Efficient access to chiral trans-2,6-dialkyl-1,2,5,6-tetrahydropyridines via allylation of chiral imines and ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(02)02586-8

Enantiomerically pure trans-2,6-dialkyl-1,2,5,6-tetrahydropyridines are synthesized in five steps from Garner's aldehyde in 37-44% overall yield. This strategy is based on the allylation of chiral iminoalcohols formed in situ followed by a ring-closing metathesis.

Full text of DOI:10.1016/S0040-4039(02)02586-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 527–530
Efficient access to chiral
trans-2,6-dialkyl-1,2,5,6-tetrahydropyridines via allylation of
chiral imines and ring-closing metathesis
Franc¸ois-Xavier Felpin and Jacques Lebreton*
Laboratoire de Synthe`se Organique, CNRS UMR 6513, Faculte´ des Sciences et des Techniques, 2 rue de la Houssinie`re,
BP 92208, 44322 Nantes Cedex 3, France
Received 24 October 2002; accepted 14 November 2002
Dedicated to the memory of our colleague Dr. Alain Reliquet who died in September 2002
Abstract—Enantiomerically pure trans-2,6-dialkyl-1,2,5,6-tetrahydropyridines are synthesized in five steps from Garner’s aldehyde
in 37–44% overall yield. This strategy is based on the allylation of chiral iminoalcohols formed in situ followed by a ring-closing
metathesis. © 2002 Elsevier Science Ltd. All rights reserved.
The piperidine ring system is a common structure unit
found in natural products and synthetic compounds
that exhibit a wide range of biological activity.1 It was
recently noted in the literature that during the last 10
years, over 12000 piperidine derivatives have been men-
tioned in clinical or preclinical studies.2 For this reason,
there has been considerable interest in the development
of practical access to piperidinic compounds, particu-
larly in their asymmetric version.3 Nevertheless, to our
knowledge the synthesis of chiral trans-2,6-dialkyl-
1,2,5,6-tetrahydropyridines is a more difficult task and
consequently have attracted much less attention4
although this moiety also occurs in many natural prod-
ucts.5 In addition, the double bond of the ring may be
of great interest for an easy access of highly functional-
ized piperidines. In the course of our studies of the
synthesis of piperidine alkaloids with biological activ-
ity,6 we wish to report here an efficient access
to trans-2,6-dialkyl-1,2,5,6-tetrahydropyridines. Our
approach involves the allylation of chiral imino-
alcohols, followed by a ring-closing metathesis (RCM)
(Fig. 1).
E/Z mixture in 82% yield and with an enantiomeric
excess of 96% for (E)-2.9 Isomers were easily separated
after flash chromatography and recrystallization in
petroleum ether. For a large scale preparation, 2 can
easily be obtained by a straightforward protocol at high
enantiomeric purity (98% ee) from the D- or L
-Serine.10
Acidic cleavage of the dimethyloxazolidine and the Boc
groups afforded the key chiral (R)-aminoalcohol 3 in
good yield (82%). The (S)-enantiomer could easily be
obtained by starting from the (R)-Garner’s aldehyde.
In a one-pot two-step procedure, the condensation of
various aldehydes with 3 afforded the corresponding
imines, which was directly reacted with an excess of
allylmagnesium bromide leading, after work-up, to
Figure 1.
Our methodology started from the commercially avail-
able (S)-Garner’s aldehyde7 (Scheme 1). A Wittig olefi-
nation of 1 without racemization, according to the
procedure described by Horikawa et al.8 led to 2 in 7/3
* Corresponding author. Tel.: +33 2 51 12 54 03; fax: +33 2 51 12 54
02; e-mail: lebreton@chimie.univ-nantes.fr
Scheme 1.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02586-8

528
F.-X. Felpin, J. Lebreton / Tetrahedron Letters 44 (2003) 527–530
Figure 2.
Scheme 2.
Table 1.
Entry
R
trans/cisa
Product
Yield (%),
trans/cisb
1
2
3
4
5
Ph
86/14
89/11
90/10
90/10
90/10
5a/6a
5b/6b
5c/6c
5d/6d
5e/6e
73/12
62/8
62/8
66/7
68/8
PhCH2CH2
C6H13
Cyclohexyl
iPropyl
Scheme 3.
a Ratios of diastereoisomers measured by 1H NMR.
b Yield of isolated product.
derivatives were isolated. We found that Et3N was
sufficient in the case of compounds 5a to 5c but with
the more hindered amines, 5d and 5e, a strong base like
DBU was required. Having a good access to diethylenic
substrates, we turned our attention to the RCM. Thus,
RCM16 using 5% mol of [Ru] proceeded in 1 h with
high yields to give trans-2,6-dialkyl-1,2,5,6-tetra-
hydropyridines 8a–e.
diethylenic amines trans 5a–e and cis 6a–e with good
yields and diastereoselectivities (Scheme 2 and Table
1).11 Diastereoisomers were separated by flash chro-
matography.12 It should be noted that the addition of
organometallic reagents over chiral iminoalcohols
derived from valinol or phenylglycinol have been widely
described in the literature to provide optically active
amines, after the removal of the auxiliary.13 An obvious
advantage of introducing a phenyl group in 2 is that
this substituent is sufficiently bulkier to induce a good
diasteroselectivity in the addition step to give trans
5a–e. Also, the styryl substrates are good candidate for
RCM.
The configuration was definitively established on the
hydrogenated product after treatment with H2 and
Pd/C. Displacement by chemical shift of Ca in 13C
NMR was characteristic of the relative configuration of
the piperidines (Scheme 4). As previously reported for
similar systems, the trans isomer showed a displacement
by chemical shift in the range of 50.6–51.2 ppm,
whereas the cis isomer appeared 7 ppm upfield.17 More-
over, for unambiguous assignment of the trans configu-
ration the compounds 8a and 8c were converted to
known derivatives.18 This difference of Ca chemical
shift between trans and cis isomers can be attributed to
the gauche 1,4-interaction19 (also called the g-effect)
between R and Ca only in the trans isomer. Thus, it
should be noted that, whatever the nature of the R
substituent, the Ca chemical shift of the trans isomer
was in the range of 50.6–51.2 ppm.
Stereoselectivity was slightly higher with aliphatic sub-
stituents than with aromatic ones, probably due to the
lower reactivity of the imine. The trans addition, the
most common in all cases (vide supra), was in accor-
dance with the generally accepted transition state.14
This high stereoselectivity may be attributed by an
internal chelation of the magnesium atom of the Grig-
nard reagent with the hydroxyl group and the imino
nitrogen. Thus, the Grignard reagent attacks the less
hindered face of the imine, the Re face for the trans
addition (Fig. 2).
It is well known that olefin metathesis is incompatible
with free amine owing to catalyst inhibition by the
basic nitrogen.15 Consequently, aminoalcohols were
protected as internal carbamates by treatment with
carbonyldiimidazole (Scheme 3 and Table 2). The use
of additional bases was necessary for the success of this
reaction. Without bases, the intramolecular cyclization
did not occur and only the O-(1-imidazolyl)-carbonyl
In conclusion, the present method provides a new use-
ful way for the stereoselective preparation of trans-2,6-
dialkyl-1,2,5,6-tetrahydropyridines. The versatility of
the strategy was demonstrated by the ease with which
the chiral aminoalcohol 3 was obtained in its R or S
form. Furthermore, applications of the approach to the
synthesis of alkaloids is in progress and will be reported
in due course.

F.-X. Felpin, J. Lebreton / Tetrahedron Letters 44 (2003) 527–530
529
Table 2.
Entry
Substrate
Base/solvent/yield (%)a
Product
RCM yield (%)a
Product
1
2
3
4
5
5a
5b
5c
5d
5e
Et3N/CH2Cl2/89
Et3N/CH2Cl2/97
Et3N/CH2Cl2/81
DBU/THF/80
7a
7b
7c
7d
7e
88
92
89
99
98
8a
8b
8c
8d
8e
DBU/CH2Cl2/93
a Yield of isolated product.
7. For a review, see: Liang, X.; Andersch, J.; Bols, M. J.
Chem. Soc., Perkin Trans. 1 2001, 2136–2157.
8. Imashiro, R.; Sakurai, O.; Yamashita, T.; Horikawa, H.
Tetrahedron 1998, 54, 10657–10670.
9. All enantiomeric excesses were determined by HPLC with
a chiral column (Chiracel OD-H 0.46×15 cm). For (E)-2
separation conditions: elution with a mixture of hexane/i-
PrOH 99:1 v/v; flow rate: 0.5 ml/min; retention time 14.1
min for minor enantiomer and 15.1 min for major.
10. (a) Garner, P.; Park, J.-M. J. Org. Chem. 1987, 52,
2361–2364; (b) McKillop, A.; Taylor, R. J. K.; Watson,
R. J.; Lewis, N. Synthesis 1994, 31–33; (c) Dondoni, A.;
Perrone, D. Synthesis 1997, 527–529.
Scheme 4.
Acknowledgements
11. Other allylic organometallic reagents (Zn, Cu, Ce) were
also tried, but no reaction (with Cu and Zn) or lower
yield with similar diastereoselectivity (with Ce) were
noted.
This program is supported in part by the MRT (grant
for F.-X.F.) and in part by the ‘Conseil Re´gional des
Pays de la Loire’. We are indebted to Drs. Andre´
Guingant and Richard J. Robins for fruitful discussions
and to Marie-Jo Bertrand for skilled technical assis-
tance in HPLC. Thanks are also due to Mr. G. Nouris-
son for the recording of the mass spectra.
12. Preparation of 5a (typical procedure for all diethylenic
aminoalcohols): To the aminoalcohol 3 (300 mg, 1.84
mmol) in THF (5 mL) was added benzaldehyde (195 mg,
1.84 mmol) and MgSO4. The mixture was stirred
overnight and then filtered. The clear solution was slowly
added over 20 min to a solution of AllMgBr (5.52 mL, 1
M in Et2O) in THF (4 mL) cooled to −78°C. The
resulting mixture was stirred 1 h at −78°C and then
slowly allowed to warm up to −10°C over 4 h. The
reaction was quenched with NH4Cl and extracted with
Et2O (4×). The combined extracts were dried over anhy-
drous MgSO4 and concentrated in vacuo. The crude
product was purified by flash chromatography (30%
EtOAc–petroleum ether) to furnish two diastereoisomers
5a (394 mg, 73%) and 6a (65 mg, 12%) as a colorless
solid. trans-5a: mp 62–63°C. [h]2D0=−90.8 (c 1.166,
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CHCl3). IR (KBr) w 1639, 2925, 3061, 3323. H NMR l
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Hz), 6.45 (d, 1H, J=16 Hz), 7.24–7.33 (m, 10H); 13C
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1
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