Asymmetric synthesis of the optically active piperidine alkaloid (+)-β-conhydrine

Article abstract of DOI:10.1016/j.tetasy.2008.04.021

A new approach for the stereoselective synthesis of the piperidine alkaloid (+)-β-conhydrine based upon a highly diastereoselective 1,2-nucleophilic addition reaction onto a diastereopure hydrazone and ring-closing metathesis as the key steps has been developed.

Full text of DOI:10.1016/j.tetasy.2008.04.021

Tetrahedron: Asymmetry 19 (2008) 1245–1249
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Tetrahedron: Asymmetry
journal homepage: http://www.elsevier.com/locate/tetasy
Asymmetric synthesis of the optically active piperidine
alkaloid (+)-b-conhydrine
*
Stéphane Lebrun, Axel Couture , Eric Deniau, Pierre Grandclaudon
Université des Sciences et Technologies de Lille 1, LCOP, Bâtiment C3(2), 59655 Villeneuve d’Ascq, France
CNRS, UMR 8009 ‘Chimie Organique et Macromoléculaire’, 59655 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2008
Accepted 22 April 2008
A new approach for the stereoselective synthesis of the piperidine alkaloid (+)-b-conhydrine based upon
a highly diastereoselective 1,2-nucleophilic addition reaction onto a diastereopure hydrazone and ring-
closing metathesis as the key steps has been developed.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
H
Hydroxylated piperidines represent a structural unit frequently
found in many biologically active alkaloids.1 2-(1-Hydroxy-
alkyl)piperidines fall into this category and consequently have
attracted considerable attention from the synthetic community
because of their potent antiviral and antitumor activities.1,2 This
class of compounds includes a- and b-conhydrine; their stereoiso-
mers (Fig. 1) are representatives of the hemlock alkaloids isolated
from the seeds and leaves of the poisonous plant Conium macula-
tum L., whose extracts were used in Ancient Greece to get rid of
criminals and undesirable intellectuals, for example, Socrates.3
Since its isolation in 1856,4 the elucidation of its structure about
eighty years later5 and following the pioneering work of Galinov-
sky et al.,6 various methods for the synthesis of the racemic piper-
idine alkaloid have been documented in the literature.7 However,
the last decade has witnessed a strong incentive in the develop-
ment of asymmetric synthetic approaches to a- and b-conhydrine
and to the stereoisomers 1, ent-1, 2, and ent-2 (Fig. 1) while inter-
est in their chemistry continues unabated. While a number of aux-
iliary supported or chiral pool approaches have been reported for
natural (ꢀ)-a-conhydrine ent-18 and (+)-a-conhydrine 19 much
less attention has been paid to the enantioselective syntheses of
unnatural (ꢀ)-b-conhydrine ent-2;9c,10 to the best of our knowl-
edge only two asymmetric syntheses of (+)-b-conhydrine 29e,11
have appeared in print. Most of these elegant approaches have
been reported to proceed with moderate yields and varying
degrees of success have been claimed with regard to their
enantioselectivities.
N
H
N
H
H
OH
OH
(1)
(-)-α-conhydrine (ent-1)
(+)-α-conhydrine
H
N
N
H
H
H
OH
OH
(+)-β-conhydrine (2)
(-)-β-conhydrine (ent-2)
Figure 1. Stereoisomers of a-and b-conhydrine.
As a result, we became interested in developing a feasible,
straightforward and highly stereoselective synthetic route to (+)-
b-conhydrine 2; herein, we report on the asymmetric synthesis
of this rare unnatural piperidine alkaloid incorporating
1,2-aminoalcohol moiety.
a
2. Results and discussion
Initially, we planned to develop the conceptually new synthetic
route which is briefly depicted in Scheme 1. We anticipated that
the target alkaloid 2 could result from the diastereoselective attack
of an appropriate Grignard reagent on the formylated cyclic hydra-
zide 3 followed by concomitant N–N bond cleavage and reduction
of the carbonyl lactam functionality. The highly functionalized
piperidine 3 could in turn derive from the polyenic hydrazide 4
through a sequence involving RCM reaction, simultaneous hydro-
genation and hydrogenolysis to release the O-benzyl protection,
and ultimate oxidation to trigger off the creation of the required
formyl functionality.
* Corresponding author. Tel.: +33 0 3 20 43 44 32; fax: +33 0 3 20 33 63 09.
E-mail address: axel.couture@univ-lille1.fr (A. Couture).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.021

1246
S. Lebrun et al. / Tetrahedron: Asymmetry 19 (2008) 1245–1249
C@N double bond.12 This procedure allowed the introduction of
the absolute configuration at the a-position to the nitrogen atom,
that is, at C2 in the final compound 2, one of the major challenging
tasks for the total synthesis of the targeted alkaloid. Ring-closing
CHO
H
CH2OBn
H
N
H
O
N
N
O
N
N
H
metathesis of 4 using 1st generation Grubbs catalyst, Cl2Ru-
OH
13
(@CHPh)(PCy3)2 (5 mol %) in refluxing CH2Cl2
proceeded
OMe
OMe
smoothly to provide a very satisfactory yield of the virtually diaste-
reochemically pure cyclic enehydrazide (R,S)-8. Catalytic hydroge-
nation with the concomitant release of the benzyl protection of the
hydroxymethyl group proceeded uneventfully to afford the corre-
sponding hydroxymethylated hydrazide (R,S)-9 in excellent yield.
Subsequent Swern oxidation of 9 delivered the cyclic hydrazide 3
equipped with the mandatory formyl functionality liable to secure
installation of the hydroxypropyl appendage with a stereodefined
configuration. Compound 3 was then allowed to react with ethyl-
magnesium bromide and standard work up delivered alcohol 10
in good yield. However, disappointingly the desired compound
was obtained as a 2:3 mixture of (R,R,S)-10 and (R,S,S)-10 diastere-
oisomers, the diastereoisomeric ratio being unambiguously evalu-
ated by 1H NMR, namely from integration of the C1 proton of the
alkyl chain bearing the hydroxy group. Furthermore all attempts
to isolate pure diastereoisomers by chromatographic treatment
proved unsuccessful.
2
4
3
Scheme 1.
We then embarked on the elaboration of the requisite dien-
ehydrazide 4. The assembly of this highly conjugated precursor,
which is disclosed in Scheme 2, was performed as a single one-
pot reaction from the readily available chiral hydrazone 5. Thus,
hydrazone 5 was submitted to an addition reaction with allyllithi-
um 6 and the intermediate lithium hydrazide salt was trapped
with acryloyl chloride 7 to give straightforward access to the
desired dienehydrazide 4. This polyenic compound was obtained
with satisfactory yield while NMR spectroscopic investigation after
chromatographic treatment indicated the presence of a single dia-
stereoisomer thus confirming the high level of diastereoselectivity
observed upon the initial 1,2 nucleophilic addition process on the
Consequently, we decided to switch our plans and we thus set
out to achieve an alternative strategy to secure the stereochemistry
of the hydroxyalkyl appendage on the piperidine template at an
early stage of the synthesis. The synthesis, which is depicted in
Scheme 3, started from the enantiopure benzyl protected 2-
hydroxypropionaldehyde 11 which was quantitatively converted
into the SAMP hydrazone 12 by simply mixing with enantiomeri-
cally pure hydrazine (S)-(ꢀ)-1-amino-2-(methoxymethyl)pyrro-
Li
1.
2.
6
- 78 ºC to r.t. , 12 h
Cl
7
CH2OBn
O
CH2OBn
H
lidine 13. Sequential treatment with allyllithium
6
and
- 78 ºC to r.t. , 3 h
interception with acryloyl chloride 7 as already described for 4
delivered the diolefin hydrazide 14 as a single diastereoisomer
detectable by NMR (de >95%) after chromatographic treatment. It
is noteworthy that the presence of the SAMP auxiliary in hydrazone
12 was rewarded here: modest selectivities have been indeed
observed upon addition of allyl Grignard reagents onto the
N-benzylaldimine derived from O-benzylglyceraldehyde which is
structurally related to 11.14 This bis-olefin was then subjected to
ring-closing metathesis; this operation delivered a 55:45 mixture
of diastereomerically pure 15 along with the NH free piperidine
16 released from the chiral appendage. N–N bond cleavage of
hydrazides has been very well documented in its synthetic and
mechanistic aspects15 but to the best of our knowledge this
phenomenon is unprecedented.
N
N
O
N
N
49%
OMe
OMe
(2S)-5
(1R,2S)-4
1st generation
Grubbs catalyst
CH2Cl2 , reflux ,12 h
H2 , Pd/C
EtOH , r.t.
12 h
CH2OBn
H
O
N
N
74%
90%
OMe
(6R,2S)-8
Catalytic hydrogenation of the olefinic double bond was accom-
plished with the concomitant retrieval of the hydroxy functionality
and this operation afforded the diastereochemically pure cyclic
hydrazide (R,R,S)-10 almost quantitatively. Interestingly, the exclu-
sive formation of (R,R,S)-10 allowed the assignment of the predom-
inant stereoisomer in the diastereoisomeric mixture obtained in
the synthetic route portrayed in Scheme 2. Finally, the reductive
N–N bond cleavage with the BH3ꢁTHF complex was accomplished
via the simultaneous reduction of the lactam carbonyl functional-
ity to complete the synthesis of the target alkaloid (+)-b-conhy-
drine 2. The absolute configuration of the stereogenic centers
was confirmed to be (1R,2R) and the enantiopurity of our synthetic
(+)-b-conhydrine was clearly established from the sign and value
of the specific rotation and from spectroscopic data that matched
those reported for the unnatural product.9e,11 The same stereoiso-
mer was also obtained by sequential catalytic hydrogenation of
(R,R)-16 followed by standard reduction of the carbonyl group of
the resulting lactam (R,R)-17. The latter procedure markedly im-
proved the yield for the formation of the title compound 2 (29%
vs 56% from 14).
DMSO , (ClCO)2
Et3N , CH2Cl2
CHO
H
CH2OH
H
-78 ºC to r.t. , 2 h
O
N
N
O
N
N
82%
OMe
OMe
3
9
(2R,2S)-
(6R,2S)-
EtMgBr
THF, r.t. , 3 h
O
N
N
O
N
H
N
H
+
OH
OMe
OH
OMe
87%
10
10
(6R,1S,2S)-
(6R,1R,2S)-
Scheme 2.

S. Lebrun et al. / Tetrahedron: Asymmetry 19 (2008) 1245–1249
1247
thetic strategy has significant potential for further extension to
the synthesis of the (1R,2S)-isomer, that is, (+)-a-conhydrine 1, ow-
ing to the availability of the RAMP chiral auxiliary.
NH2
N
OMe
13
BnO
4. Experimental
4.1. General
CH2Cl2 , MgSO4
r.t. , 12 h
N
N
BnO
86%
OMe
O
Melting points were determined on a Reichert-Thermopan
apparatus and are uncorrected. NMR spectra were recorded on a
Bruker AM 300 spectrometer. These were referenced against inter-
nal tetramethylsilane; Coupling constants (J) are rounded to the
nearest 0.1 Hz. Optical rotations were measured on a Perkin Elmer
P 241 polarimeter. Elemental analyses were obtained using a Car-
lo-Erba CHNS-11110 equipment. The silica gel used for flash col-
umn chromatography was Merck Kieselgel of 0.040–0.063 mm
particle size. Petroleum ether (PE, boiling range 40–60 °C), ethyl
acetate (AcOEt), CH2Cl2, and methanol (MeOH) were used as elu-
ents. Dry glassware was obtained by oven-drying and assembled
under Ar atmosphere. Ar was used as the inert atmosphere and
was passed through a drying tube to remove moisture. The glass-
ware was equipped with rubber septa and reagent transfer was
performed by syringe techniques. Tetrahydrofuran (THF) and
diethyl ether (Et2O) were distilled from sodium benzophenone
ketyl immediately before use. Methanol (MeOH) and ethanol
(EtOH) were distilled from magnesium turnings and dichlorometh-
ane (CH2Cl2) from CaH2, before storage on 4 Å molecular sieves.
The hydrazone 516 and the aldehyde 1117 were prepared
according to reported procedures.
11
12
(R)-
(2R,2S)-
Li
1.
2.
6
- 78 ºC to r.t. , 12 h
1st generation
Grubbs catalyst
CH2Cl2
Cl
7
O
O
N
N
H
reflux , 12 h
- 78 ºC to r.t. , 3 h
OBn
OMe
44%
14
(1R,1R,2S)-
O
N
N
O
N
H
H
H
+
OBn
OMe
OBn
(6R,1R)-16 (37%)
4.2. (2R,2S)-(ꢀ)-(E)-N-(2-Benzyloxybutylidene)-N-(2-
(6R,1R,2S)-15 (45%)
methoxymethylpyrrolidin-1-yl)amine 12
H2 , Pd/C
92%
H2 , Pd/C
EtOH ,
r.t.
(S)-1-Amino-2-methoxymethylpyrrolidine 13 (SAMP, 2.34 g,
0.018 mol, 1.2 equiv) and MgSO4 (0.5 g) were added to a solution
of the aldehyde (R)-11 (2.67 g, 0.015 mol) in CH2Cl2 (20 mL). The
mixture was stirred at rt for 12 h, filtered and after evaporation
of the solvent, the crude product was purified by flash column
chromatography on silica gel using AcOEt–PE (20:80) as eluent to
afford the hydrazone (2R,2S)-12 (4.48 g, 86%) as a colorless oil.
EtOH , r.t.
12 h
95%
12 h
O
N
H
O
N
H
N
H
OH
OH
OMe
20
½aꢂD ¼ ꢀ31:4 (c 2.0, CHCl3). 1H NMR (CDCl3, 300 MHz): d 0.96 (t,
17
(6R,1R)-
J = 7.4 Hz, 3H, CH3), 1.63–1.99 (m, 6H, 4HSMP + CH2), 2.78–2.86
(m, 1H), 3.31–3.39 (m, 1H), 3.41 (s, 3H, OCH3), 3.47–3.61 (m,
3H), 3.78–3.83 (m, 1H), 4.46 (d, J = 11.9 Hz, 1H, OCH2Ph), 4.62 (d,
J = 11.9 Hz, 1H, OCH2Ph), 6.41 (d, J = 7.3 Hz, 1H, CH@N), 7.22–
7.36 (5H, m, Harom). 13C NMR (CDCl3, 75 MHz): d 9.9, 22.2, 26.6,
27.5, 49.6, 59.3, 63.0, 70.2, 74.6, 80.8, 127.3, 127.9, 128.3, 136.6,
139.0. Anal. Calcd for C17H26N2O2: C, 70.31; H, 9.02; N, 9.65. Found:
C, 70.15; H, 9.16; N, 9.60.
LiAlH4
THF
BH3,THF
(6R,1R,2S)-10
Δ , 4 h
Δ , 12 h
80%
68%
N
H
H
OH
4.3. General procedure for the synthesis of dienehydrazides 4
and 14
2
Scheme 3.
Phenyllithium (1.8 M in dibutylether, 1.11 mL, 2 mmol) was
added dropwise to a solution of allyltriphenyltin (780 mg, 2 mmol)
in Et2O (10 mL). After stirring at room temperature for 30 min, the
suspension was cooled at ꢀ78 °C and a solution of hydrazones 5 and
12 (2 mmol) in diethyl ether (3 mL) was added dropwise by syringe.
The reaction mixture was stirred at ꢀ78 °C for 40 min then allowed
to warm to rt and stirred for an additional 12 h. The reaction mix-
ture was then recooled to ꢀ78 °C and acryloyl chloride (6 mmol,
545 mg) was added dropwise. After stirring at this temperature
for 30 min, the reaction mixture was allowed to warm to rt over
3 h. Water (10 mL) was added and the mixture was filtered and
extracted with CH2Cl2 (3 ꢃ 20 mL). The combined organic extracts
were dried over MgSO4, the solvent was removed under vacuum,
3. Conclusion
In conclusion, we have developed a simple and direct route for
the synthesis of (+)-b-conhydrine. The key steps are a highly dia-
stereoselective 1,2-nucleophilic addition process applied to a dia-
stereopure hydrazone equipped with
a stereodefined chiral
appendage, followed by RCM to form the piperidine ring system.
We believe that this conceptually new approach could be extended
to a range of analogues with varying sizes and that the formation of
unsaturated hydrazide intermediates could be exploited for further
synthetic planning; for example, including functionalization, but
not limited to epoxidation and dihydroxylation. Finally, the syn-

1248
S. Lebrun et al. / Tetrahedron: Asymmetry 19 (2008) 1245–1249
and the product was purified by flash column chromatography on
silica gel using AcOEt–PE (20:80) as eluent to afford dienehydr-
azides 4 (352 mg, 49%) and 14 (340 mg, 44%) as a yellow oil.
J = 11.6 Hz, 1H, OCH2Ph), 4.63 (d, J = 11.6 Hz, 1H, OCH2Ph), 5.71
(dd, J = 1.9, 9.8 Hz, 1H, CH@), 6.28–6.34 (m, 1H, CH@), 7.21–7.35
(m, 5H, Harom). 13C NMR (CDCl3, 75 MHz): d 10.9, 22.8, 23.5, 24.1,
27.4, 51.9, 58.7, 58.8, 60.0, 72.5, 75.4, 80.6, 125.4, 127.7, 128.0,
129.0, 136.2, 138.4, 163.8. Anal. Calcd for C21H30N2O3: C, 70.36;
H, 8.44; N, 7.81. Found: C, 70.58; H, 8.49; N, 7.69.
4.3.1. (1R,2S)-(ꢀ)-N-[1-(Benzyloxymethyl)but-3-enyl]-N-(2-
methoxymethylpyrrolidin-1-yl)acrylamide 4
20
½aꢂD ¼ ꢀ32:5 (c 0.92, CHCl3); 1H NMR (CDCl3, 300 MHz): 1.65–
1.89 (m, 4H, HSMP), 2.63–2.93 (m, 5H), 3.15–3.41 (m, 6H, HSMP),
3.79 (dd, J = 5.4, 9.5 Hz, 1H, CH2O), 4.11 (dd, J = 6.9, 9.5 Hz, 1H,
CH2O), 4.52 (s, 2H, OCH2Ph), 5.04–5.18 (m, 2H, Hvinyl), 5.59 (dd,
J = 2.3, 10.4 Hz, 1H, Hvinyl), 5.73–5.86 (m, 1H, Hvinyl), 6.30 (dd,
J = 2.3, 17.2 Hz, 1H, Hvinyl), 7.14 (dd, J = 10.5, 17.2 Hz, 1H, Hvinyl),
7.23–7.38 (m, 5H, Harom). 13C NMR (CDCl3, 75 MHz): d 21.2, 25.7,
35.4, 51.9, 56.3, 58.6, 58.8, 70.9, 73.2, 73.3, 117.4, 126.3, 127.5,
127.8, 128.3, 129.2, 135.4, 138.1, 169.3. Anal. Calcd for C21H30N2O3:
C, 70.36; H, 8.44; N, 7.81. Found: C, 70.29; H, 8.51; N, 8.02.
4.4.3. (6R,1R)-(+)-6-(1-Benzyloxypropyl)-5,6-dihydro-1H-
pyridin-2-one 16
20
½aꢂD ¼ þ15:1 (c 0.99, CHCl3); 1H NMR (CDCl3, 300 MHz): 0.98 (t,
J = 7.5 Hz, 3H, CH3), 1.43–1.61 (m, 2H, CH2), 2.11–2.24 (m, 1H,
CH2), 2.28–2.41 (m, 1H, CH2), 3.34–3.42 (m, 1H), 3.65–3.71 (m,
1H), 4.44 (d, J = 11.2 Hz, 1H, OCH2Ph), 4.66 (d, J = 11.2 Hz, 1H,
OCH2Ph), 5.91–5.98 (m, 2H, NH + CH@), 6.56–6.63 (m, 1H, CH@),
7.30–7.39 (m, 5H, Harom). 13C NMR (CDCl3, 75 MHz): d 7.8, 21.7,
26.5, 52.4, 71.5, 81.4, 124.8, 127.8, 127.9, 128.6, 137.6, 139.7,
166.2. Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found:
C, 73.33; H, 7.61; N, 5.66.
4.3.2. (1R,1R,2S)-(ꢀ)-N-[1-(1-Benzyloxypropyl)but-3-enyl]-N-
(2-methoxymethylpyrrolidin-1-yl)acrylamide 14
20
½aꢂD ¼ ꢀ9:3 (c 1.54, CHCl3); 1H NMR (CDCl3, 300 MHz): 1.02 (t,
4.5. General procedure for the synthesis of piperidin-2-ones 9,
10 and 17
J = 7.3 Hz, 3H, CH3), 1.41–1.93 (m, 6H), 2.47–2.53 (m, 1H), 2.75–
3.18 (m, 5H), 3.20–3.35 (m, 5H), 4.16–4.24 (m, 1H), 4.48 (d,
J = 11.0 Hz, 1H, OCH2Ph), 4.52 (d, J = 11.0 Hz, 1H, OCH2Ph), 5.03–
5.18 (m, 2H, Hvinyl), 5.61 (dd, J = 2.4, 10.5 Hz, 1H, Hvinyl), 5.72–
5.85 (m, 1H, Hvinyl), 6.33 (dd, J = 2.4, 17.1 Hz, 1H, Hvinyl), 7.13 (dd,
J = 10.5, 17.1 Hz, 1H, Hvinyl), 7.24–7.39 (m, 5H, Harom). 13C NMR
(CDCl3, 75 MHz): d 9.2, 21.5, 25.4, 26.7, 36.2, 51.8, 58.9, 59.0,
60.2, 73.7, 74.1, 79.2, 117.0, 126.3, 127.3, 128.0, 128.1, 136.1,
136.3, 137.2, 169.6. Anal. Calcd for C23H34N2O3: C, 71.47; H, 8.87;
N, 7.25. Found: C, 71.61; H, 8.59; N, 7.03.
A solution of enehydrazides 8, 15, 16 (1.0 mmol) in EtOH
(15 mL) was stirred with activated Pd/C (10%, 15 mg) under H2 (1
atm) at rt for 12 h at which time TLC indicated complete consump-
tion of the starting material. The mixture was filtered on a pad of
Celite that was further eluted with EtOH (30 mL) and CH2Cl2
(30 mL). The filtrate was concentrated under vacuum and purifica-
tion of the residue by column chromatography on silica gel using
AcOEt–PE (80:20) as eluent gave piperidin-2-ones 9 (218 mg,
90%), 10 (256 mg, 95%) and 17 (144 mg, 92%) as a yellow oil.
4.4. General procedure for the ring-closing metathesis of
dienehydrazides 4, 14
4.5.1. (6R,2S)-(ꢀ)-6-Hydroxymethyl-1-(2-methoxy-
methylpyrrolidin-1-yl)piperidin-2-one 9
20
A solution of the dienehydrazides 4 and 14 (1 mmol) and the
first generation Grubbs catalyst (0.05 mmol, 5 mol %) in anhydrous
CH2Cl2 (10 mL) was refluxed for 12 h under Ar (reaction monitored
by TLC). The reaction mixture was concentrated under vacuum and
the residue was purified by column chromatography on silica gel
using AcOEt–PE (40:60) as eluent.
½aꢂD ¼ ꢀ23:4 (c 0.80, CHCl3); 1H NMR (CDCl3, 300 MHz): 1.33–
1.81 (m, 6H), 1.94–2.38 (m, 4H), 3.07–3.15 (m, 1H), 3.24–3.31
(m, 5H, HSMP), 3.35 (dd, J = 3.6, 9.7 Hz, 1H), 3.48–3.56 (m, 2H),
3.64–3.74 (m, 2H), 3.80–3.85 (m, 1H). 13C NMR (CDCl3, 75 MHz):
d 19.2, 23.4, 27.1, 27.3, 33.7, 53.5, 58.8, 60.3, 64.1, 67.3, 75.1,
168.9. Anal. Calcd for C12H22N2O3: C, 59.48; H, 9.15; N, 11.56.
Found: C, 59.66; H, 8.96; N, 11.44.
Ring-closing metathesis of 4 afforded enehydrazide 8 (244 mg,
74%) as a yellow oil.
For the ring-closing metathesis of 14, chromatographic treat-
ment furnished two fractions containing enehydrazide 15
(242 mg, 45%) as a yellow oil and enamide 16 (136 mg, 37%) as a
colorless oil.
4.5.2. (6R,1R,2S)-(+)-6-(1-Hydroxypropyl)-1-(2-methoxy-
methylpyrrolidin-1-yl)piperidin-2-one 10
20
½aꢂD ¼ þ24:1 (c 0.54, CHCl3); 1H NMR (CDCl3, 300 MHz): 1.00 (t,
J = 7.3 Hz, 3H, CH3), 1.43–1.91 (m, 9H), 2.15–2.22 (m, 1H), 2.31 (t,
J = 6.5 Hz, 2H, CH2C@O), 3.12–3.21 (m, 2H, HSMP), 3.26–3.44 (m, 6H,
4.4.1. (6R,2S)-(ꢀ)-6-Benzyloxymethyl-1-(2-methoxymethyl-
pyrrolidin-1-yl)-5,6-dihydro-1H-pyridin-2-one 8
HSMP), 3.61–3.68 (m, 1H), 4.05–4.12 (m, 1H), 6.24 (br s, 1H, OH).
13C NMR (CDCl3, 75 MHz): d 9.4, 19.5, 23.4, 26.1, 27.1, 27.4, 34.3,
50.3, 58.7, 60.3, 65.2, 75.4, 75.9, 170.6. Anal. Calcd for C14H26N2O3:
C, 62.19; H, 9.69; N, 10.36. Found: C, 61.94; H, 9.87; N, 10.21.
20
½aꢂD ¼ ꢀ7:0 (c 0.30, CHCl3); 1H NMR (CDCl3, 300 MHz): 1.48–
1.53 (m, 1H, HSMP), 1.64–1.77 (m, 1H, HSMP), 1.93–2.11 (m, 2H,
HSMP), 2.52–2.71 (m, 2H, CH2), 3.04–3.13 (m, 1H), 3.31–3.36 (m,
6H, HSMP), 3.52–3.65 (m, 2H, HSMP), 3.74–3.96 (m, 2H, CH2O),
4.50 (d, J = 11.8 Hz, 1H, OCH2Ph), 4.56 (d, J = 11.8 Hz, 1H, OCH2Ph),
5.79 (m, 1H, Hvinyl), 6.31–6.38 (m, 1H, Hvinyl), 7.24-7.37 (m, 5H,
4.5.3. (6R,1R)-(+)-6-(1-Hydroxypropyl)piperidin-2-one 17
20
½aꢂD ¼ þ15:3 (c 0.84, CHCl3); 1H NMR (CDCl3, 300 MHz): 1.02 (t,
J = 7.3 Hz, 3H, CH3), 1.31–1.44 (m, 2H, CH2), 1.53–1.70 (m, 2H, CH2),
H
arom). 13C NMR (CDCl3, 75 MHz): d 23.1, 26.6, 27.2, 52.8, 58.9,
1.88–2.01 (m, 2H, CH2), 2.17–2.29 (m, 1H, CH2), 2.35–2.48 (m, 1H,
60.4, 60.7, 68.9, 73.3, 76.5, 125.8, 127.6, 127.7, 128.4, 137.2,
138.0, 162.9. Anal. Calcd for C19H26N2O3: C, 69.06; H, 7.93; N,
8.48. Found: C, 69.17; H, 8.09; N, 8.62.
CH2), 3.19–3.31 (m, 2H), 4.04 (br s, 1H, OH), 6.99 (br s, 1H, NH). 13
C
NMR (CDCl3, 75 MHz): d 9.4, 19.9, 25.0, 26.3, 31.1, 57.4, 76.0, 172.8.
Anal. Calcd for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C,
61.26; H, 9.83; N, 8.74.
4.4.2. (6R,1R,2S)-(+)-6-(1-Benzyloxypropyl)-1-(2-methoxy-
methylpyrrolidin-1-yl)-5,6-dihydro-1H-pyridin-2-one 15
4.6. (2S,2R)-(ꢀ)-1-(2-Methoxymethylpyrrolidin-1-yl)-6-oxo-
20
½aꢂD ¼ þ24:7 (c 0.72, CHCl3); 1H NMR (CDCl3, 300 MHz): 0.98 (t,
piperidin-2-carbaldehyde 3
J = 7.2 Hz, 3H, CH3), 1.23–1.37 (m, 2H, CH2), 1.52–1.91 (m, 4H,
HSMP), 2.14–2.25 (m, 1H), 2.51–2.68 (m, 2H, CH2), 3.16–3.35 (m,
A solution of DMSO (320 mg, 4.1 mmol) in CH2Cl2 (2 mL) was
6H, SMP), 3.65–3.71 (m, 1H), 3.78–4.03 (m, 2H), 4.52 (d,
H
added dropwise at ꢀ78 °C to
a solution of oxalyl chloride

S. Lebrun et al. / Tetrahedron: Asymmetry 19 (2008) 1245–1249
1249
(470 mg, 3.72 mmol) in CH2Cl2 (5 mL). The mixture was stirred at
ꢀ78 °C for 30 min, and a solution of alcohol 9 (450 mg, 1.86 mmol)
in CH2Cl2 (5 mL) was added dropwise. After 30 min, Et3N (10 mg,
10 mmol, 5 equiv) was added and the mixture was allowed to
warm to rt and stirred for 2 h. Water (5 mL) was added and the lay-
ers were separated. The aqueous layer was extracted with CH2Cl2
(3 ꢃ 10 mL). The combined organic layers were dried over MgSO4
and concentrated under vacuum. The residue was purified by flash
column chromatography on silica gel using AcOEt as eluent to give
refluxing for 12 h, the reaction mixture was cooled to rt and care-
fully quenched with HCl (3 M, 10 mL). Then CH2Cl2 (20 mL) was
added and the mixture was stirred for 4 h. After separation of the
organic layer, the aqueous layer was extracted with CH2Cl2
(3 ꢃ 15 mL). The combined organic layers were dried over Na2SO4
and concentrated under vacuum. The residue was purified by flash
column chromatography using CH2Cl2-MeOH (50:50) as eluent to
give (+)-b-conhydrine
½aꢂD ¼ þ7:9 (c 0.6, EtOH).
2 (48 mg, 68%) as a colorless oil.
20
20
aldehyde 3 (366 mg, 82%) as a yellow oil. ½aꢂD ¼ ꢀ41:1 (c 2.30,
CHCl3); 1H NMR (CDCl3, 300 MHz): 1.35–1.41 (m, 1H), 1.52–1.64
(m, 3H), 1.78–2.02 (m, 4H), 2.31 (t, J = 6.6 Hz, 2H, CH2C@O),
3.03–3.24 (m, 6H, HSMP), 3.58–3.66 (m, 1H, HSMP), 3.73–3.84 (m,
1H, HSMP), 4.29 (td, J = 2.5, 6.6 Hz, 1H, CHN), 9.54 (d, J = 2.5 Hz,
1H, CHO). 13C NMR (CDCl3, 75 MHz): d 18.7, 22.9, 24.5, 27.1, 33.6,
53.3, 58.6, 60.2, 71.2, 77.1, 168.9, 199.9. Anal. Calcd for
References
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A solution of ethylmagnesium bromide (1.0 M in THF, 1.25 mL,
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ature, the reaction mixture was allowed to warm to rt and
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4.8. Synthesis of b-(+)-conhydrine 2
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4.8.1. Starting from piperidin-2-one 17
A solution of piperidin-2-one 17 (100 mg, 0.64 mmol) in THF
(2 mL) was added slowly to a suspension of LiAlH4 (36 mg,
0.95 mmol) in anhydrous THF (5 mL) at 0 °C under Ar. The resulting
mixture was stirred at reflux for 4 h. After cooling satd aq NH4Cl
(5 mL) was carefully added followed by CH2Cl2 (10 mL). The organ-
ic layer was separated and the aqueous layer was extracted with
CH2Cl2 (2 ꢃ 10 mL). The combined organic layers were dried over
Na2SO4 and concentrated under vacuum. The crude residue was
purified by column chromatography using CH2Cl2-MeOH (50:50)
as eluent to give (+)-b-conhydrine 2 (66 mg, 80%) as a colorless
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20
oil. ½aꢂD ¼ þ8:3 (c 0.9, EtOH).
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4.8.2. Starting from piperidin-2-one 10
BH3ꢁTHF (1 M in THF, 15 equiv, 8,5 mL) was slowly added to a
solution of 10 (150 mg, 0.55 mmol) in dry THF (3 mL) at 0 °C. After