) 0.6, 1.0, 28.1
(CH3), 32.8, 35.0 (CH2), 45.2 (CH), 50.9 (CH2), 75.7
(C); HRMS (ESI) m/z calcd for C12H31NOSi2 + H:
262.2022. Found: 262.2031 (M+H+).
4.4.2. (4S)-4-Amino-1-trimethylsilyl-2-trimethylsilylmeth-
ylheptan-2-ol 10b. Liquid purified by distillation on
Kugelrohr: 187 °C/0.5 mmHg; yield: 80%; TLC:
25
D
Rf = 0.33 (AcOEt)); ½aꢀ ¼ ꢁ3 (c 1.11, CHCl3); IR
(CCl4): m (cmꢁ1) 3300; 1H NMR d 0.04 (s, 9H),
0.06 (s, 9H), 0.92 (t, 3H, J = 6.8 Hz), 1.02 (AB system,
2H, Dm = 41 Hz, dA = 1.07 (d, 1H, JAB = 14.7 Hz),
dB = 0.97 (d, 1H, JAB = 14.7 Hz)), 1.15 (AB system,
2H, Dm = 83 Hz, dA = 1.26 (d, 1H, JAB = 14.7 Hz),
dB = 1.05 (d, 1H, JAB = 14.7 Hz)), 1.18–1.46 (m, 5H),
1.50 (dd, 1H, J = 14.1 Hz, J = 2.8 Hz), 2.96 (m, 1H);
13C NMR d 1.0, 1.3, 14.2 (CH3), 18.7, 32.4, 35.1, 43.9,
49.2 (CH2), 49.4 (CH), 75.6 (C); MS (CI, methane) m/
z calcd for C14H35NOSi2 + H: 290 (M+H+). Anal. Calcd
for C14H35NOSi2: C, 58.06; H, 12.18; N, 4.84. Found: C,
57.99; H, 13.52; N, 5.04.
4.3.3. (30S,4S)-4-(N-a-Methylbenzyl-N0-benzylamino)-
1-trimethylsilyl-2-trimethylsilylmethyltridecan-2-ol
Y. ellow oil; yield: 71%; TLC: Rf = 0.48 (cyclohexane/
9c.
25
AcOEt 95:5); ½aꢀ ¼ ꢁ3 (c 0.95, CHCl3); FTIR (film):
D
m (cmꢁ1) 3256; 1H NMR d major diastereoisomer
ꢁ0.15 (s, 9H), 0.00 (s, 10H), 0.37 (d, 1H), 0.80–0.92
(m, 5H), 1.10–1.42 (m, 17H), 1.35 (d, 3H, J = 6.9 Hz),
1.80 (dd, 1H, J = 14.3 Hz, J = 11.4 Hz), 3.1 (t, 1H,
J = 9.9 Hz), 3.75 (AB system, 2H, Dm = 159 Hz,
dA = 3.95 (d, 1H, JAB = 13.1 Hz), dB = 3.55 (d, 1H,
JAB = 13.1 Hz)), 3.90 (q, 1H, J = 6.9 Hz), 6.35 (br s,
1H), 7.13–7.40 (m, 10H); 13C NMR d major diastereo-
isomer 0.8, 1.0, 14.1, 14.7 (CH3), 22.7, 26.9, 27.9, 29.3,
29.6, 32.0, 35.0, 43.4, 49.4 (CH2), 54.6, 57.2 (CH), 75.9
(C), 127.1, 127.3, 128.3, 128.5, 128.9, 129.6 (CH),
139.5, 142.7 (C); MS (CI, methane) for C35H61NO-
Si2 + H: m/z 568 (M+H+). Anal. Calcd for C35H61NO-
Si2: C, 74.01; H, 10.82; N, 2.47. Found: C, 74.53; H,
11.11; N, 2.65.
4.4.3. (4S)-4-Amino-1-trimethylsilyl-2-trimethylsilylmeth-
yltridecan-2-ol 10c. Oil; yield: 89%; TLC: Rf = 0.25
25
D
(AcOEt); ee = 80%; ½aꢀ ¼ ꢁ2:5 (c 1.07, CHCl3);
IR (CCl4): m (cmꢁ1) 3300; 1H NMR (400 MHz, CDCl3):
d (ppm) 0.00 (s, 9H), 0.02 (s, 9H), 0.83 (t, 3H,
J = 6.8 Hz), 0.98 (AB system, 2H, Dm = 34 Hz,
dA = 1.03 (d, 1H, JAB = 14.4 Hz), dB = 0.94 (d, 1H,
JAB = 14.4 Hz)), 0.99 (d, 1H, J = 14.3 Hz), 1.18–1.27
(m, 15H), 1.29–1.36 (m, 2H), 1.44 (AB part of ABX sys-
tem, 2H, m = 21 Hz, dA = 1.47 (dd, 1H, JAB = 14.2 Hz,
JAX = 2.2 Hz), dB = 1.41 (dd, 1H, JAB = 14.2 Hz,
`
JBX = 11.5 Hz)), 2.91 (partie X de systeme ABX, m,
1H), 3.21 (br s, 2H); 13C NMR (100 MHz, CDCl3): d
(ppm) 0.8, 1.0, 14.8 (CH3), 22.8, 25.7, 29.4, 29.6, 29.7,
32.0, 32.4, 35.2, 41.0, 49.3 (CH2), 49.5 (CH), 75.8 (C);
HRMS (EI) m/z calcd for C20H47NOSi2–CH2SiMe3:
286.2566. Found: 286.2554 (MꢁCH2SiMe3+).
4.4. General procedure for preparation of 10
To a solution of 9 (1 g) in methanol (13 mL), acetic acid
(0.31 mL), water (2.7 mL) and THF (2.4 mL) was added
Pearlmanꢀs catalyst (0.3 g). The resulting mixture was
stirred under 3.5 atm of hydrogen at room temperature
for 24 h in Parr apparatus. The mixture was filtered
through Celite and concentrated to give a residue which
was treated with sodium hydrogenocarbonate then ex-
tracted with methylene chloride and organic layers were
dried (K2CO3) and evaporated.
4.5. (2R)-4-Trimethylsilylmethylpent-4-en-2-amine 5a
A solution of HCl 1 M (4.4 equiv) was added slowly to a
cooled (0 °C) 0.5 M solution of (R)-10a in diethylether
and stirred at 0 °C for 1 h. The excess of acid was neu-
tralized with a saturated solution of sodium hydrogeno-
carbonate and the aqueous phase was extracted with
ether. The organic phase was dried (K2CO3) and con-
centrated under atmospheric pressure. Liquid; yield:
25
D
93%; TLC: Rf = 0.07 (AcOEt); ee = 82%; ½aꢀ ¼ þ20
4.4.1. (4R)-4-Amino-1-trimethylsilyl-2-trimethylsilyl-
methylpentan-2-ol 10a. Liquid purified by distillation
(c 0.88, CHCl3); Bp = 43 °C (1 mmHg); IR (CCl4): m
1
(cmꢁ1) 3080, 1630; H NMR d 0.00 (s, 9H), 1.07 (d,

1032
J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
3H, J = 6.4 Hz), 1.35 (br s, 2H), 1.51 (AB system, 2H,
Dm = 13 Hz, dA = 1.52 (d, 1H, JAB = 13.4 Hz),
dB = 1.49 (d, 1H, JAB = 13.4 Hz)), 1.94 (AB part of
ABX system ABX, 2H, Dm = 70 Hz, dA = 2.03 (dd, 1H,
JAB = 13.6 Hz, JAX = 4.6 Hz), dB = 1.86 (dd, 1H,
JAB = 13.6 Hz, JBX = 8.8 Hz)), 3.05 (m, 1H), 4.60 (s,
1H), 4.62 (s, 1H); 13C NMR d ꢁ1.3, 23.9 (CH3), 26.5
(CH2), 44.6 (CH), 49.4, 109.6 (CH2), 145.3 (C); HRMS
(ESI) m/z calcd for C9H21NSi + H: 172.1521. Found:
172.1518 (M+H+).
(cmꢁ1 3071, 1651; 1H NMR
) d 1.08 (d, 3H,
J = 6.2 Hz), 1.63 (d, 3H, J = 6.3 Hz), 1.72 (t, 1H,
J = 12.5 Hz), 1.86 (t, 1H, J = 12.2 Hz), 2.13–2.17 (2H,
m), 2.58–2.66 (m, 1H), 3.01 (ddd, 1H, J = 11.3 Hz,
J = 6.9 Hz, J = 2.6 Hz), 4.63 (2H, s), 5.43 (ddd, 1H,
J = 15.3 Hz, J = 6.9 Hz, J = 1.4 Hz), 5.58 (dq, 1H, J =
6.3 Hz, J = 15.3 Hz); 13C NMR d 17.8, 22.6 (CH3),
41.3, 42.9 (CH2), 53.0, 60.1 (CH), 108.0 (CH2), 125.8,
134.1 (CH), 146.3 (C); HRMS (ESI) m/z calcd for
C10H17N + H: 152.1439. Found: 152.1457 (M+H+).
4.6. General procedure for preparation of 4-methyl-
enepiperidines
4.6.5. (2R,6S)-2-Methyl-4-methylen-6-nonylpiperidine
19a. Liquid. (a) From aminoallylsilane (R)-5a. Yield:
49%; TLC: Rf = 0.44 (AcOEt + drops of NH4OH
21
4.6.1. From aminoallylsilane (R)-5a. To a solution of
the aminoallylsilane (R)-5a in a mixture of THF and
water (1:1 v/v; 0.73 mol Lꢁ1) was added at ambient tem-
perature aldehyde or cyclohexanone (1.2 equiv). The
solution was stirred for 20 min and trifluoroacetic acid
(1.1 equiv) was added dropwise. After stirring for one
day, the reaction mixture was neutralized with a satu-
rated solution of sodium hydrogenocarbonate and the
aqueous phase was extracted with ether. The organic
layers were collected, dried (K2CO3) and evaporated at
atmospheric pressure. The crude product was purified
by flash chromatography (elution gradient: pentane then
pentane/diethylether).
28%); ½aꢀ ¼ ꢁ1:5 (c 0.94, CHCl3); ee = 28% FTIR
D
(film): m (cmꢁ1) 3071, 1651; 1H NMR d 0.83 (t, 3H,
J = 7.0 Hz), 1.07 (d, 3H, J = 6.2 Hz), 1.14–1.46 (m,
16H), 1.67 (t, 1H, J = 12.8 Hz), 1.70 (t, 1H,
J = 12.8 Hz), 2.16 (d, 1H, J = 13.2 Hz), 2.19 (d, 1H,
J = 13.2 Hz), 2.41–2.49 (m, 1H), 2.53–2.62 (m, 1H),
4.59 (s, 2H); 13C NMR d 14.1 (CH3), 22.8 (CH3), 22.7,
26.0, 29.3, 29.6, 29.7, 29.8, 31.9, 37.2, 41.3, 43.5 (CH2),
53.3, 57.9 (CH), 107.6 (CH2), 146.9 (C); HRMS (EI)
m/z calcd for C16H31N ꢁ CH3: 222.2222. Found:
222.2200 (MꢁCH3+). (b) From aminoalcohol (R)-10a.
21
Yield: 73%; ½aꢀ ¼ ꢁ4:5 (c 0.98, CHCl3); ee = 74%. (c)
21
D
From aminohydroxysilane (S)-10c. Yield: 53%;
½aꢀ ¼ ꢁ6 (c 1.00, CHCl3); ee = 76% (method A).
D
4.6.2. From b-aminohydroxysilanes (R)-10a, (S)-10b and
(S)-10c. To a solution of aminoalcohol (S)-10b and
4.6.6. (2R,6S)-2-Methyl-4-methylen-6-undecylpiperidine
20a. Liquid (a) From aminoallylsilane (R)-5a. Yield:
58%; TLC: Rf = 0.56 (AcOEt + drops of NH4OH
(S)-10c in
a mixture of THF and water (1:1;
0.76 mol Lꢁ1) was added at room temperature the car-
bonyl compound. The solution was stirred for 24 h
and trifluoroacetic acid (10 equiv) added. One day after
the addition, the acid was neutralized with a saturated
solution of sodium hydrogenocarbonate. The aqueous
phase was extracted with diethyl ether. The organic lay-
ers were collected, dried over K2CO3 and evaporated at
atmospheric pressure. The crude product was purified
by flash chromatography (elution gradient: pentane then
pentane/diethyl ether).
21
28%); ½aꢀ ¼ ꢁ2:5 (c 1.16, CHCl3); ee = 38%; FTIR
D
(film): m (cmꢁ1) 3071, 1651; 1H NMR d 0.86 (t, 3H,
J = 6.6 Hz), 1.09 (d, 3H, J = 6.2 Hz), 1.20–1.43 (m,
20H), 1.70 (t, 1H, J = 13.2 Hz), 1.74 (t, 1H,
J = 13.2 Hz), 2.19 (d, 1H, J = 12.7 Hz), 2.22 (d, 1H,
J = 12.7 Hz), 2.43–2.51 (m, 1H), 2.55–2.65 (m, 1H),
4.62 (s, 2H); 13C NMR d 14.1, 22.7 (CH3), 22.8, 26.0,
29.4, 29.6, 29.7, 29.8, 31.9, 37.2, 41.4, 43.5 (CH2), 53.3,
57.9 (CH), 107.6 (CH2), 147.0 (C); HRMS (EI) m/z calcd
for C18H35N: 265.2769. Found: 265.2765 (M+). (b) From
aminohydroxysilane (R)-10a. Yield: 70%; ee = 64%.
4.6.3. (2R,6S)-2-Methyl-4-methylen-6-propylpiperidine
17a. Liquid. (a) From aminoallylsilane (R)-5a. Yield:
49%; TLC: Rf = 0.38 (AcOEt + drops of NH4OH
21
4.6.7. (2R,6R)-2-Methyl-4-methylen-6-phenylpiperidine
21a. Liquid (a) From aminoallylsilane (R)-5a. Yield:
70%; TLC: Rf = 0.85 (AcOEt + drops of NH4OH
28%); ½aꢀ ¼ ꢁ4 (c 1.05, CHCl3); FTIR (film): m
D
(cmꢁ1
)
3071, 1651; 1H NMR
d
0.87 (t, 3H,
J = 7.0 Hz), 1.06 (d, 3H, J = 6.2 Hz), 1.26–1.39 (m,
4H), 1.53 (br s, 1H), 1.67 (t, 1H, J = 13.4 Hz), 1.70 (t,
1H, J = 13.4 Hz), 2.15 (d, 1H, J = 13.4 Hz), 2.20 (d,
1H, J = 13.4 Hz), 2.42–2.50 (m, 1H), 2.52–2.62 (m,
1H), 4.59 (s, 2H); 13C NMR d 14.2 (CH3), 19.1 (CH2),
22.7 (CH3), 39.3, 41.3, 43.4 (CH2), 52.3, 57.5 (CH),
107.6 (CH2), 146.9 (C); HRMS (ESI) m/z calcd for
C10H19N + H: 154.1596. Found: 154.1591 (M+H+). (b)
21
28%); ½aꢀ ¼ ꢁ9:5 (c 1.12, CHCl3); ee = 74%; FTIR
D
1
(film): m (cmꢁ1) 3071, 1651; H NMR d 1.12 (d, 3H,
J = 6.4 Hz), 1.60 (br s, 1H), 1.85 (t, 1H, J = 12.9 Hz),
2.14 (t, 1H, J = 12.8 Hz), 2.22 (1H, d, J = 12.8 Hz),
2.32 (1H, d, J = 12.8 Hz), 2.70–2.77 (m, 1H), 3.59 (dd,
1H, J = 2.7 Hz, J = 11.4 Hz), 4.67–4.69 (2H, m), 7.20–
7.35 (m, 5H); 13C NMR d 22.7 (CH3), 42.9, 43.3
(CH2), 53.7, 62.9 (CH), 108.2 (CH2), 126.7, 127.2,
128.4 (CH), 144.5. 146.7 (C); HRMS (EI) m/z calcd
From aminohydroxysilane (R)-10a. Yield: 53%;
21
D
½aꢀ ¼ ꢁ5:5 (c 0.94, CHCl3). (c) From aminohydroxy-
for C13H17N: 187.1361. Found: 187.1370 (M+). (b) From
21
silane (S)-10b. Yield: 34%; ½aꢀ ¼ ꢁ5:5 (c 0.93, CHCl3).
D
21
D
aminohydroxysilane (R)-10a. Yield: 70%; ½aꢀ ¼ ꢁ11:5
(c 1.09, CHCl3); ee = 84%.
4.6.4. (2R,6R)-2-Methyl-4-methylen-6-propenylpiperidine
18a. From aminoallylsilane (R)-5a. Liquid, yield: 39%;
TLC: Rf = 0.56 (AcOEt + drops of NH4OH 28%);
4.6.8. (2R)-Methyl-4-methylen-1-aza-spiro[5,5]undecane
22. Liquid (a) From aminoallylsilane (R)-5a. Yield:
21
½aꢀ ¼ ꢁ4 (c 0.86, CHCl3); ee = 78%; FTIR (film): m
D

J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
1033
46%; TLC: Rf = 0.55 (AcOEt + drops of NH4OH 28%);
4.8.1.
White solid; yield: 68%; TLC: Rf = 0.51 (AcOEt + drops
(2R,6S)-2-Methyl-6-nonylpiperidin-4-one
25.
21
½aꢀ ¼ 0 (c 1.04, CHCl3); ee = 24%; FTIR (film): m
D
25
D
1
(cmꢁ1) 3071, 1651; H NMR d 1.03 (d, 3H, J = 6.2 Hz),
1.28–1.55 (m, 11H), 1.65 (t, 1H, J = 10.7 Hz), 1.77 (d,
1H, J = 12.7 Hz), 2.15–2.23 (2H, m), 2.80–2.88 (m, 1H),
4.56–4.58 (m, 1H), 4.66–4.68 (m, 1H); 13C NMR d 21.8,
21.9, 31.7, 40.9 (CH2), 23.1 (CH3), 43.9, 44.8 (CH2),
46.1 (CH), 52.9 (C), 108.8 (CH2), 145.1 (C); HRMS
(EI) m/z calcd for C12H21N: 179.1674. Found: 179.1667
of NH4OH 28%); ½aꢀ ¼ ꢁ1 (c 0.79, CHCl3) {lit.13b
25
½aꢀ ¼ ꢁ1:1 (c 1.56, CHCl3)}; mp = 25–28 °C (lit.13b
D
mp = 29–30 °C); FTIR (KBr): m (cmꢁ1) 1720; 1H
NMR
d 0.83 (t, 3H, J = 6.8 Hz), 1.19 (d, 3H,
J = 6.2 Hz), 1.23–1.56 (m, 17H), 2.01–2.11 (m, 2H),
2.32–2.41 (m, 2H), 2.81–2.87 (m, 1H), 2.93–3.01 (m,
1H); 13C NMR d 14.2, 22.7 (CH3), 22.7, 25.8, 29.4,
29.6, 29.7, 31.9, 37.1, 48.2, 50.2 (CH2), 52.2,
56.7 (CH), 210.0 (C); MS (EI) m/z for C15H29NO: 239
(M+).
(M+). (b) From aminohydroxysilane (R)-10a. Yield:
21
D
25%; ½aꢀ ¼ 0 (c 0.98, CHCl3); ee = 14%.
4.7. General procedure for preparation of 24
4.8.2. (2R,6S)-2-Methyl-6-undecylpiperidin-4-one 27.
White solid; yield: 67%; TLC: Rf = 0.55 (AcOEt + drops
To a solution of aminohydroxysilane (R)-10a in a
mixture of THF and water (1:1; 0.76 mol Lꢁ1) was
added at room temperature the carbonyl compound.
The mixture was stirred 24 h and extracted with diethyl
ether. The organic layers were collected, dried over
K2CO3 and concentrated. The crude product was puri-
fied by flash chromatography (elution gradient: cyclo-
hexane then cyclohexane/AcOEt).
25
of NH4OH 28%); ½aꢀ ¼ ꢁ1:5 (c 0.89, CHCl3);
D
1
mp = 38–40 °C; FTIR (KBr): m (cmꢁ1) 1720; H NMR
d 0.87 (t, 3H, J = 6.8 Hz), 1.21 (d, 3H, J = 6.4 Hz),
1.22–1.56 (m, 20H), 2.01–2.12 (m, 2H), 2.17 (br s, 1H),
2.30–2.39 (m, 2H), 2.79–2.87 (m, 1H), 2.92–3.01 (m,
1H); 13C NMR d 14.2, 22.6 (CH3), 22.7, 25.7, 29.5,
29.5, 29.6, 31.9, 37.0, 48.1, 50.1 (CH2), 52.2,
56.6 (CH), 209.5 (C); MS (EI) m/z for C17H33NO: 267
(M+).
4.7.1. (4R)-4-Methyl-2-nonyl-6,6-bis-trimethylsilyl-
methyl-[1,3]-oxazinane 24a. Oil; yield: 79%; TLC:
25
D
Rf = 0.64 (AcOEt/cyclohexane 1:9); ½aꢀ ¼ þ17:5 (c
4.9. (2R,4S,6S)-2-Methyl-6-nonylpiperidin-4-ol, (+)-
alkaloid 241D 4
1
1.08, CHCl3); ee = 82%; H NMR d 0.05 (s, 9H), 0.06
(s, 9H), 0.88 (t, 3H, J = 6.8 Hz), 0.93 (d, 1H,
J = 11.2 Hz), 1.04 (d, 3H, J = 6.4 Hz), 1.07–1.51 (m,
21H); 2.88–2.97 (m, 1H), 4.26 (t, 1H, J = 5.2 Hz); 13C
NMR d 0.8, 1.2, 14.2, 22.8 (–CH3), 22.7, 25.1, 26.4,
29.4, 29.6, 29.8, 32.0, 35.0, 36.7 (CH2), 46.2 (CH), 47.3
(CH2), 76.7 (C), 80.8 (CH); MS (ESI) m/z for
C22H49NOSi2: 400 (M+H+).
To a solution of piperidin-4-one 25 (0.15 g, 0.63 mmol)
in methanol (3.7 mL) was added sodium borohydride
(0.04 g, 1.08 mmol, 1.7 equiv). The mixture was stirred
for 10 min and a saturated solution of ammonium chlo-
ride added. The aqueous phase was extracted with
dichloromethane. The organic layers were collected,
dried over MgSO4 and evaporated. The crude product
was purified by flash chromatography (elution gradient:
AcOEt then AcOEt/methanol 9:1) to give 0.10 g of 4.
4.7.2. (4R)-4-Methyl-2-phenyl-6,6-bis-trimethylsilyl-
methyl-[1,3]-oxazinane 24b. Oil; yield: 59%; TLC:
25
White solid; yield: 66%; TLC: Rf = 0.33 (AcOEt + drops
Rf = 0.70 (AcOEt/cyclohexane 2:8); ½aꢀ ¼ ꢁ5 (c 0.91,
D
25
D
of NH4OH 28%); ½aꢀ ¼ þ5:5 (c 1.04, MeOH) {lit.13a
CHCl3); ee = 82%; 1H NMR d 0.00 (s, 9H), 0.04 (s,
9H), 1.01 (d, 1H, J = 14.7 Hz), 1.05 (d, 3H,
J = 6.4 Hz), 1.15–1.24 (m, 3H), 1.37 (d, 1H,
J = 14.8 Hz), 1.51 (dd, 1H, J = 2.9 Hz, J = 13.2 Hz),
5.27 (s, 1H), 7.19–7.46 (m, 5H); 13C NMR d 0.9, 1.2,
22.7 (–CH3), 26.3, 35.0 (CH2), 46.6 (CH), 47.2 (CH2),
77.8 (C), 82.3 (CH), 126.3, 128.1, 128.8 (CH), 141.5
(C); MS (ESI) m/z for C19H34NOSi2: 350 (M+H+).
25
D
½aꢀ ¼ þ6:5 (c 2, MeOH)}; ee = 74%; mp = 106 °C
(lit.13a mp = 108–109 °C); spectral data are identical to
literature;13a MS (ESI) m/z for C15H31NO + H: 242
(M+H+).
4.10. (7R,9S)-7-Methyl-9-undecyl-1,4-dithia-8-aza-
spiro[4.5]decane 28
4.8. General procedure for oxidation of 4-methylenepi-
peridines 19a and 19b
To a solution of piperidin-4-one 27 (0.20 g, 0.75 mmol)
in dry dichloromethane (1.25 mL) was added ethane-
dithiol (0.71 g, 7.5 mmol, 10 equiv) and boron trifluo-
ride etherate (0.24 mL, 1.89 mmol, 2.5 equiv). The
mixture was stirred for 20 h and hydrolyzed with a solu-
tion of sodium hydroxide 1 M. The aqueous phase was
extracted with dichloromethane. The organic layers
were collected, washed with a solution of sodium
hydroxide 1 M, dried over MgSO4 and evaporated.
The crude product was purified by flash chromatogra-
To a solution of 4-methylenepiperidine 19a or 19b pre-
pared from aminohydroxysilane (R)-10a (2.3–2.5 mmol)
in aqueous acetic acid solution (80%, 0.09 mol Lꢁ1) was
added sodium paraperiodate (Na3H3IO6, 2.2 equiv) and
a crystal of osmium tetroxide. The mixture was stirred
for 22 h at 10 °C and acetic acid then evaporated under
vacuum. A saturated solution of sodium hydrogenocar-
bonate was added and the aqueous phase extracted with
dichloromethane. The organic layers were collected,
dried over MgSO4 and evaporated. The crude product
was purified by flash chromatography (elution gradient:
AcOEt/cyclohexane, 25:75–1:1).
phy (AcOEt) to give 0.21 g of 28. Liquid; yield: 82%;
25
D
TLC: Rf = 0.42 (AcOEt); ½aꢀ ¼ þ6 (c 0.80, CHCl3)
25
{lit.14c ½aꢀ ¼ þ7:36 (c 1.3, CHCl3)}; spectral data are
D
identical to literature;14c MS (EI) m/z for C19H37NS2:
343 (M+).

1034
J. Monfray et al. / Tetrahedron: Asymmetry 16 (2005) 1025–1034
6. For recent reviews on the stereoselective synthesis of 2,6-
dialkylpiperidines, see: (a) Husson, H.-P.; Royer, J. Chem.
Soc. Rev. 1999, 28, 383–394; (b) Davis, F. A.; Chao, B.;
Fang, T.; Szenczyck, J. M. Org. Lett. 2000, 2, 1041–1043;
(c) Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett.
1998, 39, 3505–3508; (d) Felpin, F. X.; Lebreton, J. Eur. J.
Org. Chem. 2003, 3693–3712; (e) Molander, G. A.; Dowdi,
E. D.; Pack, S. K. J. Org. Chem. 2001, 66, 4344–4347; (f)
Kuethe, J. T.; Comins, D. L. Org. Lett. 2000, 2, 855–857;
(g) Carbonnel, S.; Troin, Y. Heterocycles 2002, 10, 1807.
7. Schneider, M. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon: Oxford,
1996; Vol. 10, pp 155–299.
8. (a) Cellier, M.; Gelas-Mialhe, Y.; Husson, H.-P.; Perrin,
B.; Remuson, R. Tetrahedron: Asymmetry 2000, 11, 3913–
3919; (b) Chalard, P.; Remuson, R.; Gelas-Mialhe, Y.;
Gramain, J.-C.; Canet, I. Tetrahedron Lett. 1999, 40,
1661–1664, and references cited therein.
9. Monfray, J.; Gelas-Mialhe, Y.; Gramain, J.-C.; Remuson,
R. Tetrahedron Lett. 2003, 44, 5785–5787.
10. (a) Daub, G. W.; Heerding, D. A.; Overman, L. E.
Tetrahedron 1988, 44, 3919–3930; (b) Wu, X.-D.; Khim,
S.-K.; Zhang, X.; Cederstrom, E. M.; Mariano, P. S. J.
Org. Chem. 1998, 63, 841–859.
4.11. (2R,6S)-2-Methyl-6-undecylpiperidine hydrochlo-
ride, (+)-isosolenopsin A hydrochloride 3a
To a solution of 28 (0.20 g, 0.58 mmol) in absolute eth-
anol (9.5 mL) was added Raney nickel (4.38 g). The mix-
ture was placed under hydrogen atmosphere and heated
to reflux for 5 h. After cooling, the reaction mixture was
filtered on VericelÒ membrane and washed with diethyl-
ether. The filtrate was concentrated and the crude prod-
uct was diluted in diethylether (10 mL). To this solution
was added a solution of hydrochloric acid 1 M in diethyl
ether (1 mL). A solid precipitated and was then recrys-
tallized in a mixture of ethanol and AcOEt (1:3).
0.07 g of (+)-isosolenopsin A hydrochloride was ob-
25
D
tained. White needles; yield: 43%; ½aꢀ ¼ þ5:5 (c 1.00,
25
D
CHCl3) {lit.14c ½aꢀ ¼ þ10 (c 1.17, CHCl3)}; ee = 64%;
mp = 135–140 °C (lit.14c mp = 150–151 °C); spectral
data are identical to literature;14b MS (ESI) m/z for
C17H35NCl ꢁ HCl + H: 253 (M+HꢁHCl+).
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