A Novel Route to Chiral trans-6-Alkyl-2-hydroxymethyl-1,2,5,6-tetrahydropyridines by Allylation of Chiral Imines and Ring-Closing Metathesis - Total Synthesis of (-)-3-epi-Deoxoprosopinine

Article abstract of DOI:10.1002/ejoc.200300423

A novel route to enantiomerically pure trans-6-alkyl-2-hydroxymethyl-1,2,5,6-tetrahydropyridines is reported in five steps from Garner's aldehyde with overall yields higher than 35%. This strategy is based on the allylation of chiral imino alcohols formed

Full text of DOI:10.1002/ejoc.200300423

FULL PAPER
A Novel Route to Chiral trans-6-Alkyl-2-hydroxymethyl-1,2,5,6-
tetrahydropyridines by Allylation of Chiral Imines and Ring-Closing
Metathesis ؊ Total Synthesis of (؊)-3-epi-Deoxoprosopinine
Francois-Xavier Felpin,[a] Kamal Boubekeur,[b] and Jacques Lebreton*[a]
¸
Keywords: Nitrogen heterocycles / Metathesis / Cyclization / Allylation / Imines
A novel route to enantiomerically pure trans-6-alkyl-2-hy- This new method was used for the first total synthesis of (−)-
droxymethyl-1,2,5,6-tetrahydropyridines is reported in five
steps from Garner’s aldehyde with overall yields higher than
35 %. This strategy is based on the allylation of chiral imino
alcohols formed in situ followed by a ring-closing metathesis.
3-epi-deoxoprosopinine.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
The therapeutic potential of piperidines has been the sub-
ject of intensive research and various synthetic strategies
have been reported[1]. Consequently, synthesis of this class
of heterocycles is still undergoing considerable improve-
ment and innovation. For example, the efficient chiral syn-
thesis of 2,6-disubstituted piperidines has been developed
in recent years.[2] On the other hand, the chiral synthesis of
the corresponding tetrahydropyridines has attracted much
less attention[3] although its unit occurs in many natural
biologically active compounds.[4] In addition, the double
bond offers an easy access to highly substituted piperidines.
In fact, this lack of interest is due, in part at least, to the
difficulty of controlling regio- and stereochemistry with the
double bond in the right position. Our interest in this field
has been focused on the synthesis of trans-2,6-disubstituted-
1,2,5,6-tetrahydropyridines. Indeed, in connection with our
program directed toward the synthesis of piperidine alka-
loids with biological activity[5], we wish here to describe a
flexible and efficient asymmetric route to the trans-2,6-di-
substituted-1,2,5,6-tetrahydropyridines. The basic strategy
we used involved two key reactions including a dia-
stereoselective allylation of chiral imines and a ring-closing
metathesis (RCM) (Figure 1).
Figure 1. Retrosynthetic analysis
To demonstrate the efficacy of this new methodology, the
first total synthesis of (Ϫ)-3-epi-deoxoprosopinine (2) is
also described in this report (Figure 2).
[a]
`
Laboratoire de Synthese Organique, CNRS UMR 6513,
´
Faculte des Sciences et des Techniques,
`
2 rue de la Houssiniere, B. P. 92208, 44322 Nantes Cedex 03,
France.
Fax: (internat.) ϩ 33-2-51125402
E-mail: lebreton@chimie.univ-nantes.fr
Institut des Materiaux Jean Rouxel, CNRS UMR 6502
[b]
´
´
Universite de Nantes,
`
B. P. 32229, 2 rue de la Houssiniere, 44322 Nantes Cedex 03,
France
Figure 2. Structure of (Ϫ)-3-epi-deoxopropinine (2)
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300423
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Total Synthesis of (Ϫ)-3-epi-Deoxoprosopinine
FULL PAPER
Results and Discussion
of natural products in all enantiomeric forms and demon-
strates the versatility of this strategy. We chose to introduce
a styryl group in the requisite imine for the following re-
asons:
The first aim of our strategy concerned the synthesis of
the chiral amino alcohol 1 (Scheme 1). In our previous
studies,[6] we showed that a Wittig olefination on Garner’s
aldehyde 3 with benzylidene ylide afforded the correspond-
ing styryl derivative 4 as a E/Z (7:3) mixture of isomers in
good yield (85 %). Although the stereochemistry induced
by the double bond was destroyed in the RCM step, (E)-4
and (Z)-4 isomers had to be separated by column chroma-
tography for easier purification, NMR analysis and dr
measurement in the next steps, particularly for the allylation
step (vide infra). Thus, we were pleased to find that the
HornerϪWadworthϪEmmons olefination of 3 using the
semi-stabilized diethyl benzylphosphonate proceeded
stereospecifically to give (E)-4 as the sole isolable product
in 75 % yield. Moreover, this procedure is more convenient
for the preparation of (E)-4 on a large scale (Ͼ 25 mmol).
(1) The styryl group is a good substrate for the RCM re-
action.[7]
(2) The phenyl group represents a sufficiently bulky sub-
stituent to induce a good diastereoselectivity in the al-
lylation step.
The next step involved the formation of an imine by con-
densation of (E)-4 with an aldehyde, followed by allylation
of the CϭN double bond formed. The diastereoselective
addition of organometallic reagents to imines has been
widely described,[8] but principally for chiral imino alcohols
derived from valinol or phenylglycinol. In order to investi-
gate this crucial step, we decided to prepare in situ the imine
derived from the chiral amino alcohol 1 with benzaldehyde
used as the model substrate. The imine was first prepared
in THF by condensation of (E)-4 with benzaldehyde in the
presence of an excess of MgSO4 during 12 h stirring
(Scheme 2). After filtration of the magnesium salts, the re-
sulting solution of the imine 5 was treated with various al-
lylmetals. The results are summarized in Table 1. No reac-
tion was observed with allylzinc bromide and allylcuprate,
while allylzinc bromide catalyzed with cerium chloride hep-
tahydrate[9] gave disappointingly low yields (Ͻ 10 %). In the
case of allylcerium chloride,[10] prepared in situ by stirring
allylmagnesium bromide with cerium chloride, the desired
diethylenic amines were isolated in a mixture of trans-6a/
cis-6a (85:15) with a satisfactory yield (60Ϫ70 %). However,
10Ϫ15 % of the starting materials was also recovered. Fi-
nally, we found that allylmagnesium bromide gave better
results by a careful control of the reaction temperature. In-
deed, after 12 h stirring at Ϫ78 °C the reaction was not
total. After several attempts, we found that the optimum
Scheme 1
The protecting groups were removed from the amine and
hydroxy functions of intermediate 4 by treatment with con-
centrated HCl in methanol to give the corresponding amino
alcohol 1 in nearly quantitative yield (98 %). In spite of its
extensive degradation in air at room temperature, 1 can be
stored at Ϫ20 °C for one year, at least, without detectable
degradation. It should be noted that the opposite enanti-
omers of (E)-1 could be obtained by starting from the (R)-
Garner’s aldehyde 3. This could be useful for the synthesis Scheme 2
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F.-X. Felpin, K. Boubekeur, J. Lebreton
FULL PAPER
Table 1. Diastereoselective allylation with various allylmetals
Entry
Organometallic (equiv.)
Solvent
Yield
trans-6a:cis-6a
1
2
3
4
5
All-ZnBr (3)
THF
Et2O/THF
THF
Et2O/THF
Et2O/THF
No reaction
No reaction
Ͻ 10 %[a]
60Ϫ70 %[b]
85 %[b]
Ϫ
Ϫ
(All)2CuMgBr (3)
All-ZnBr, CeCl3·7H2O (3)
All-CeCl2 (3)
n.d.
85:15[c]
86:14[c]
All-MgBr (3)
[a]
1
[b]
[c]
Yield estimated by H NMR spectroscopy.
Yield of isolated product. Ratios of diastereoisomers measured by 1H NMR spec-
troscopy.
diastereoselectivities and yields were obtained when the re-
action mixture was stirred for 1 h at Ϫ78 °C and then care-
fully warmed up to Ϫ10 °C over a period of 5 h.
To establish the scope and limitations of this method-
ology, various chiral imino alcohols were prepared from
aromatic to hindered aldehydes and were treated as de-
scribed previously with allylmagnesium bromide
(Scheme 3, Table 2).
Table 2. Diastereoselective synthesis of chiral amino alcohols
Entry
R
trans:cis[a] Product Yield (%), trans:cis[b]
1
2
3
4
5
6
Ph
86:14
6a
6b
6c
6d
6e
6f
73:12
62:8
62:8
66:7
68:8
PhCH2CH2 89:11
C6H13
cyclohexyl
isopropyl
C12H25
90:10
90:10
90:10
87:13
56:n.d.
[a]
1
Ratios of diastereoisomers measured by H NMR spectroscopy.
Yield of isolated product.
[b]
In all cases, the trans adduct was preferentially formed
with good diastereoselectivity and correct yield. The good
stereocontrol observed in this reaction can be rationalized
in terms of a chelation-controlled model[11] (Figure 3). One
magnesium cation would be coordinated by a hydroxy
group and the lone pair electrons of the imino nitrogen.
The attack of the magnesium reagent occurs from the less
hindered face (Re face) of the chelate to give the trans ad-
duct as the main product.
The remaining task for the synthesis of the desired tetra-
hydropyridine was the RCM reaction. In recent years, RCM
has emerged as a powerful method for CϪC bond forma-
tion.[12] Its efficiency has been proven in the synthesis of
numerous natural products. However, it is well known that
RCM is ineffective with free amine owing to chelations with
ruthenium.[13] To save one step of protection, we attempted
to carry out RCM in acidic media to form an ammonium
Scheme 3
Figure 3. Stereoselectivity of the diastereoselective addition of allymagnesium bromide over imino alcohols
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2003, 4518Ϫ4527

Total Synthesis of (Ϫ)-3-epi-Deoxoprosopinine
FULL PAPER
derivative without complexation ability[14] (Scheme 4). In and 6e, only the O-carbonylimidazole derivatives were iso-
these conditions, diethylenic amino alcohol 6a exposed to lated. We envisaged that this difficulty could be overcome
second-generation Grubbs’ catalyst 7 gave the expected by the use of a stronger base such as DBU to raise the
tetrahydropyridine 8 in good yield (70 %). However, in spite amine nucleophilicity. This alternative, indeed, led to the
of several successive chromatographic runs on silica gel, the formation of the required oxazolidinones 9d and 9e in excel-
dark brown color of the RCM products indicated a con- lent yield.
tamination by residual ruthenium species.
Having obtained the diethylenic substrate, we considered
the RCM step. Treatment of 9aϪf with the second-genera-
tion Grubbs’ catalyst 7 in refluxing dichloromethane af-
forded the expected tetrahydropyridines 10aϪf in nearly
quantitative yields.
To confirm the relative stereochemistry of our tetra-
hydropyridines 10aϪf, we analyzed the displacement by the
chemical shift of C-2 in 13C NMR on the hydrogenated
derivatives (Scheme 6). Indeed, the C-2 chemical shift of the
trans isomer was generally at 51 ppm whereas the cis isomer
appeared 7 ppm downfield (δ ϭ 58 ppm).[16] This differ-
ence can be attributed to the gauche 1Ϫ4 interaction (also
called the γ-effect) between R and C-2, which is only pos-
sible in the trans isomer (Figure 4).[17] In the case of our
compounds, the 13C NMR spectroscopic data of C-2, in the
range 50.6 to 51.2 ppm, were in total accordance with the
data expected for trans isomers.
Scheme 4
To avoid this problem, we focused our effort on protect-
ing amine and hydroxy functions as oxazolidinones by
treatment of trans-diethylenic amino alcohols with carbon-
yldiimidazole in the presence of Et3N[15] (Scheme 5,
Table 3). However, in the case of more hindered amines 6d
Scheme 6
Figure 4. Conformation of the trans-oxazolidinones
Scheme 5
In addition the spectroscopic data (IR, 1H, 13C) of 8
matched those reported in the literature.[18] The X-ray crys-
tal structure of the 11f derivative confirmed also a trans
relative stereochemistry (vide infra).
Table 3. Formation of the oxazolidinones and RCM reaction
Entry Sub- Base/Solvent
strate Yield (%)
Product RCM
Yield (%)[a]
Product
We demonstrated the synthetic usefulness of this new
methodology through the first total synthesis of (Ϫ)-3-epi-
deoxoprosopinine (2) (Scheme 7). Hydroxylated piperidines
are naturally occurring compounds that exhibit a wide
range of biological activities.[19] Among these, Prosopis al-
kaloids possess interesting properties, including analgesic,
anesthetic and antibiotic activity.[20] While natural products
have been the subject of considerable attention, to the best
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
Et3N/CH2Cl2 (89) 9a
Et3N/CH2Cl2 (97) 9b
Et3N/CH2Cl2 (81) 9c
88
92
89
99
98
99
10a
10b
10c
10d
10e
10f
DBU/THF (80)
DBU/THF (93)
9d
9e
Et3N/CH2Cl2 (91) 9f
[a]
Yield of isolated product.
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F.-X. Felpin, K. Boubekeur, J. Lebreton
FULL PAPER
of our knowledge only a few analogues have been reported
The final step comprises the deprotection of amine and
in the literature. From our point of view, it could be inter- primary hydroxy functions by hydrolysis of the oxazolidi-
esting to investigate the biological properties of some ana- none. This conversion was achieved in nearly quantitative
logues. In this context, by application of our novel method- yield using hard basic conditions and reflux in methanol.
ology, we concentrated on the preparation of (Ϫ)-3-epi-de- In this way, (Ϫ)-3-epi-deoxoprosopinine (2) was obtained in
oxoprosopinine (2).
27 % overall yield and eight steps from the commercially
available Garner’s aldehyde 3.
Conclusion
A novel and general synthesis of trans-2,6-disubstituted
tetrahydropyridines in five steps with overall yields up to 37
% was introduced. Highlights of these synthetic ventures
include a diastereoselective allylation of chiral imines and
an RCM. Furthermore, we demonstrated the versatility of
this strategy by the ease with which the chiral amino al-
cohol 1 was obtained in its (R) or (S) form. Its synthetic
usefulness was illustrated by the short and efficient total
synthesis of the (Ϫ)-3-epi-deoxoprosopinine (2) in eight
steps and 38 % overall yield. Further application of this
procedure to other polyhydroxylated alkaloids is currently
under investigation.
Scheme 7
Experimental Section
Starting from 10f as described previously, epoxidation of
the double bond with mCPBA gave the endo epoxide 12 as
the major isomer (dr ϭ 90:10), which is easily separated
from the exo minor isomer by flash chromatography. It
should be noted that the use of dimethyldioxirane, gener-
ated from oxone and acetone[21], gave essentially the same
ratio. To provide the hydroxy function in the C-3 position,
the epoxide 12 was opened by Super Hydride in quantitat-
ive yield. To confirm the endo selectivity of the epoxidation
step, an X-ray crystal structure of 13 was determined. As
shown in Figure 5, a cis relation was observed between C-
2 C-3 substituents. In addition, the trans relation between
C-2 C-6 confirms the relative stereochemistry envisaged in
the allylation step (vide supra).
1
General Methods: H NMR and 13C NMR spectra were recorded
at 200 and 50 MHz using residual CDCl3 (δ ϭ 7.26 ppm) and
CDCl3 (δ ϭ 77.16 ppm) as internal standards, respectively. Flash
column chromatography was performed on Merck silica gel (60 A,
230Ϫ400 mesh). HMRS were recorded at the ‘‘Service Commun
d’Analyse Spectroscopique d’Anger’’ or at the ‘‘Centre Regional
Universitaire de Spectroscopie de Rouen’’. Grubbs’ catalyst was
purchased from Strem. All reactions were performed under N2 in
a flame-dried flask using anhydrous solvents. Grignard reagents
were titrated by Watson and Eastham’s method.[22]
˚
´
(4R,1ЈE)-3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4-styryloxazolidine
(4): A solution of the phosphonate (6.95 g, 30.48 mmol) in THF
(100 mL) was treated with BuLi (15.24 mL, 1.6  in hexane,
24.38 mmol), at Ϫ78 °C. The resulting mixture was stirred at Ϫ78
°C for 30 min and then
a solution of aldehyde 3 (3.49 g,
15.24 mmol) in THF (35 mL) was slowly added over 30 min. After
addition, the mixture was stirred at Ϫ78 °C for 2 h and at room
temperature for 12 h . The mixture was quenched with water and
diluted with Et2O. The aqueous phase was extracted with Et2O (3
ϫ). The combined organic extracts were washed with brine (1 ϫ),
dried with anhydrous MgSO4, filtered and concentrated under re-
duced pressure. Purification by flash chromatography (5 % EtOAc/
petroleum ether) and crystallization from petroleum ether gave (E)-
4 (3.46 g, 75 %) as colorless crystals. [α]2D0 ϭ Ϫ83.0 (c ϭ 0.976,
CHCl3) [ref.:[23] [α]2D0 ϭ Ϫ88.7 (c ϭ 1, CHCl3)]. M.p. 85 °C (ref.:[23]
1
m.p. 81 °C). IR (KBr): ν˜ ϭ 1700, 2977 cmϪ1. H NMR: δ ϭ 1.46
(s, 9 H), 1.57 (s, 3 H), 1.68 (s, 3 H), 3.85 (dd, J ϭ 2.3, J ϭ 8.8 Hz,
1 H), 4.13 (dd, J ϭ 6.1, J ϭ 8.8 Hz, 1 H), 4.66 (m, 1 H), 6.17 (dd,
J ϭ 7.6, J ϭ 15.1 Hz, 1 H), 6.52 (d, J ϭ 15.1 Hz, 1 H), 7.24Ϫ7.41
(m, 5 H) ppm. 13C NMR: δ ϭ 23.9, 26.8, 28.6, 59.6, 68.4, 79.9,
94.4, 126.5, 127.7, 128.7, 131.8, 136.8, 152.1 ppm. HRMS (EI)
calcd. for C18H25NO3 [Mϩ] 303.1834, found 303.1834.
Figure 5. Molecular diagram of 13. Atoms of the asymmetric unit
are depicted as ellipsoids at the 50 % probability level
4522
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Total Synthesis of (Ϫ)-3-epi-Deoxoprosopinine
FULL PAPER
(2R,3E)-2-Amino-4-phenylbut-3-en-1-ol (1): A solution of 4 (5.2 g,
6.00 (dd, J ϭ 7.8, J ϭ 16.0 Hz, 1 H), 6.54 (d, J ϭ 16.0 Hz, 1 H),
17.16 mmol) in MeOH (55 mL) was treated with concentrated HCl 7.14Ϫ7.40 (m, 10 H) ppm. 13C NMR: δ ϭ 32.4, 36.6, 38.2, 53.5,
(2.7 mL, 5 % v/v). After stirring at reflux for 4 h, the volatiles were
evaporated under reduced pressure. The residue was taken up with
CH2Cl2 and H2O and the resulting mixture was basified with solid
NaOH. The aqueous layer was extracted with CH2Cl2 (5 ϫ) and
the combined extracts were dried with anhydrous MgSO4. Removal
of the solvent left an oil which was precipitated in CH2Cl2/petro-
leum ether to give 1 (2.77 g, 98 %) as a white solid. Owing to its
rapid degradation in air, 1 was used in the next step without further
purification. [α]2D0 ϭ Ϫ21 (c ϭ 0.162, CHCl3). M.p. 98 °C. IR
60.0, 65.3, 117.7, 125.9, 126.5, 127.8, 128.5, 128.7, 129.5, 132.6,
135.0, 136.7, 142.1 ppm. HRMS (FAB) calcd. for C22H28NO [M
ϩ Hϩ] 322.2171, found 322.2172.
(2R,1ЈR)-4-Phenyl-2-(1-phenylethylbut-3-enylamino)but-3-en-1-ol
(cis-6b): Purification by flash chromatography (30 % EtOAc/petro-
leum ether) gave cis-6b (47 mg, 8 %) as a pale-yellow oil. [α]2D0
ϭ
Ϫ95.0 (c ϭ 0.370, CHCl3). IR (KBr): ν˜ ϭ 1601, 1638, 2924, 3061,
3315 cmϪ1 1H NMR: δ ϭ 1.68Ϫ1.86 (m, 2 H), 2.10Ϫ2.20 (m, 1
.
(KBr): ν˜ ϭ 1591, 2902, 3060, 3282, 3342 cmϪ1 1H NMR: δ ϭ
.
H), 2.35Ϫ2.43 (m, 1 H), 2.58Ϫ2.80 (m, 3 H), 3.33Ϫ3.42 (m, 2 H),
3.59Ϫ3.67 (m, 1 H), 5.11Ϫ5.15 (m, 2 H), 5.71Ϫ5.79 (m, 1 H), 5.93
(dd, J ϭ 6.6, J ϭ 15.9 Hz, 1 H), 6.38 (d, J ϭ 15.9 Hz, 1 H),
7.15Ϫ7.35 (m, 10 H) ppm. 13C NMR: δ ϭ 31.7, 36.0, 39.3, 52.9,
59.8, 64.9, 118.2, 126.0, 126.5, 127.9, 128.5, 128.7, 129.1, 132.6,
135.5, 136.7, 142.4 ppm.
1.99Ϫ2.06 (m, 3 H), 3.42Ϫ3.50 (m, 1 H), 3.65Ϫ3.71 (m, 2 H), 6.17
(dd, J ϭ 6.4, J ϭ 16 Hz, 1 H), 6.57 (d, J ϭ 16 Hz, 1 H), 7.20Ϫ7.40
(m, 5 H) ppm. 13C NMR: δ ϭ 55.5, 66.7, 126.5, 127.8, 128.7, 130.8,
131.0, 136.8 ppm. HRMS (ESI) calcd. for C10H14NO [M ϩ Hϩ]
164.1075, found 164.1076. C10H13NO: calcd. C 73.59, H 8.03, N
8.58; found C 73.64, H 7.95, N 8.49.
(2R,1ЈS)-2-(1-Hexylbut-3-enylamino)-4-phenylbut-3-en-1-ol (trans-
6c): Purification by flash chromatography (40 % EtOAc/petroleum
ether) gave trans-6c (343 mg, 62 %) as a colorless oil. [α]2D0 ϭ Ϫ97.0
Synthesis of Diethylenic Amino Alcohols. General Procedure: The
appropriate aldehyde (1.84 mmol) and MgSO4 were added to a
solution of amino alcohol 1 (300 mg, 1.84 mmol) in THF (4 mL).
The mixture was stirred overnight and filtered. The resulting mix-
ture was slowly added over 30 min to a solution of allylmagnesium
bromide (1  in Et2O, 5.52 mmol) in THF (5 mL) cooled to Ϫ78
°C. After the addition, the mixture was stirred at Ϫ78 °C for 1 h
and slowly warmed up to Ϫ10 °C over 5 h. Then, the reaction
mixture was hydrolyzed with saturated aqueous NH4Cl. The aque-
ous phase was extracted with Et2O (4 ϫ). The combined organic
extracts were washed with brine (1 ϫ), dried with anhydrous
MgSO4 and concentrated in vacuo. The residue was purified by
flash chromatography affording the corresponding diethylenic am-
ino alcohols.
(c ϭ 1.014, CHCl3). IR (KBr): ν˜ ϭ 1639, 2927, 3078, 3317 cmϪ1
.
1H NMR: δ ϭ 0.85 (t, J ϭ 7.0 Hz, 3 H), 1.25Ϫ1.42 (m, 10 H), 2.19
(t, J ϭ 6.3 Hz, 2 H), 2.66Ϫ2.77 (m, 1 H), 3.35Ϫ3.50 (m, 2 H),
3.59Ϫ3.71 (m, 1 H), 5.06Ϫ5.13 (m, 2 H), 5.72Ϫ5.89 (m, 1 H), 6.00
(dd, J ϭ 7.8, J ϭ 15.9 Hz, 1 H), 6.54 (d, J ϭ 15.9 Hz, 1 H),
7.21Ϫ7.41 (m, 5 H) ppm. 13C NMR: δ ϭ 14.2, 22.7, 26.0, 29.5,
32.0, 35.0, 38.5, 54.0, 59.9, 65.2, 117.3, 126.5, 127.8, 128.7, 129.7,
132.3, 135.5, 136.8 ppm. HRMS (EI) calcd. for C20H29NO [Mϩ]
299.2249, found 299.2247.
(2R,1ЈR)-2-(1-Hexylbut-3-enylamino)-4-phenylbut-3-en-1-ol (cis-6c):
Purification by flash chromatography (40 % EtOAc/petroleum
ether) gave cis-6c (44 mg, 8 %) as a colorless oil. [α]2D0 ϭ Ϫ68 (c ϭ
0.233, CHCl3). IR (KBr): ν˜ ϭ 1639, 2927, 3078, 3317 cmϪ1 1H
.
(2R,1ЈR)-4-Phenyl-2-(1-phenylbut-3-enylamino)but-3-en-1-ol (trans-
6a): Purification by flash chromatography (30 % EtOAc/petroleum
ether) gave trans-6a (394 mg, 73 %) as a yellow oil. [α]2D0 ϭ Ϫ90.8
(c ϭ 1.166, CHCl3). M.p. 62 °C. IR (KBr): ν˜ ϭ 1599, 1639, 2925,
3061, 3323 cmϪ1. 1H NMR: δ ϭ 2.14 (br. s, 2 H), 2.45Ϫ2.53 (m, 2
H), 3.39Ϫ3.49 (m, 2 H), 3.65Ϫ3.75 (m, 1 H), 3.82 (t, J ϭ 6.7 Hz,
1 H), 5.02Ϫ5.12 (m, 2 H), 5.60Ϫ5.81 (m, 1 H), 5.99 (dd, J ϭ 7.3,
J ϭ 16 Hz, 1 H), 6.45 (d, J ϭ 16 Hz, 1 H), 7.24Ϫ7.33 (m, 10 H)
ppm. 13C NMR: δ ϭ 42.1, 59.9, 60.0, 64.2, 117.7, 126.5, 127.3,
127.8, 128.6, 129.5, 132.1, 135.1, 136.8, 144.0 ppm. HRMS (EI)
calcd. for C19H20N (M Ϫ CH2OHϩ) 262.1596, found 262.1593.
NMR: δ ϭ 0.84Ϫ0.90 (m, 3 H), 1.11Ϫ1.50 (m, 10 H), 2.05Ϫ2.37
(m, 2 H), 2.74Ϫ2.77 (m, 1 H), 3.41Ϫ3.49 (m, 2 H), 3.67-.3.69 (m,
1 H), 5.11Ϫ5.15 (m, 2 H), 5.71Ϫ5.78 (m, 1 H), 6.00 (dd, J ϭ 7.6,
J ϭ 16 Hz, 1 H), 6.54 (d, J ϭ 16 Hz, 1 H), 7.25Ϫ7.39 (m, 5 H)
ppm. 13C NMR: δ ϭ 14.3, 22.8, 25.4, 29.7, 32.0, 33.9, 39.1, 53.7,
59.9, 64.7, 118.4, 125.1, 126.6, 128.0, 128.8, 132.9, 135.5, 136.4
ppm.
(2R,1ЈR)-2-(1-Cyclohexylbut-3-enylamino)-4-phenylbut-3-en-1-ol
(trans-6d): Purification by flash chromatography (30 % EtOAc/
petroleum ether) gave trans-6d (363 mg, 66 %) as a yellow oil.
[α]D20 ϭ Ϫ106.2 (c ϭ 1.068, CHCl3). IR (KBr): ν˜ ϭ 1638, 2924, 3076,
(2R,1ЈS)-4-Phenyl-2-(1-phenylbut-3-enylamino)but-3-en-1-ol
(cis-
1
3334 cmϪ1. H NMR: δ ϭ 0.89Ϫ1.26 (m, 5 H), 1.37Ϫ1.48 (m, 1
6a): Purification by flash chromatography (30 % EtOAc/petroleum
ether) gave cis-6a (65 mg, 12 %) as a yellow oil. [α]2D0 ϭ Ϫ228.2
(c ϭ 0.953, CHCl3). M.p. 102 °C. IR (KBr): ν˜ ϭ 1600, 1642, 2911,
H), 1.64Ϫ1.79 (m, 5 H), 2.01 (s, 2 H), 2.09Ϫ2.33 (m, 2 H), 2.51
(app. q, J ϭ 5.5 Hz, 1 H), 3.36Ϫ3.49 (m, 2 H), 3.58Ϫ3.70 (m, 1
H), 5.06Ϫ5.14 (m, 2 H), 5.74Ϫ5.91 (m, 1 H), 6.00 (dd, J ϭ 7.5,
J ϭ 15.9 Hz, 1 H), 6.54 (d, J ϭ 15.9 Hz, 1 H), 7.24Ϫ7.41 (m, 5 H)
ppm. 13C NMR: δ ϭ 26.7, 26.8, 29.1, 29.5, 35.9, 41.2, 59.0, 60.3,
65.2, 117.0, 126.5, 127.8, 128.7, 129.9, 132.4, 136.4, 136.9 ppm.
HRMS (EI) calcd. for C20H29NO [Mϩ] 299.2249, found 299.2247.
1
3031, 3198 cmϪ1. H NMR: δ ϭ 2.30 (br. s, 2 H), 2.36Ϫ2.53 (m,
2 H), 3.11Ϫ3.21 (m, 1 H), 3.38Ϫ3.62 (m, 2 H), 3.87 (dd, J ϭ 5.8,
J ϭ 7.9 Hz, 1 H), 5.10Ϫ5.20 (m, 2 H), 5.64Ϫ5.85 (m, 1 H), 5.96
(dd, J ϭ 8.4, J ϭ 16 Hz, 1 H), 6.40 (d, J ϭ 16 Hz, 1 H), 7.27Ϫ7.44
(m, 10 H) ppm. 13C NMR: δ ϭ 43.7, 58.8, 59.2, 65.4, 118.1, 126.5,
127.4, 127.5, 127.9, 128.6, 128.7, 128.7, 133.1, 135.4, 136.7, 143.6
ppm.
(2R,1ЈS)-2-(1-Cyclohexylbut-3-enylamino)-4-phenylbut-3-en-1-ol
(cis-6d): Purification by flash chromatography (30 % EtOAc/petro-
(2R,1ЈS)-4-Phenyl-2-(1-phenylethylbut-3-enylamino)but-3-en-1-ol leum ether) gave cis-6d (38 mg, 7 %) as a yellow oil. [α]2D0 ϭ Ϫ60.2
(trans-6b): Purification by flash chromatography (30 % EtOAc/
(c ϭ 0.772, CHCl3). IR (KBr): ν˜ ϭ 1639, 2924, 3076, 3386 cmϪ1
.
petroleum ether) gave trans-6b (366 mg, 62 %) as a pale-yellow oil. 1H NMR: δ ϭ 1.00Ϫ1.37 (m, 5 H), 1.41Ϫ1.51 (m, 1 H), 1.63Ϫ1.79
[α]2D0 ϭ Ϫ84.7 (c ϭ 1.255, CHCl3). IR (KBr): ν˜ ϭ 1601, 1638, 2924,
(m, 5 H), 1.93Ϫ2.07 (m, 1 H), 2.25Ϫ2.33 (m, 3 H), 2.51 (dt, J ϭ
3.8, J ϭ 8.8 Hz, 1 H), 3.31Ϫ3.44 (m, 2 H), 3.57Ϫ3.70 (m, 1 H),
1
3061, 3315 cmϪ1. H NMR: δ ϭ 1.62Ϫ1.91 (m, 2 H), 2.09 (s br, 2
H), 2.27 (t, J ϭ 6.1 Hz, 2 H), 2.57Ϫ2.85 (m, 3 H), 3.39Ϫ3.53 (m, 5.06Ϫ5.14 (m, 2 H), 5.62Ϫ5.83 (m, 1 H), 5.95 (dd, J ϭ 7.6, J ϭ
2 H), 3.59-.3.72 (m, 1 H), 5.09Ϫ5.17 (m, 2 H), 5.74Ϫ5.91 (m, 1 H), 15.9 Hz, 1 H), 6.51 (d, J ϭ 15.9 Hz, 1 H), 7.28Ϫ7.36 (m, 5 H) ppm.
Eur. J. Org. Chem. 2003, 4518Ϫ4527
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4523

F.-X. Felpin, K. Boubekeur, J. Lebreton
FULL PAPER
13C NMR: δ ϭ 26.8, 26.9, 27.0, 28.3, 29.7, 36.0, 41.0, 58.4, 60.4,
64.9, 117.7, 126.4, 127.8, 128.7, 129.5, 132.2, 136.7, 136.8 ppm.
(4R,1ЈS)-3-(1-Phenylethylbut-3-enyl)-4-styryloxazolidin-2-one (9b):
Purification by flash chromatography (15 % EtOAc/petroleum
ether) gave 9b (337 mg, 81 %) as a colorless oil. [α]2D0 ϭ Ϫ118.1
(c ϭ 1.475, CHCl3). IR (KBr): ν˜ ϭ 1641, 1655, 1747, 2924, 3061
(2R,1ЈR)-2-(1-Isopropylbut-3-enylamino)-4-phenylbut-3-en-1-ol
(trans-6e): Purification by flash chromatography (30 % EtOAc/
petroleum ether) gave trans-6e (324 mg, 68 %) as a yellow oil.
[α]2D0 ϭ Ϫ133.8 (c ϭ 1.11, CHCl3). IR (KBr): ν˜ ϭ 1599, 1639, 2958,
cmϪ1 1H NMR: δ ϭ 1.83Ϫ2.00 (m, 1 H), 2.06Ϫ2.36 (m, 2 H),
.
2.46Ϫ2.57 (m, 1 H), 2.62Ϫ2.77 (m, 2 H), 3.63Ϫ3.78 (m, 1 H),
3.91Ϫ4.04 (m, 1 H), 4.31Ϫ4.45 (m, 2 H), 5.05Ϫ5.13 (m, 2 H),
5.70Ϫ5.91 (m, 1 H), 6.06 (dd, J ϭ 6.9, J ϭ 15.9 Hz, 1 H), 6.57 (d,
J ϭ 15.9 Hz, 1 H), 7.17Ϫ7.38 (m, 10 H) ppm. 13C NMR: δ ϭ 33.3,
38.3, 54.4, 59.1, 67.4, 118.0, 126.2, 126.8, 128.5, 128.6, 128.9, 129.0,
135.0, 135.3, 135.4, 141.4, 157.8 ppm. HRMS (EI) calcd. for
C23H25NO2 [Mϩ] 3471885, found 347.1888.
3077, 3333 cmϪ1 1H NMR: δ ϭ 0.92 (d, J ϭ 6.9 Hz, 6 H),
.
1.71Ϫ1.87 (m, 1 H), 2.05Ϫ2.31 (m, 4 H), 2.52 (dt, J ϭ 5.3, J ϭ
6.1 Hz, 1 H), 3.37Ϫ3.49 (m, 2 H), 3.60Ϫ3.71 (m, 1 H), 5.06Ϫ5.17
(m, 2 H), 5.74Ϫ5.92 (m, 1 H), 6.01 (dd, J ϭ 7.8, J ϭ 16.0 Hz, 1
H), 6.55 (d, J ϭ 16.0 Hz, 1 H), 7.24Ϫ7.41 (m, 5 H) ppm. 13C NMR:
δ ϭ 18.4, 18.9, 30.8, 35.9, 59.6, 60.3, 65.2, 117.0, 126.4, 127.7,
128.7, 129.8, 132.4, 136.3, 136.8 ppm. HRMS (CI/NH3) calcd. for (4R,1ЈS)-3-(1-Hexylbut-3-enyl)-4-styryloxazolidin-2-one (9c): Puri-
C17H26NO [M ϩ Hϩ] 260.2014, found 260.2003.
fication by flash chromatography (15 % EtOAc/petroleum ether)
gave 9c (381 mg, 97 %) as a colorless oil. [α]2D0 ϭ Ϫ119.1 (c ϭ 1.006,
(2R,1ЈS)-2-(1-Isopropylbut-3-enylamino)-4-phenylbut-3-en-1-ol (cis-
6e): Purification by flash chromatography (30 % EtOAc/petroleum
ether) gave cis-6e (38 mg, 8 %) as a yellow oil. [α]2D0 ϭ Ϫ36.2 (c ϭ
CHCl3). IR (KBr): ν˜ ϭ 1641, 1654, 1747, 2928, 3028 cmϪ1 1H
.
NMR: δ ϭ 0.84Ϫ0.91 (m, 3 H), 1.26Ϫ1.30 (m, 8 H), 1.50Ϫ1.60
(m, 1 H), 1.69Ϫ1.84 (m, 1 H), 2.19Ϫ2.33 (m, 1 H), 2.42Ϫ2.57 (m,
1 H), 3.59Ϫ3.74 (m, 1 H), 3.92Ϫ4.05 (m, 1 H), 4.36Ϫ4.49 (m, 2
H), 5.04Ϫ5.13 (m, 2 H), 5.72Ϫ5.89 (m, 1 H), 6.09 (dd, J ϭ 8.7,
J ϭ 15.7 Hz, 1 H), 6.60 (d, J ϭ 15.7 Hz, 1 H), 7.27Ϫ7.40 (m, 5 H)
ppm. 13C NMR: δ ϭ 14.2, 22.7, 26.7, 29.1, 31.7, 31.9, 38.5, 54.5,
58.9, 67.3, 117.6, 126.8, 127.2, 128.7, 129.0, 134.7, 135.5, 135.6,
157.9 ppm. HRMS (EI) calcd. for C21H29NO2 [Mϩ] 327.2198,
found 327.2195.
0.55, CHCl3). IR (KBr): ν˜ ϭ 1599, 1639, 2958, 3077, 3333 cmϪ1
.
1H NMR: δ ϭ 0.92 (d, J ϭ 6.9 Hz, 6 H), 1.76Ϫ2.33 (m, 5 H), 2.54
(dt, J ϭ 3.8, J ϭ 9.3 Hz, 1 H), 3.29Ϫ3.43 (m, 2 H), 3.58Ϫ3.66 (m,
1 H), 5.06Ϫ5.14 (m, 2 H), 5.61Ϫ5.79 (m, 1 H), 5.93 (dd, J ϭ 7.6,
J ϭ 15.9 Hz, 1 H), 6.50 (d, J ϭ 15.9 Hz, 1 H), 7.24Ϫ7.39 (m, 5 H)
ppm. 13C NMR: δ ϭ 17.2, 19.0, 30.0, 35.1, 58.6, 60.3, 64.9, 117.8,
126.4, 127.8, 128.7, 129.5, 132.2, 136.7 ppm.
(2R,1ЈS)-2-(1-Dodecylbut-3-enylamino)-4-phenylbut-3-en-1-ol
(trans-6f): Purification by flash chromatography (30 % EtOAc/
petroleum ether) gave trans-6f (397 mg, 56 %) as a pale-yellow oil.
[α]2D0 ϭ Ϫ58.0 (c ϭ 0.933, CHCl3). IR (KBr): ν˜ ϭ 1600, 1639, 1653,
(4R,1ЈS)-3-(1-Dodecylbut-3-enyl)-4-styryloxazolidin-2-one
(9f):
Purification by flash chromatography (10 % EtOAc/petroleum
ether) gave 9f (449 mg, 91 %) as a colorless oil. [α]2D0 ϭ Ϫ41.3 (c ϭ
1.067, CHCl3). IR (KBr): ν˜ ϭ 1641, 1662, 1750, 2926, 3027 cmϪ1
.
1
2924, 3079, 3320 cmϪ1. H NMR: δ ϭ 0.88 (t, J ϭ 6.7 Hz, 3 H),
1H NMR: δ ϭ 0.88 (t, J ϭ 6.7 Hz, 3 H), 1.25 (br. s, 20 H),
1.48Ϫ1.86 (m, 2 H), 2.18Ϫ2.31 (m, 1 H), 2.41Ϫ2.56 (m, 1 H),
3.58Ϫ3.73 (m, 1 H), 3.92Ϫ4.04 (m, 1 H), 4.35Ϫ4.49 (m, 2 H),
5.03Ϫ5.12 (m, 2 H), 5.64Ϫ5.91 (m, 1 H), 6.08 (dd, J ϭ 8.7, J ϭ
15.9 Hz, 1 H), 6.59 (d, J ϭ 15.9 Hz, 1 H), 7.32Ϫ7.39 (m, 5 H) ppm.
13C NMR: δ ϭ 14.3, 22.8, 26.8, 29.5, 29.7, 29.8, 31.7, 32.1, 38.5,
54.6, 58.9, 67.3, 117.6, 126.8, 127.2, 128.8, 129.0, 134.7, 135.5,
135.6, 157.9 ppm. HRMS (EI) calcd. for C27H41NO2 [Mϩ]
411.3137, found 411.3135.
1.24 (br. s, 22 H), 1.97 (br. s, 2 H), 2.20 (app. t, J ϭ 6.4 Hz, 2
H), 2.66Ϫ2.78 (m, 1 H), 3.35Ϫ3.50 (m, 2 H), 3.59Ϫ3.71 (m, 1 H),
5.06Ϫ5.13 (m, 2 H), 5.71Ϫ5.89 (m, 1 H), 6.00 (dd, J ϭ 7.8, J ϭ
15.9 Hz, 1 H), 6.04 (d, J ϭ 15.9 Hz, 1 H), 7.24Ϫ7.41 (m, 5 H) ppm.
13C NMR: δ ϭ 14.3, 22.8, 26.1, 29.5, 29.8, 32.1, 34.9, 38.4, 54.0,
60.0, 65.2, 117.4, 126.5, 127.8, 128.7, 129.4, 132.5, 135.4, 136.7
ppm. HRMS (CI/NH3) calcd. for C26H44NO [M ϩ Hϩ] 386.3423,
found 386.3442. The cis-6f diastereoisomer was obtained only in
impure form and was not further characterized.
Synthesis of Cyclic Carbamates. General Procedure with DBU:
DBU (536 µL, 3.60 mmol) and carbonyldiimidazole (486 mg,
3.0 mmol) were added to a solution of the appropriate diethylenic
amino alcohols (1.20 mmol) in THF (7 mL). The mixture was
stirred for 60 h and then filtered. Removal of the solvent left a
residue, which was purified by flash chromatography affording the
corresponding cyclic carbamates.
Synthesis of Cyclic Carbamates. General Procedure with Et3N: Et3N
(175 µL, 1.26 mmol) and carbonyldiimidazole (292 mg, 1.80 mmol)
were added to a solution of the appropriate diethylenic amino al-
cohols (1.20 mmol) in CH2Cl2 (7 mL). The mixture was stirred
overnight and then diluted with CH2Cl2 (10 mL) and washed with
0.5  aqueous HCl solution (2 ϫ). The combined aqueous phases
were extracted with CH2Cl2 (3 ϫ). The combined organic extracts
were dried with anhydrous MgSO4 and concentrated under reduced (4R,1ЈR)-3-(1-Cyclohexylbut-3-enyl)-4-styryloxazolidin-2-one (9d):
pressure. Purification by flash chromatography gave the corre-
sponding cyclic carbamates.
Purification by flash chromatography (10 % EtOAc/petroleum
ether) gave 9d (312 mg, 80 %) as a colorless oil. [α]2D0 ϭ Ϫ108.5
(c ϭ 1.310, CHCl3). IR (KBr): ν˜ ϭ 1641, 1654, 1735, 2927, 3062
(4R,1ЈR)-3-(1-Phenylbut-3-enyl)-4-styryloxazolidin-2-one (9a): Puri-
fication by flash chromatography (15 % EtOAc/petroleum ether)
gave 9a (341 mg, 89 %) as a white solid. [α]2D0 ϭ Ϫ148.8 (c ϭ 1.06,
CHCl3). M.p. 88 °C. IR (KBr): ν˜ ϭ 1642, 1654, 1747, 2979, 3062
cmϪ1 1H NMR: δ ϭ 0.82Ϫ0.94 (m, 2 H), 1.02Ϫ1.35 (m, 3 H),
.
1.63Ϫ1.81 (m, 6 H), 2.41Ϫ2.49 (m, 2 H), 3.24Ϫ3.36 (m, 1 H),
3.90Ϫ4.02 (m, 1 H), 4.34Ϫ4.47 (m, 2 H), 5.06Ϫ5.15 (m, 2 H),
5.74Ϫ5.94 (m, 1 H), 6.10 (dd, J ϭ 8.5, J ϭ 15.9 Hz, 1 H), 6.57 (d,
J ϭ 15.9 Hz, 1 H), 7.31Ϫ7.37 (m, 5 H) ppm. 13C NMR: δ ϭ 26.0,
26.3, 30.6, 30.7, 34.8, 38.9, 59.4, 59.9, 67.3, 117.6, 126.8, 127.0,
128.7, 128.9, 134.9, 135.5, 136.1, 158.1 ppm. HRMS (EI) calcd. for
C1H2NO2 [Mϩ], found.
cmϪ1 1H NMR: δ ϭ 2.70Ϫ2.83 (m, 1 H), 2.89Ϫ3.05 (m, 1 H),
.
3.95 (app. t, J ϭ 7.9 Hz, 1 H), 4.11 (app. q, J ϭ 7.9 Hz, 1 H), 4.32
(app. t, J ϭ 7.9 Hz, 1 H), 5.12Ϫ5.24 (m, 3 H), 5.79Ϫ5.99 (m, 1 H),
6.12 (dd, J ϭ 8.7, J ϭ 15.7 Hz, 1 H), 6.41 (d, J ϭ 15.7 Hz, 1 H),
7.39Ϫ7.41 (m, 10 H) ppm. 13C NMR: δ ϭ 36.2, 57.5, 58.1, 67.0,
117.9, 126.7, 126.9, 128.1, 128.3, 128.5, 128.7, 128.9, 134.5, 134.8, (4R,1ЈR)-3-(1-Isopropylbut-3-enyl)-4-styryloxazolidin-2-one
135.4, 137.9, 158.2 ppm. HRMS (EI) calcd. for C13H13NO2 [Mϩ]
Purification by flash chromatography (15 % EtOAc/petroleum
215.0946, found 215.0946. C21H21NO2: calcd. C 78.97, H 6.63, N ether) gave 9e (318 mg, 93 %) as a colorless oil. [α]2D0 ϭ Ϫ117.4
4.39; found C 78.84, H 6.51, N 4.63. (c ϭ 0.680, CHCl3). IR (KBr): ν˜ ϭ 1641, 1656, 1747, 2963, 3028
(9e):
4524
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4518Ϫ4527

Total Synthesis of (Ϫ)-3-epi-Deoxoprosopinine
FULL PAPER
cmϪ1. 1H NMR: δ ϭ 0.96 (d, J ϭ 6.7 Hz, 3 H), 0.98 (d, J ϭ 6.7 Hz, (5R,8aR)-5-Isopropyl-4,5,6,8a-tetrahydroxazolidino[3,4-a]pyridin-3-
3 H), 2.04Ϫ2.18 (m, 1 H), 2.43Ϫ2.51 (m, 2 H), 3.26 (dt, J ϭ 10, one (10e): Purification by flash chromatography (20 % EtOAc/
J ϭ 6.1 Hz, 1 H), 3.92Ϫ4.05 (m, 1 H), 4.37Ϫ4.51 (m, 2 H), petroleum ether) gave 10e (177 mg, 98 %) as a colorless oil. [α]2D0
ϭ
5.07Ϫ5.16 (m, 2 H), 5.76Ϫ5.96 (m, 1 H), 6.12 (ddd, J ϭ 1.2, J ϭ
Ϫ69.9 (c ϭ 0.783, CHCl3). IR (KBr): ν˜ ϭ 1653, 1750, 2963 cmϪ1
.
7.6, J ϭ 15.7 Hz, 1 H), 6.59 (d, J ϭ 15.7 Hz, 1 H), 7.31Ϫ7.42 (m, 1H NMR δ 0.94 (d, J ϭ 6.7 Hz, 3 H), 0.95 (d, J ϭ 6.6 Hz, 3 H),
5 H) ppm. 13C NMR: δ ϭ 20.4, 20.7, 30.0, 35.4, 59.8, 60.7, 67.3, 1.70Ϫ1.88 (m, 1 H), 2.15 (dm, J ϭ 18.1 Hz, 1 H), 2.40 (dm, J ϭ
117.6, 126.8, 127.0, 128.7, 129.0, 134.9, 135.5, 136.0, 158.1 ppm.
18.1 Hz, 1 H), 3.56 (dd, J ϭ 6.9, J ϭ 10.4 Hz, 1 H), 3.91 (dd, J ϭ
HRMS (EI) calcd. for C18H23NO2 [Mϩ] 285.1729, found 285.1730. 6.9, J ϭ 7.9 Hz, 1 H), 4.22Ϫ4.33 (m, 1 H), 4.47 (app. t, J ϭ 8.7 Hz,
1 H), 5.61 (dm, J ϭ 10.4 Hz, 1 H), 5.77Ϫ5.87 (m, 1 H) ppm. 13C
RCM. General Procedure: [Ru]-7 (43 mg, 0.05 mmol) was added at
NMR: δ ϭ 19.8, 20.2, 25.5, 28.5, 49.9, 54.4, 68.1, 124.7, 126.4,
158.0 ppm. HRMS (EI) calcd. for C10H15NO2 [Mϩ] 181.1102,
found 181.1105.
room temperature to
a solution of cyclic carbamates 9a؊f
(1.0 mmol) in CH2Cl2 (200 mL). After stirring at reflux for 1 h the
solution was cooled to room temperature and DMSO (177 µL,
2.5 mmol) was added. The solution was stirred overnight, concen-
trated under reduced pressure and purified by flash chromatogra-
phy to give the tetrahydropyridines 10aϪf.
(5R,8aR)-5-Dodecyl-4,5,6,8a-tetrahydroxazolidino[3,4-a]pyridin-3-
one (10f): Purification by flash chromatography (20 % EtOAc/
petroleum ether) gave 10f (304 mg, 99 %) as a colorless solid.
[α]2D0 ϭ Ϫ20.7 (c ϭ 1.030, CHCl3). M.p. 30 °C. IR (KBr): ν˜ ϭ 1653,
1751, 2924 cmϪ1 1H NMR: δ ϭ 0.88 (t, J ϭ 6.2 Hz, 3 H),
.
(5R,8aR)-5-Phenyl-4,5,6,8a-tetrahydroxazolidino[3,4-a]pyridin-3-
one (10a): Purification by flash chromatography (30 % EtOAc/
petroleum ether) gave 10a (189 mg, 88 %) as colorless crystals.
[α]2D0 ϭ ϩ36.3 (c ϭ 1.076, CHCl3). M.p. 90 °C. IR (KBr): ν˜ ϭ 1646,
1.25Ϫ1.33 (m, 20 H), 1.38Ϫ1.46 (m, 1 H), 1.58Ϫ1.66 (m, 1 H),
1.91 (dm, J ϭ 18.0 Hz, 1 H), 2.52 (dm, J ϭ 18 Hz, 1 H), 3.96 (dd,
J ϭ 6.3, J ϭ 7.9 Hz, 2 H), 4.00Ϫ4.06 (m, 1 H), 4.25Ϫ4.31 (m, 1
H), 4.48 (app. t, J ϭ 8.2 Hz, 1 H), 5.61 (dm, J ϭ 10.2 Hz, 1 H),
5.81Ϫ5.89 (m, 1 H) ppm. 13C NMR: δ ϭ 14.2, 22.8, 26.3, 28.2,
29.4, 29.7, 29.8, 31.6, 32.0, 48.1, 49.5, 68.0, 124.7, 126.6, 158.0
ppm.
1747, 2923 cmϪ1 1H NMR: δ ϭ 2.54Ϫ2.68 (dm, J ϭ 18.3 Hz, 1
.
H), 2.73Ϫ2.90 (dm, J ϭ 18.3 Hz, 1 H), 3.96Ϫ4.07 (m, 2 H),
4.38Ϫ4.50 (m, 1 H), 5.24 (app. d, J ϭ 7.0 Hz, 1 H), 5.64Ϫ5.71 (dm,
J ϭ 11.6 Hz, 1 H), 6.03Ϫ6.13 (m, 1 H), 7.27Ϫ7.41 (m, 5 H) ppm.
13C NMR: δ ϭ 26.4, 49.6, 50.5, 68.0, 125.8, 126.8, 127.3, 127.9,
128.8, 138.9, 157.6 ppm. HRMS (EI) calcd. for C13H17NO2 [Mϩ]
215.0946, found 215.0946. C13H13NO2: calcd. C 72.54, H 6.09, N
6.51; found C 72.50, H 6.31, N 6.43.
Hydrogenation of Tetrahydropyridines 10a؊f. General Procedure:
Pd/C (50.5 mg, 0.05 mmol) was added to a solution of tetrahydro-
pyridines 26Ϫ31 (0.5 mmol) in EtOH (7 mL). The mixture was
stirred under H2 for 4 h. The catalyst was removed by filtration to
give piperidines 11aϪf.
(5R,8aR)-5-Phenylethyl-4,5,6,8a-tetrahydroxazolidino[3,4-a]pyridin-
3-one (10b): Purification by flash chromatography (30 % EtOAc/
5(5R,8aR)-5-Phenyloxazolidino[3,4-a]piperidin-3-one (11a):
(108 mg, quant.) was isolated as a colorless oil. [α]2D0 ϭ ϩ73.1 (c ϭ
petroleum ether) gave 10b (224 mg, 92 %) as a colorless oil. [α]2D0
ϭ
ϩ2.4 (c ϭ 0.970, CHCl3). IR (KBr): ν˜ ϭ 1648, 1749, 2923, 3028
1.380, CHCl3). IR (KBr): ν˜ ϭ 1747, 2938 cmϪ1 1H NMR: δ ϭ
.
1
cmϪ1. H NMR δ 1.69Ϫ2.08 (m, 3 H), 2.49Ϫ2.68 (m, 1 H), 2.72
1.40Ϫ1.54 (m, 2 H), 1.72Ϫ1.82 (m, 2 H), 1.91Ϫ2.00 (m, 1 H),
2.32Ϫ2.40 (m, 1 H), 3.74Ϫ3.88 (m, 1 H), 3.97 (dd, J ϭ 5.8, J ϭ
8.5 Hz, 1 H), 4.48 (app. t, J ϭ 8.4 Hz, 1 H), 5.21 (app. d, J ϭ
5.5 Hz, 1 H), 7.23Ϫ7.42 (m, 5 H) ppm. 13C NMR δ 18.4, 27.5,
30.9, 51.2, 51.8, 68.5, 126.5, 127.1, 128.8, 138.7, 157.7 ppm. HRMS
(EI) calcd. for C13H15NO2 [Mϩ] 217.1103, found 217.1098.
(t, J ϭ 7.5 Hz, 3 H), 3.99 (dd, J ϭ 6.1, J ϭ 7.9 Hz, 1 H), 4.06Ϫ4.18
(m, 1 H), 4.18Ϫ4.30 (m, 1 H), 4.47 (app. t, J ϭ 8.1 Hz, 1 H), 5.63
(dm, J ϭ 10.4 Hz, 1 H), 5.84Ϫ5.92 (m, 1 H), 7.20Ϫ7.35 (m, 5 H)
ppm. 13C NMR: δ ϭ 28.3, 32.8, 33.6, 48.0, 49.4, 68.0, 124.7, 126.1,
126.5, 128.5, 128.6, 141.6, 157.9 ppm. HRMS (EI) calcd. for
C15H17NO2 [Mϩ] 243.1259, found 243.1264 ppm. HRMS (EI)
calcd. for C10H17NO2 [Mϩ] 183.1259, found 183.1258.
(5R,8aR)-5-Phenylethyloxazolidino[3,4-a]piperidin-3-one
(122 mg, quant.) was isolated as a colorless oil. [α]2D0 ϭ ϩ60.9 (c ϭ
0.660, CHCl3). IR (KBr): ν˜ ϭ 1748, 2938 cmϪ1 1H NMR δ
(11b):
(5R,8aR)-5-Hexyl-4,5,6,8a-tetrahydroxazolidino[3,4-a]pyridin-3-one
(10c): Purification by flash chromatography (15 % EtOAc/petro-
leum ether) gave 10c (207 mg, 89 %) as a colorless oil. [α]2D0 ϭ Ϫ30.8
.
1.26Ϫ1.43 (m, 1 H), 1.54Ϫ1.83 (m, 6 H), 1.96Ϫ2.15 (m, 1 H),
2.55Ϫ2.80 (m, 2 H), 3.61Ϫ3.75 (m, 1 H), 3.86 (dd, J ϭ 5.3, J ϭ
8.4 Hz, 1 H), 4.00Ϫ4.09 (1H), 4.28 (app. t, J ϭ 8.4 Hz, 1 H) ppm.
13C NMR: δ ϭ 18.3, 28.0, 31.0, 32.1, 32.9, 49.8, 50.6, 68.3, 126.0,
128.4, 128.5, 141.8, 157.2 ppm. HRMS (EI) calcd. for C15H19NO2
[Mϩ] 245.1416, found 245.1416.
(c ϭ 0.684, CHCl3). IR (KBr): ν˜ ϭ 1648, 1750, 2927, 3034 cmϪ1
.
1H NMR: δ ϭ 0.83Ϫ0.91 (m, 3 H), 1.26Ϫ1.68 (m, 10 H),
1.84Ϫ1.96 (m, 1 H), 2.43Ϫ2.60 (m, 1 H), 3.95 (dd, J ϭ 6.1, J ϭ
7.8 Hz, 1 H), 3.94Ϫ4.06 (m, 1 H), 4.24Ϫ4.33 (m, 1 H), 4.47 (dd,
J ϭ 7.9, J ϭ 8.7 Hz, 2 H), 5.60 (dm, J ϭ 10.2 Hz, 1 H), 5.79Ϫ5.89
(m, 1 H) ppm. 13C NMR: δ ϭ 14.2, 22.7, 26.3, 28.2, 29.1, 31.6,
31.8, 48.0, 49.4, 68.0, 124.7, 126.6, 158.0 ppm. HRMS (EI) calcd.
for C13H21NO2 [Mϩ] 223.1572, found 223.1583.
(5R,8aR)-5-Hexyloxazolidino[3,4-a]piperidin-3-one (11c): (112 mg,
quant.) was isolated as a colorless oil. [α]2D0 ϭ ϩ18.0 (c ϭ 1.340,
CHCl3). IR (KBr): ν˜ ϭ 1752, 2928 cmϪ1 1H NMR δ 0.83Ϫ0.89
.
(m, 3 H), 1.26Ϫ1.33 (m, 10 H), 1.40Ϫ1.47 (m, 1 H), 1.57Ϫ1.70 (m,
4 H), 1.77Ϫ1.81 (m, 1 H), 3.67Ϫ3.81 (m, 1 H), 3.86Ϫ3.95 (m, 1
H), 3.86 (dd, J ϭ 5.8, J ϭ 8.1 Hz, 1 H), 4.37 (app. t, J ϭ 7.9 Hz,
1 H) ppm. 13C NMR: δ ϭ 14.2, 18.2, 22.7, 26.4, 27.6, 29.2, 30.1,
31.1, 31.9, 49.8, 50.7, 68.3, 157.2 ppm. HRMS (EI) calcd. for
C13H23NO2 [Mϩ] 225.1724, found 225.1735.
(5R,8aR)-5-Cyclohexyl-4,5,6,8a-tetrahydroxazolidino[3,4-a]pyridin-
3-one (10d): Purification by flash chromatography (20 % EtOAc/
petroleum ether) gave 10d (219 mg, 99 %) as a colorless solid.
[α]2D0 ϭ Ϫ26.9 (c ϭ 0.975, CHCl3). M.p. 120 °C. IR (KBr): ν˜ ϭ
1
1652, 1747, 2925 cmϪ1. H NMR: δ ϭ 0.82Ϫ1.77 (m, 11 H), 2.18
(dm, J ϭ 18.1 Hz, 1 H), 2.37 (dm, J ϭ 18.1 Hz, 1 H), 3.66 (dd,
J ϭ 6.7, J ϭ 10.2 Hz, 1 H), 3.92 (app. t, J ϭ 7.5 Hz, 1 H),
(5R,8aR)-5-Cyclohexyloxazolidino[3,4-a]piperidin-3-one
(11d):
4.26Ϫ4.31 (m, 1 H), 4.47 (app. t, J ϭ 8.4 Hz, 1 H), 5.62 (dm, J ϭ (108 mg, quant.) was isolated as colorless crystals. [α]2D0 ϭ ϩ19.6
10.2 Hz, 1 H), 5.78Ϫ5.88 (m, 1 H) ppm. 13C NMR: δ ϭ 25.0, 26.0, (c ϭ 0.680, CHCl3). M.p. 68 °C. IR (KBr): ν˜ ϭ 1759, 2932 cmϪ1
26.0, 26.4, 30.0, 30.7, 37.6, 50.0, 53.1, 68.1, 124.7, 126.6, 158.0 ppm.
1H NMR: δ ϭ 0.82Ϫ1.88 (m, 17 H), 3.51Ϫ3.59 (m, 1 H),
.
Eur. J. Org. Chem. 2003, 4518Ϫ4527
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4525

F.-X. Felpin, K. Boubekeur, J. Lebreton
FULL PAPER
3.64Ϫ3.78 (m, 1 H), 3.87 (dd, J ϭ 5.3, J ϭ 8.4 Hz, 1 H), 4.38 (app. (؊)-3-epi-Deoxoprosopine (2): A solution of the oxazolidinone 13
t, J ϭ 8.2 Hz, 1 H) ppm. 13C NMR: δ ϭ 18.4, 24.9, 26.1, 26.1,
26.2, 29.6, 30.3, 31.3, 36.0, 51.0, 54.9, 68.3, 157.5 ppm.
(150 mg, 0.46 mmol) in MeOH (7.5 mL) and 8  NaOH (3 mL)
was heated at 100 °C for 18 h. The mixture was extracted with
CH2Cl2 (3 ϫ), washed with brine, dried with anhydrous MgSO4
and concentrated under reduced pressure. The residue was crys-
tallized from acetone / pentane to give pure (Ϫ)-3-epi-deoxoprosop-
inine (124 mg, 90 %) as a colorless solid. [α]2D0 ϭ Ϫ3.4 (c ϭ 1.957,
(5R,8aR)-5-Isopropyloxazolidino[3,4-a]piperidin-3-one (11e):
(91 mg, quant.) was isolated as a colorless oil. [α]2D0 ϭ ϩ10.8 (c ϭ
0.757, CHCl3). IR (KBr): ν˜ ϭ 1743, 2960 cmϪ1 1H NMR: δ ϭ
.
1
CHCl3). M.p. 64 °C. IR (KBr): ν˜ ϭ 2925, 3335 cmϪ1. H NMR:
0.89 (d, J ϭ 6.6 Hz, 3 H), 0.91 (d, J ϭ 6.6 Hz, 3 H), 1.26Ϫ2.02 (m,
7 H), 3.43 (dd, J ϭ 3.8, J ϭ 10.7 Hz, 1 H), 3.65Ϫ3.77 (m, 1 H),
3.85 (dd, J ϭ 5.2, J ϭ 8.4 Hz, 1 H), 4.36 (app. t, J ϭ 8.4 Hz, 1 H)
ppm. 13C NMR: δ ϭ 18.2, 19.7, 19.9, 25.3, 26.8, 31.1, 50.8, 56.2,
68.2, 157.4 ppm. HRMS (EI) calcd. for C10H17NO2 [Mϩ] 183.1259,
found 183.1258.
δ ϭ 0.87 (t, J ϭ 6.8 Hz, 3 H), 1.25 (br. s, 21 H), 1.40 (m, 1 H),
1.50 (m, 1 H), 1.64Ϫ1.66 (m, 1 H), 1.75Ϫ1.80 (m, 1 H), 1.90Ϫ1.94
(m, 1 H), 2.86Ϫ2.88 (m, 1 H), 3.10 (m, 1 H), 3.17 (br. s, 3 H), 3.72
(dd, J ϭ 7.6, J ϭ 11 Hz, 1 H), 3.84 (dd, J ϭ 5.2, J ϭ 11 Hz, 1 H),
3.92Ϫ3.94 (m, 1 H) ppm. 13C NMR: δ ϭ 4.2, 22.8, 26.3, 26.7, 27.7,
29.5, 29.8, 32.1, 32.7, 50.6, 55.6, 61.4, 67.8 ppm.
(5R,8aR)-5-Dodecyloxazolidino[3,4-a]piperidin-3-one (11f):
(154 mg, quant.) was isolated as colorless crystals. [α]2D0 ϭ ϩ13.1
X-ray Crystallographic Study: Data were collected on an
EnrafϪNonius Kappa CCD diffractometer at 123 K using graph-
(c ϭ 0.673, CHCl3). M.p. 54 °C. IR (KBr): ν˜ ϭ 1744, 2919 cmϪ1
.
1H NMR δ 0.87 (t, J ϭ 6.4 Hz, 3 H), 1.24Ϫ1.33 (m, 21 H),
1.41Ϫ1.45 (m, 1 H), 1.60Ϫ1.70 (m, 5 H), 1.76Ϫ1.80 (m, 1 H),
3.73Ϫ3.78 (m, 1 H), 3.86 (dd, J ϭ 5.6, J ϭ 8.4 Hz, 1 H), 3.90Ϫ3.94
(m, 1 H), 4.37 (t, J ϭ 8.4 Hz, 1 H) ppm. 13C NMR: δ ϭ 14.2,
18.2, 22.8, 26.4,27.6, 29.5, 29.6, 29.8, 30.2, 31.1, 32.0, 49.8, 50.7,
68.4 ppm.
˚
ite-monochromated Mo-Kα radiation (λ ϭ 0.71073 A, and ω
scans). The structure was solved by direct methods using the pro-
gram SHELXS-97[24] and refined by full-matrix least-squares re-
finement on F2 using the program SHELXL-97.[25] Non-hydrogen
atoms were refined anisotropically. The hydrogen atoms, all visible
from the difference Fourier map, were placed in geometrically cal-
culated positions and included in the final refinement using the
‘‘riding’’ model with isotropic temperature factors fixed at 1.2-times
that of the parent atom.
(5R,7S,8R,8aR)-5-Dodecyl-7,8-epoxyoxazolidino[3,4-a]piperidine-3-
one (12): mCPBA (1.93 g, 7.82 mmol) was added to a solution of
the tetrahydropyridine 10f (0.60 g, 1.95 mmol) in CH2Cl2 (25 mL)
cooled to 0 °C. The solution was stirred for 72 h at room tempera-
ture and then hydrolyzed with satd. aqueous NaHCO3/10 % aque-
ous Na2S2O3 (1:1) solution. The aqueous phase was extracted with
CH2Cl2 (3 ϫ), washed with brine, dried with anhydrous MgSO4
filtered and concentrated in vacuo. Purification by flash chroma-
tography (30 % EtOAc/petroleum ether) gave 12 (0.51 g, 81 %) as
colorless crystals which could be recrystallized from pentane.
[α]2D0 ϭ ϩ13.5 (c ϭ 1.513, CHCl3). M.p. 55 °C. IR (KBr): ν˜ ϭ 1751,
Crystal Data for 13: C19H35NO3, Mr ϭ 325.48, monoclinic, space
˚
group P21, a ϭ 6.4649(11), b ϭ 8.6141(12), c ϭ 17.005(2) A, β ϭ
3
100.092(7)°, V ϭ 932.4(2) A , Z ϭ 2, Dcalcd. ϭ 1.159 g·cmϪ3
,
˚
µ(Mo-Kα) ϭ 0.077 mmϪ1. Of 12671 reflections measured, 3790
were unique (Rint ϭ 0.036), with 2058 having I ϭ 2σ(I), R indices
[I ϭ 2σ(I)] R1 ϭ 0.0680, wR2 ϭ 0.1528, GoF on F2 ϭ 1.032 for
209 refined parameters and 1 restraint.
CCDC-213577 (13) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223-336-033; E-mail:
deposit@ccdc.cam.ac.uk].
1
2924 cmϪ1. H NMR: δ ϭ 0.87 (t, J ϭ 6.1 Hz, 3 H), 1.24 (br. s,
20 H), 1.39Ϫ1.63 (m, 2 H), 1.72 (dd, J ϭ 6.3, J ϭ 15.6 Hz, 1 H),
2.25 (dd, J ϭ 7.8, J ϭ 15.6 Hz, 1 H), 3.10 (m, 1 H), 3.31 (app. t,
J ϭ 4.7 Hz, 1 H), 3.71Ϫ3.83 (m, 1 H), 4.10Ϫ4.16 (m, 1 H), 4.30
(dd, J ϭ 5.3, J ϭ 8.5 Hz, 1 H), 4.48 (t, J ϭ 8.5 Hz, 1 H) ppm. 13C
NMR: δ ϭ 14.2, 22.8, 25.7, 26.1, 29.3, 29.5, 29.7, 29.7, 32.0, 33.0,
45.5, 49.0, 50.0, 50.2, 65.2, 157.6 ppm. C19H33NO3: calcd. C 70.55,
H 10.28, N 4.33; found C 70.40, H 10.32, N 4.41.
Acknowledgments
The exo diastereoisomer was obtained only in impure form and
´ ´
This work was supported by the ‘‘Conseil General de la Loire
was not further characterized.
Atlantique’’ the ‘‘Centre National de la Recherche Scientifique’’
`
and the ‘‘Ministere de l’Education Nationale de la Recherche et de
(5R,8S,8aR)-5-Dodecyl-8-hydroxyoxazolidino[3,4-a]piperidine-3-one
(13): Super-Hydride (1  in THF, 1.86 mL, 1.86 mmol) was ad-
ded to a solution of the epoxide 12 (200 mg, 0.62 mmol) in THF
(9 mL) at 0 °C. The resulting mixture was stirred at room tempera-
ture for 2 h, then hydrolyzed with 1  HCl. The aqueous phase was
extracted with Et2O (3 ϫ). The combined organic extracts were
washed with brine, dried with anhydrous MgSO4 and filtered. Re-
moval of solvent left a solid that was precipitated in pentane to
give 13 (197 mg, 98 %) as a white solid. The residue was used with-
out further purification. [α]2D0 ϭ ϩ26.3 (c ϭ 0.820, CHCl3). M.p.
la Technologie’’ with a doctoral fellowship for F.-X. F.
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113 °C. IR (KBr): ν˜ ϭ 1715, 2920, 3397 cmϪ1. H NMR δ 0.87 (t,
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H), 3.79Ϫ3.82 (m, 1 H), 3.92Ϫ3.99 (m, 1 H), 4.30 (t, J ϭ 8.8 Hz,
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4518Ϫ4527

Total Synthesis of (Ϫ)-3-epi-Deoxoprosopinine
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