Modified fry cyanation of a chiral pyridinium salt: Asymmetric syntheses of (-)-coniine and (-)-solenopsin A

Article abstract of DOI:10.1002/ejoc.201300595

The synthesis of chiral 2-cyano-Δ⁴-tetrahydropyridine 5 was carried out in 85 % yield through a modified two-step Fry reductive cyanation of pyridinium salt (+)-3c that used lithium triethylborohydride as the hydride donor. An alkylation-reduction sequence provided 2-alkyl-substituted tetrahydropyridines (+)-10a and (+)-10b in 72-75 % yield after chromatographic purification. This protocol has been applied to the asymmetric syntheses of piperidine alkaloids (-)-coniine and (-)-solenopsin A. The two-step reductive cyanation of chiral pyridinium salt (+)-3c afforded α-amino nitrile 5 in 85 % yield, which underwent an alkylation-reduction sequence followed by removal of the chiral moiety to yield the hemlock alkaloid (-)-coniine as its mandelate salt (>99:1 er). This reaction sequence was also used for the synthesis of the trans-2,6-disubstituted piperidine alkaloid (-)-solenopsin A. Copyright

Full text of DOI:10.1002/ejoc.201300595

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FULL PAPER
α-Amino Nitrile Synthesis
V. H. Vu, L.-A. Jouanno, A. Cheignon,
T. Roisnel, V. Dorcet, S. Sinbandhit,
J.-P. Hurvois* .................................. 1–12
Modified Fry Cyanation of a Chiral Pyrid-
inium Salt: Asymmetric Syntheses of (–)-
Coniine and (–)-Solenopsin A
The two-step reductive cyanation of chiral
pyridinium salt (+)-3c afforded α-amino
nitrile 5 in 85% yield, which underwent an
alkylation–reduction sequence followed by
removal of the chiral moiety to yield the
hemlock alkaloid (–)-coniine as its mandel-
ate salt (Ͼ99:1 er). This reaction sequence
was also used for the synthesis of the trans-
2,6-disubstituted piperidine alkaloid (–)-
solenopsin A.
Keywords: Total synthesis / Alkaloids /
Asymmetric synthesis / Lithiation / Chiral
resolution
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J.-P. Hurvois et al.
FULL PAPER
DOI: 10.1002/ejoc.201300595
Modified Fry Cyanation of a Chiral Pyridinium Salt: Asymmetric Syntheses of
(–)-Coniine and (–)-Solenopsin A
Van Ha Vu,[a] Laurie-Anne Jouanno,[a] Adèle Cheignon,[a] Thierry Roisnel,[b]
Vincent Dorcet,[b] Sourisak Sinbandhit,[c] and Jean-Pierre Hurvois*[a]
Keywords: Total synthesis / Alkaloids / Asymmetric synthesis / Lithiation / Chiral resolution
The synthesis of chiral 2-cyano-Δ4-tetrahydropyridine 5 was
carried out in 85% yield through a modified two-step Fry
reductive cyanation of pyridinium salt (+)-3c that used lith-
ium triethylborohydride as the hydride donor. An alkylation–
reduction sequence provided 2-alkyl-substituted tetra-
hydropyridines (+)-10a and (+)-10b in 72–75% yield after
chromatographic purification. This protocol has been applied
to the asymmetric syntheses of piperidine alkaloids (–)-
coniine and (–)-solenopsin A.
nich addition,[4] an aza-Michael reaction,[5] the stereoselec-
tive reduction of iminium systems,[6] the dynamic resolution
of N-Boc-2-lithiopiperidine,[7] an asymmetric allylic imidate
rearrangement of trifluoroacetimidates,[8] a Mo-catalyzed
asymmetric ring-closing metathesis (RCM),[9] and chemo-
enzymatic resolution methods.[10] As shown in Scheme 1,
chiral N-alkylpyridinium salts 3, which are derived from
(R)-(+)-1-phenylethylamine through the Zincke reaction,
have occupied an interesting but somewhat understated po-
sition.[11] Marazano and Guilloteau-Bertin reported that
the addition of Grignard reagents to 3a (X– = dodecyl sulf-
ate) yielded unstable 1,2-dihydropyridine 4a, which was
converted in a two-step procedure into alkaloids 1 and
2.[11a] However, the regioselectivity of the attack at C-2 de-
creases with bulky Grignard reagents, and the stereoselecti-
vities do not exceed 75:25 dr. As far as the piperidine ring
is concerned, we were interested in transforming pyridinium
salt 3 into a new derivative to allow for substitution at the
α-position to the nitrogen atom. For this purpose, we
sought to reverse the previous reaction sequence. Accord-
ingly, the hydride anion should first be incorporated at C-2
to afford the intermediary 1,2-dihydropyridine 4b (R = H),
which in the presence of cyanide anions could then be con-
verted into α-amino nitrile 5.
Introduction
Piperidine derivatives are found in both the plant and
animal kingdoms and are part of an important broad group
of alkaloids. An ever-growing array of such substances that
display various substitution patterns now exists, and their
syntheses have been the subject of several reviews.[1] For
example, (–)-coniine (1) is a toxic component of Conium
maculatum, and (–)-solenopsin A (2) is one of many non-
proteinaceous piperidine alkaloids that are secreted by the
fire ant Solenopsis invicta (see Figure 1).
Figure 1. Structures of piperidine alkaloids 1 and 2.
The difficulty of isolating more than milligram quantities
from natural sources has led chemists to elaborate new
chemical pathways for the synthesis of compounds 1 and 2.
Recent studies have included the asymmetric alkylation of
imines and iminium or acyl pyridinium salts,[2] metal-cata-
lyzed cyclizations,[3] an enantioselective vinylogous Man-
[a] Sciences Chimiques de Rennes, UMR 6226, CNRS – Université
de Rennes 1,
2 Avenue Leon Bernard, 35043 Rennes Cedex, France
Fax: +33-2-23234425
E-mail: jean-pierre.hurvois@univ-rennes1.fr
Homepage: www.univ-rennes1.fr/
[b] Sciences Chimiques de Rennes, UMR 6226, CNRS-Université
de Rennes 1, Campus de Beaulieu,
Avenue du général Leclerc, 35042 Rennes Cedex, France
[c] Régional de Mesures Physiques de l’Ouest (CRMPO), Campus
de Beaulieu,
Scheme 1. Synthetic approaches to alkaloids 1 and 2 from pyridin-
ium salt 3.
For the second step and on the basis of our previous
experience with α-amino nitrile chemistry, we reasoned that
5 could lead stereoselectively to 2-substituted piperidines
Avenue du général Leclerc, 35042 Rennes Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300595.
2
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Asymmetric Syntheses of (–)-Coniine and (–)-Solenopsin A
through an alkylation–reduction sequence.[12] In this paper, be relatively soluble in this solvent. Thus, the addition of
we report the potential of this approach to demonstrate the KPF6 to an aqueous solution of pyridinium chloride 3b led
concise syntheses of the title alkaloids 1 and 2. The key to the immediate precipitation of the corresponding hexa-
feature incorporates a modified two-step Fry reductive fluorophosphate salt (+)-3c, which was recovered in 75%
–
cyanation of pyridinium salt 3c (X– = PF6 ). To the best of yield.[16]
our knowledge, the lithiation of a chiral nonracemic 2-
cyano-Δ4-tetrahydropyridine system has never been re-
ported in the literature.
Results and Discussion
Synthesis of α-Amino Nitrile 5
Scheme 3. Modified two-step Fry synthesis of α-amino nitrile 5.
Reagents and conditions: (a) KPF6, H2O, room temp. 12 h; (b) Li-
The reaction of 1-(2,4-dinitrophenyl)pyridinium chloride
Et3BH, THF, –70 °C; (c) NaCN/HCN, pH = 9.5.
(Zincke salt 6) with optically pure amines offered an ef-
ficient entry to pyridinium salts 3, which are ideally suited
An evaluation of complex boron hydrides showed that
the best yields and reaction rates were obtained by the slow
addition of 1.1 equiv. of lithium triethylborohydride (1.0 m
solution in THF) to a stirred suspension of pyridinium (+)-
3c in THF at –70 °C. The resulting clear solution of 4b was
warmed to 0 °C, and an oxygen-free NaCN/HCN (pH =
for our chemistry.[13] Hence, the treatment of 6 with 1 equiv.
of (R)-(+)-1-phenylethylamine in n-butanol and heating to
reflux for 24 h provided pyridinium chloride 3b in 75–80%
yield. The synthesis of α-amino nitrile 5 was first carried
out by using the protocol described by Fry in 1963 (see
Scheme 2).[14] Accordingly, pyridinium chloride 3b
9.5) buffer solution was slowly added at that temperature.
(5 mmol) and 6 equiv. of NaCN were stirred at 0 °C for 4 h
The stirring was continued for 12 h to afford α-amino nitrile
in a two-phase system (Et2O/H2O, NaCN, pH = 9.5) in the
presence of 1 equiv. of NaBH4. Workup and purification
of the crude reaction mixture by column chromatography
afforded a mixture of α-amino nitrile 5 (20–25%) and tetra-
5 as an epimeric mixture (50:50) in 85% yield.[17] Crystalli-
zation of the mixture in a biphasic system of diethyl ether
and petroleum ether afforded single crystals {m.p. 76 °C,
[α]D22 = –2.5 (c = 1.1, CHCl3)}[18] that were analyzed by X-
hydropyridine (–)-7 (30–35%). Neither altering the reaction
ray diffraction, which indicated that the less soluble dia-
conditions nor varying the hydride source improved the
stereoisomer (–)-5-A displayed an absolute configuration of
(1ЈR,2S). This study also revealed that the tetrahydropyr-
yields significantly. In addition, the unfavorable 5/7 product
distribution indicated that the entire sequence of reactions
took place in the two-phase system and the reductive decy-
idine ring adopts a half-chair conformation in which the
nitrile group is axially oriented (see Figure 2).[19]
anation of 5 (or the stepwise reduction of 3b into 7) was an
unavoidable process.[15]
Scheme 2. Fry synthesis of α-amino nitrile 5 and tetrahydropyridine
(–)-7. Reagents and conditions: (a) (R)-(+)-1-phenylethylamine, n-
butanol, reflux, 24 h; (b) NaBH4, NaCN/HCN, Et2O/H2O, pH =
9.5, 0 °C.
To overcome this drawback, it seemed a two-step pro-
cedure that included prior formation of unstable 1,2-di-
hydropyridine 4b in an aprotic solvent and its subsequent
transformation upon contact with an aqueous NaCN/HCN
buffer system would efficiently lead to α-amino nitrile 5 (see
Scheme 3). In addition, the exclusive formation of 1,2-di-
hydropyridine 4b required the regiospecific addition of a
hydride anion at C-2. Because this reaction sequence would
be more efficiently carried out in tetrahydrofuran (THF) in
the presence of a stoichiometric amount of a complex
hydride, we thus searched for a pyridinium salt that would were drawn with 60% probability.
Figure 2. ORTEP drawing of α-amino nitrile (–)-5-A. Elipsoid plots
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Synthesis of Tetrahydropyridines 10a and 10b
pendage was best achieved by stirring either (–)-12a or (–)-
12b in methanol in the presence of Pearlman’s catalyst un-
der hydrogen pressure at 5 bars. To avoid handling the toxic
hemlock alkaloid,[23] (R)-(–)-coniine was obtained as its
mandelate salt (+)-13b in 95% yield, and a similar treat-
ment of the (R)-2-methylpiperidine afforded the mandelate
salt (+)-13a.[24] For further chemical purposes [vide infra
the synthesis of (–)-solenopsin A], these complexes were
heated at reflux in acetonitrile in the presence of (Boc)2O
and an excess amount of Hünig’s base to afford N-tert-
butoxycarbonyl (Boc) derivatives (–)-14a and (–)-14b in
very high yields.
To introduce the requisite side chains at C-2, lithiation
of α-amino nitrile 5 (as a 50:50 epimeric mixture) was car-
ried out in THF at –80 °C by the addition of a solution
of lithium diisopropylamide (LDA, see Scheme 4).[20,21] The
addition of iodomethane or n-propyl iodide to the resulting
α-amino carbanion led to the synthesis of unstable quater-
nary aminonitriles 8a and 8b, respectively. Analogous to
previous experiments, reductive decyanation was best
achieved by the introduction of 4 equiv. of NaBH4 at 0 °C
to solutions of α-amino nitriles 8a and 8b (in THF/EtOH,
50:50) to provide 2-alkyl-tetrahydropyridine (+)-10a as a
mixture with its isomer (+)-11a (10a/11a, 90:10) and (+)-
10b as a mixture with its isomer (+)-11b (10b/11b, 85:15),
respectively, in yields ranging from 90–94%.
Scheme 4. Synthesis of 2-alkyl-tetrahydropyridines. Reagents and
conditions: (a) LDA, THF, –80 °C to –20 °C and then CH3I or n-
C3H7I, –80 °C to room temp. (b) NaBH4, THF/EtOH, 50:50, 0 °C.
At this point, the major diastereoisomers (+)-10a and
(+)-10b could be obtained as sole products (72–75%) after
a careful separation by chromatography. The proposed
mechanism to account for the observed stereoselectivities
involves the formation of planar iminium ion 9 in which
incorporation of the hydride anion to the least hindered si
face produces the (R,R) absolute configuration. Conversely,
delivery of the hydride anion to the more sterically de-
manding re face produces the (R,S) absolute configuration.
As expected and observed, the structural differences of the
R alkyl groups do not modify the diastereoisomeric ratio.
Scheme 5. Synthesis of N-Boc-(R)-coniine, N-Boc-(R)-2-methyl-
piperidine, and (–)-solenopsin A. Reagents and conditions: (a) Wil-
kinson’s catalyst (5% by mass), MeOH, H2 (5 bars), 72 h, room
temp.; (b) 20% Pd(OH)2/C, MeOH, 72 h, room temp. and then (S)-
(+)-mandelic acid, Et2O, room temp.; (c) (Boc)2O, Hünig’s base,
CH3CN, reflux, 4 h; (d) sBuLi, TMEDA, Et2O, –80 °C, 2 h and
then CuCN·2LiCl (THF), 1 h; (e) 1-iodoundecane, –80 °C to room
temp.; (f) HCl, room temp., 3 h.
Synthesis of (–)-Solenopsin A
The synthesis of (–)-solenopsin A required the elabora-
tion of a new stereogenic center at C-6, which displayed the
R absolute configuration.[25,26] To place both alkyl substitu-
Synthesis of N-Boc-(R)-Coniine and N-Boc-(R)-2-
Methylpiperidine
In the next step, hydrogenation of the olefinic double ents in a trans disposition, the lithiation procedure that was
bond of tetrahydropyridines (+)-10a and (+)-10b was car- developed by Beak seemed to be the method of choice.[27]
ried out in methanol in the presence of Wilkinson’s catalyst We also believed that the best synthetic approach was to
under hydrogen pressure at 5 bars (see Scheme 5). The selec- incorporate the n-undecyl chain in a single operation.[28]
tive saturation of the olefin did occur, and piperidines (–)- Hence, the treatment of an ethereal solution of (–)-14a with
12a and (–)-12b were obtained as sole products in yields sBuLi in the presence of N,N,NЈ,NЈ-tetramethyl-1,2-ethyl-
ranging from 90 to 93%.[22] The removal of the chiral ap- enediamine (TMEDA) at –80 °C led to the formation of the
4
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Asymmetric Syntheses of (–)-Coniine and (–)-Solenopsin A
corresponding stabilized carbanion (see Scheme 5). Unfor- process, single crystals were obtained by the slow crystalli-
tunately, the use of 1-iodoundecane as the electrophile led zation of α-amino nitrile 18 from a mixture of diethyl ether
to the recovery of the starting material. Therefore, for the and petroleum ether (see Figure 3).
stereoselective introduction of the C-6 undecyl group to
(–)-14a, we turned to the addition of an organocuprate rea-
gent, as recently reported by Dieter.[29] Addition of a THF
solution of CuCN·2LiCl to lithiated (–)-14a ensured the
formation of cuprate 15, to which the addition of 1-iodoun-
decane provided (–)-16 in 65% yield with a 95:5 dr as shown
by proton NMR spectroscopic analysis. The high diastereo-
selectivity of that transformation can be explained by the
prior formation of a conformer in which the methyl group
is axially oriented to release the A1,3 strain between the
methyl group and the N-Boc substituent.[30] Thus, as shown
in Scheme 5, equatorial deprotonation and condensation of
resulting cuprate 15 with the requisite electrophilic reagent
took place with retention of configuration at C-6 to place
both alkyl substituents in a trans geometry. Deprotection of
the carbamate moiety of (–)-16 was routinely carried out by
treatment with gaseous hydrogen chloride in Et2O to yield
a crude reaction mixture, which was purified through a sil-
ica gel column with diethyl ether that was saturated with
gaseous ammonia as the eluent. A trace amount of cis iso-
mer (–)-isosolenopsin A eluted first followed by the more
polar trans isomer (–)-solenopsin A, which was obtained as
a colorless oil in 80% yield. The optical rotation of our
synthetic solenopsin A was consistent with that reported in
Scheme 7. Synthesis and optical resolution of rac-coniine. Reagents
and conditions: (a) Et4BHLi, THF, –70 °C and then NaCN/HCN,
pH = 9.5; (b) LDA, THF, –80 °C to –20 °C and then C3H7I, –80 °C
to room temp.; (c) NaBH4, MeOH, 0 °C; (d) Wilkinson’s catalyst
(5% by mass), MeOH, H2 (5 bars), 72 h, room temp.; (e) 10% Pd/
C, MeOH, 72 h, room temp.; (f) (S)-(+)-mandelic acid, then (R)-
(–)-mandelic acid, Et2O, room temp.
the literature {[α]2D2 = –1.2 (c = 1.0, CHCl3); ref.[28d] [α]D22
–1.2 (c = 1.2, CHCl3)}.
=
Determination of Enantiomeric Ratios of Coniine by Proton
and Carbon NMR Spectroscopy
The enantiomeric composition of our sample of (R)-(–)-
coniine was determined by proton and carbon NMR spec-
troscopy utilizing (R)-(+)-tert-butylphenylphosphanylthioic
acid [(+)-22] as a chiral resolving agent (see Scheme 6).[31–34]
Figure 3. ORTEP drawing of α-amino nitrile 18. Elipsoid plots
were drawn with 60% probability.
Scheme 6. Determination of enantiomeric ratio of (–)-coniine by
proton spectroscopy. Reagents and conditions: (a) NaOH (5%)/
Et2O, 5 min and then (+)-22 (ca. 1.1 equiv.).
Then, two standard solutions of enantioenriched (–)-
coniine (90:10 er and 95:5 er) were prepared by means of
With this purpose in mind, mandelate salt (–)-13b was an accurate gravimetric method by weighing mandelate
obtained in 52% yield (based on isomer content) from the salts (+)-13b and (–)-13b. Both enantiomers of coniine were
optical resolution of rac-coniine, which was synthesized displaced from their respective salts by treatment with base,
from hexafluorophosphate salt 17 (see Scheme 7). In this and stoichiometric amounts of (+)-22 were added to the
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CDCl3): δ = 1.40 (d, J = 6.7 Hz, 3 H), 2.00–2.22 (m, 2 H), 2.38
(ddd, J = 12.0, 8.0, 5.0 Hz, 1 H), 2.59 (dt, J = 12.0, 6.0 Hz, 1 H),
2.86 (dm, J = 17.0 Hz, 1 H), 3.17 (dm, J = 17.0 Hz, 1 H), 3.42 (q,
J = 6.7 Hz, 1 H), 5.60–5.70 (m, 1 H), 5.71–5.80 (m, 1 H), 7.19–
7.35 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.2 (p), 26.6
(s), 47.3 (s), 50.4 (s), 64.9 (t), 125.3 (t), 125.7 (t), 126.9 (t), 127.6
(t), 128.3 (t), 144.2 (q) ppm.
resulting mixtures. The samples were analyzed by proton
NMR spectroscopy (see the detailed procedure in the Sup-
porting Information), and the er values were determined by
integration of the methyl resonance signals of the diastereo-
isomeric salts (–)-coniine·(+)-22 and (+)-coniine·(+)-22,
which displayed two triplet systems at δ = 0.79 and
0.74 ppm (Δδ = 0.05), respectively. When a similar process
was carried out with an optically pure sample of mandelate
(+)-13b, a single triplet was observed, which indicates that
our synthetic sample of coniine had a Ͼ99:1 er.
(1ЈR,2S)-(–)-1-(1-Phenylethyl)-1,2,3,6-tetrahydropyridine-2-carbo-
nitrile [(–)-5-A]: Caution: Because of the possible emission of toxic
HCN, the preparation of the HCN/NaCN buffer should be carried
out under a well-ventilated hood. An oven-dried, one-necked
Schlenk tube (200 mL), which was fitted with a magnetic stirring
bar and connected to an argon inlet, was charged with pyridinium
salt (+)-3c (5.30 g, 16.09 mmol) and THF (25 mL). The resulting
suspension was cooled to –70 °C, and lithium triethylborohydride
(1.0 m solution in THF, 17.70 mL, 17.7 mmol, 1.1 equiv.) was
added dropwise through a syringe. The solution was warmed to
0 °C over a 2 h period. Then, an aqueous buffer solution of HCN/
NaCN [35 mL, prepared from the addition of a 10% HCl solution
(12 mL) to a solution of NaCN (4.73 g, 96.53 mmol, 6.0 equiv.)
dissolved in water (35 mL)] was slowly added at that temperature
over a period of 15 min. The stirring was continued overnight at
that temperature. Then, water (25 mL) was added, and the resulting
solution was covered by a layer of diethyl ether (100 mL). The or-
ganic layer was washed with water, dried with MgSO4, and concen-
trated to afford a crude residue, which was transferred to a chroma-
tographic column (30ϫ3.5 cm, prepared with 20 g of silica, diethyl
ether/petroleum ether, 20:80). The combined fractions were evapo-
rated to yield α-amino nitriles (–)-5-A and (+)-5-B (2.90 g, 85%,
50:50 mixture of diastereoisomers) as a viscous, orange oil; Rf =
0.2 (diethyl ether/petroleum ether, 20:80). A mixture of α-amino
nitriles (–)-5-A and (+)-5-B (0.3 g) was dissolved in a 50:50 mixture
of diethyl ether and petroleum ether. The solution was kept at room
temperature until the solvents completely evaporated. The residue
was combined with petroleum ether (5 mL) to afford (–)-5-A
(0.15 g) as colorless crystals, which were analyzed by X-ray diffrac-
tion; m.p. 76 °C. [α]2D2 = –2.5 (c = 1.06, CHCl3). As a result of the
slow epimerization of the (S) configuration at C-2, the optical rota-
tion should be recorded in ethanol within 5 min. [α]2D2 = –2.5 (c =
1.0, ethanol); at 5 min, (R,S)/(R,R), 95:5 dr. [α]2D2 = +56 (c = 1.0,
ethanol); at equilibrium, (R,S)/(R,R), 35:75 dr. 1H NMR
(400 MHz, CDCl3): δ = 1.40 (d, J = 6.6 Hz, 3 H), 2.37 (dm, J =
16.0 Hz, 1 H), 2.70 (dm, J = 16.0 Hz, 1 H), 2.85 (dm, J = 16.0 Hz,
1 H), 3.04 (dm, J = 6.6 Hz, 1 H), 3.53 (q, J = 6.6 Hz, 1 H), 4.29
(dd, J = 6.0, 1.4 Hz, 1 H), 5.61–5.71 (m, 2 H), 7.24–7.34 (m, 5
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.5 (p), 30.0 (s), 45.7
(t), 48.0 (s), 63.1 (t), 116.8 (q), 120.7 (t), 125.9 (t), 127.3 (t), 127.4
(t), 128.6 (t), 143.6 (q) ppm. HRMS: calcd. for C14H16N2Na [M +
Na]+ 235.12112; found 235.1210; calcd. for C13H15NNa [M – HCN
+ Na]+ 208.11022; found 208.1110. C14H16N2 (212.13): calcd. C
79.21, H 7.60, N 13.20; found C 79.26, H 7.59, N 13.34.
Conclusions
The stereocontrolled syntheses of (–)-coniine (Ͼ99:1 er)
and (–)-solenopsin A from a chiral pyridinium salt were de-
veloped. Because both enantiomers of α-phenylethylamine
(PEA) are commercially available, the application of a
modified Fry synthesis provided an efficient synthesis to 2-
substituted enantioenriched piperidines with the requisite
absolute configuration. In addition, the combination of this
reaction sequence with the Beak’s lithiation–trans-
metalation procedure afforded direct access to trans-2,6-di-
substituted piperidines.
Experimental Section
General Methods: Purification by column chromatography was per-
formed with 70–230 mesh silica gel using diethyl ether and petro-
leum ether (b.p. 60 to 80 °C). TLC analyses were carried out with
alumina sheets precoated with silica gel 60 F254, and the Rf values
are given. The NMR spectroscopic data were recorded with either
a 500, 400, or 300 MHz spectrometer (“p” denotes “primary C”).
Positive-ion mass spectra were recorded with an orthogonal accel-
eration quadrupole time-of-flight mass spectrometer that was
equipped with a standard electrospray probe. Melting points were
measured with a Kofler apparatus, and the values are reported in
°C. Optical rotations were recorded at 20 °C with a 1 dm cell.
(R)-(+)-1-(1-Phenylethyl)pyridinium Hexafluorophosphate [(+)-3c]:
(R)-(+)-1-phenylethylamine (5.43 g, 44.10 mmol, 1.1 equiv.) was
added slowly to a suspension of 1-(2,4-dinitrophenyl)pyridinium
chloride (6,[35] 11.50 g, 40.92 mmol) in n-butanol (40 mL), and the
solution was heated at reflux for 24 h. The solvent was evaporated,
and the resulting paste was combined with water (50 mL). The ex-
cess amount of 2,4-dinitroaniline hydrochloride was removed by
filtration, and the aqueous phase was basified by the addition of
concentrated aqueous ammonia (2 mL). The resulting solution was
extracted with EtOAc (2ϫ50 mL). The organic phases were dis-
carded, and the pyridinium chloride solution was treated with
KPF6 (8.30 g, 45.10 mmol, 1.1 equiv.) for 12 h to afford pyridinium
salt (+)-3c (10.0 g, 75%) as a slightly yellow powder; m.p. 86–88 °C
(ethanol). [α]2D2 = +26 (c = 1.50, acetone); ref.[16] [α]2D2 = +9 (c =
(1ЈR,2R)-(–)-1-(1-Phenylethyl)-1,2,3,6-tetrahydropyridine-2-carbo-
nitrile (5-B): Compound 5-B was obtained as a mixture of dia-
stereoisomers [(1ЈR,2S)/(1ЈR,2R), 50:50 dr]. 1H NMR (400 MHz,
CDCl3): δ = 1.39 (d, J = 6.6 Hz, 3 H), 2.15 (dm, J = 16.5 Hz, 1
H), 2.46 (dm, J = 16.0 Hz, 1 H), 3.00–3.10 (m, 1 H), 3.53 (q, J =
6.6 Hz, 1 H), 3.63–3.70 (m, 2 H), 5.60–5.75 (m, 1 H), 5.80–5.85 (m,
1 H), 7.23–7.36 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.4 (p), 29.6 (s), 46.4 (s), 47.7 (t), 63.5 (t), 116.81 (q), 121.4 (t),
125.7 (t), 127.1 (t), 127.8 (t), 128.7 (t), 128.8 (t), 129.0 (t), 143.64
(q) ppm.
1
1.0, methanol)]. H NMR (400 MHz, [D6]DMSO): δ = 2.06 (d, J
= 7.0 Hz, 3 H), 6.23 (q, J = 7.0 Hz, 1 H), 7.41–7.50 (m, 3 H), 7.53–
7.56 (dm, J = 4.5 Hz, 2 H), 8.17 (t, J = 6.9 Hz, 2 H), 8.61 (tt, J =
7.8, 1.3 Hz, 1 H), 9.22 (dd, J = 6.8, 1.2 Hz, 2 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 19.7 (p), 69.6 (t), 127.2 (t), 128.5 (t),
129.16 (t), 129.36 (t), 137.8 (q), 143.4 (q), 146.1 (q) ppm. HRMS:
calcd. for C13H14N [M]+ 184.11262; found 184.1132.
(1ЈR)-(–)-1-(1-Phenylethyl)-1,2,3,6-tetrahydropyridine [(–)-7]: Pale (1ЈR,2R)-(–)-1-(1-Phenylethyl)-2-methyl-1,2,3,6-tetrahydropyridine
yellow oil; [α]2D2 = –7.0 (c = 1.10, CHCl3). 1H NMR (300 MHz,
[(+)-10a]: An oven-dried, one-necked Schlenk tube (200 mL), which
6
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Asymmetric Syntheses of (–)-Coniine and (–)-Solenopsin A
was fitted with a magnetic stirring bar and connected to an argon
inlet, was flushed with argon. The flask was then cooled to –80 °C,
and dry THF (20 mL) and diisopropylamine (4.78 mL, 3.39 g,
33.6 mmol) were added followed by the dropwise addition of butyl-
lithium (2.5 m solution in hexane, 11.80 mL, 29.50 mmol). The stir-
ring was continued for 30 min, and the solution was warmed to
0 °C over a 1 h period. The solution was then added dropwise to a
Schlenk tube (200 mL) that was cooled to –80 °C and contained a
50:50 mixture of α-amino nitrile 5 (4.20 g, 19.78 mmol) dissolved
in dry THF (5 mL). The solution was warmed to 0 °C over 2.0 h
and then was cooled to –80 °C. Then, iodomethane (2.06 mL,
4.74 g, 33.39 mmol, 1.7 equiv.) was added dropwise, and the reac-
tion mixture was warmed to –10 °C for 2 h. The Schlenk tube was
phenylphosphane)rhodium(I) (0.10 g, 3% by mass). Hydrogen
pressure (3.75ϫ103 Torr, 5 bars) was applied, and the solution was
stirred for 72 h at room temperature. The solution was concen-
trated under reduced pressure to afford a crude oily residue, which
was transferred to a chromatographic column (20ϫ2.0 cm, pre-
pared with 10 g of silica, diethyl ether/petroleum ether, 50:50). The
combined fractions were evaporated to afford piperidine (–)-12a
(2.03 g, 90%) as a colorless viscous oil; Rf = 0.4 (diethyl ether/
petroleum ether, 60:40). [α]2D2 = –40 (c = 1.3, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.15 (d, J = 6.3 Hz, 3 H), 1.24 (d, J =
6.7 Hz, 3 H), 1.26–1.45 (m, 4 H), 1.55–1.64 (m, 1 H), 1.65–1.73 (m,
1 H), 2.12 (ddd, J = 11.9, 8.8, 3.1 Hz, 1 H), 2.30–2.80 (m, 1 H),
2.78–2.85 (m, 1 H), 4.05 (q, J = 6.7 Hz, 1 H), 7.19 (tt, J = 6.4,
then charged with ethanol (30 mL), and NaBH4 (3.00 g, 1.4 Hz, 1 H), 7.28 (t, J = 6.4 Hz, 2 H), 7.41 (d, J = 7.5 Hz, 2
79.30 mmol, 4.0 equiv.) was added in portions. The stirring was
continued for 12 h at 0 °C. The solvents were evaporated under
reduced pressure, and the crude material was dissolved in 15% am-
monia solution (20 mL). The aqueous layer was extracted with
dichloromethane (2ϫ25 mL), and the organic phases were dried
with MgSO4 and concentrated. The crude oily residue (4.58 g) was
transferred to a chromatographic column (50ϫ2.5 cm, prepared
with 30 g of silica, diethyl ether/petroleum ether, 10:90) to afford
tetrahydropyridines (+)-10a and (+)-11a (3.73 g, 94% based on α-
amino nitrile 5, 85:15 mixture of diastereoisomers). A careful puri-
fication of the mixture on silica (diethyl ether/petroleum ether,
10:90) afforded tetrahydropyridine (+)-10a (2.96 g, 75%) as a color-
less oil; Rf = 0.2 (diethyl ether/petroleum ether, 20:80). [α]2D2 = +19
(c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.01 (d, J =
7.3 Hz, 3 H), 1.31 (d, J = 6.7 Hz, 3 H), 1.85 (dm, J = 17.3 Hz, 1
H), 2.47 (dm, J = 17.3 Hz, 1 H), 2.71 (dm, J = 16.5 Hz, 1 H), 2.88
(dm, J = 16.5 Hz, 1 H), 3.32–3.40 (m, 1 H), 3.64 (q, J = 6.7 Hz, 1
H), 5.48–5.54 (m, 1 H), 5.61–5.67 (m, 1 H), 7.20 (tt, J = 6.4, 1.4 Hz,
1 H), 7.28 (td, J = 6.4, 1.0 Hz, 2 H), 7.36 (d, J = 7.5, 1.4 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.8 (p), 19.2 (p), 33.1
(s), 45.3 (s), 46.6 (t), 60.4 (t), 123.2 (t), 125.2 (t), 126.6 (t), 127.5
(t), 128.2 (t), 146.0 (q) ppm. HRMS: calcd. for C14H20N [M +
H]+ 202.15902; found 202.1589. C14H19N (201.30): calcd. C 83.53,
H 9.51, N 6.96; found C 83.73, H 9.53, N 6.94.
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 12.5 (p), 17.0 (p), 23.4
(s), 26.4 (s), 34.7 (s), 44.9 (s), 52.0 (t), 56.6 (t), 126.2 (t), 127.6 (t),
127.9 (t), 145.8 (q) ppm. HRMS: calcd. for C14H22N [M + H]+
204.17522; found 204.1747. C14H21N (203.32): calcd. C 82.70, H
10.41, N 6.89; found C 82.65, H 10.35, N 6.85.
(1ЈR,2R)-(–)-1-(1-Phenylethyl)-2-propylpiperidine [(–)-12b]: The
synthesis was as reported for (–)-12a, but with (+)-10b (2.20 g) to
afford piperidine (–)-12b (2.06 g, 93%) as a colorless viscous oil; Rf
= 0.4 (diethyl ether/petroleum ether, 60:40). [α]2D2 = –10 (c = 2.72,
1
CHCl3). H NMR (500 MHz, CDCl3): δ = 0.91 (t, J = 7.3 Hz, 3
H), 1.25 (d, J = 6.7 Hz, 3 H), 1.26–1.70 (m, 10 H), 2.19–2.24 (m,
1 H), 2.34–2.39 (m, 1 H), 2.72 (dq, J = 10.1, 4.0 Hz, 1 H), 4.00 (q,
J = 6.7 Hz, 1 H), 7.19 (tt, J = 6.4, 1.4 Hz, 1 H), 7.28 (t, J = 6.4 Hz,
2 H), 7.41 (d, J = 7.5 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 14.6 (p), 14.7 (p), 18.9 (s), 22.7 (s), 25.8 (s), 29.6 (s), 30.1 (s),
45.0 (s), 55.7 (t), 56.8 (t), 126.2 (t), 127.5 (t), 128.0 (t), 146.4
(q) ppm. HRMS: calcd. for C16H26N [M + H]+ 232.20653; found
232.2065. C16H25N (231.37): calcd. C 83.06, H 10.89, N 6.05; found
C 82.26, H 10.65, N 6.08.
tert-Butyl (2R)-(–)-Methylpiperidine-1-carboxylate [(–)-14a]: A low-
pressure hydrogenator (50 mL) was charged with methanol
(30 mL), piperidine (–)-12a (1.50 g, 7.38 mmol), and 20% Pd(OH)
2/C (0.30 g, 20% by mass). Hydrogen pressure (3.75ϫ103 Torr,
5 bars) was applied, and the homogeneous solution was stirred for
72 h at room temperature. The suspension was filtered through a
short pad of Celite, and (S)-(+)-mandelic acid (1.15 g, 7.55 mmol)
was added to the methanolic solution, which was then concen-
trated. The solid residue was combined with diethyl ether (20 mL)
to afford (2R)-(–)-methylpiperidine·(S)-(+)-mandelic acid salt [(+)-
13a, 1.76 g, 95% from (–)-12a, Ͼ98:2 dr] as a white solid, m.p.
119 °C; ref.[36] m.p. 118 °C. [α]2D2 = +78 (c = 1.0, CHCl3); ref.[36]
[α]2D2 = +60 (c = 2.5, MeOH). 1H NMR (400 MHz, CDCl3): δ =
1.09 (d, J = 7.2 Hz, 3 H), 1.10–1.30 (m, 2 H), 1.50–1.59 (m, 3 H),
1.64–1.70 (m, 1 H), 2.18–2.26 (m, 1 H), 2.63–2.70 (m, 1 H), 2.97
(dm, J = 13.0 Hz, 1 H), 3.50–4.50 (br. s, 1 H), 4.84 (s, 1 H), 7.20
(t, J = 7.1 Hz, 1 H), 7.27 (t, J = 7.1 Hz, 2 H), 7.45 (d, J = 7.1 Hz,
2 H), 9.50–10.00 (br. s, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 19.1 (p), 21.8 (s), 22.5 (s), 30.2 (s), 43.8 (s), 52.2 (t), 74.5 (t),
126.6 (t), 127.0 (t), 128.0 (t), 142.6 (q), 178.2 (q) ppm. HRMS:
calcd for C6H14N [M]+ 100.11262; found 100.1125. C14H21NO3
(251.32): calcd. C 66.91, H 8.42, N 5.57; found C 66.80, H 8.40, N
5.60. Mandelate salt (+)-13a (0.50 g, 1.99 mmol) was dissolved in
dry acetonitrile (20 mL), and to the resulting solution were success-
ively added N,N-diisopropylethylamine (1.25 mL, 0.95 g,
7.35 mmol) and di-tert-butyldicarbonate (0.43 g, 1.97 mmol). The
reaction mixture was heated at reflux for 4 h, and the solvent was
evaporated. The residue was dissolved in water (20 mL), and the
organic phase was extracted with diethyl ether (50 mL). The or-
(1ЈR,2R)-(–)-1-(1-Phenylethyl)-2-propyl-1,2,3,6-tetrahydropyridine
[(+)-10b]: The synthesis was as reported for (+)-10a, but with the
addition of 1-iodopropane (3.28 mL, 5.71 g, 33.59 mmol) as the
electrophile. Workup and chromatographic purification of the
crude oil over a silica column afforded tetrahydropyridines (+)-10b
and (+)-11b (4.08 g, 90%, 90:10 mixture of diastereoisomers).
Chromatographic purification of the mixture on a silica column
(diethyl ether/petroleum ether, 10:90) afforded tetrahydropyridine
(+)-10b (3.26 g, 72%) as a colorless oil; Rf = 0.2 (diethyl ether/
1
petroleum ether, 20:80). [α]2D2 = +20 (c = 3.24, CHCl3). H NMR
(400 MHz, CDCl3): δ = 0.92 (t, J = 7.3 Hz, 3 H), 1.30 (d, J =
6.7 Hz, 3 H), 1.20–1.40 (m, 4 H), 1.45–1.55 (m, 1 H), 1.90 (dm, J =
18.0 Hz, 1 H), 2.37 (dm, J = 18.0 Hz, 1 H), 2.83 (dm, J = 17.5 Hz, 1
H), 2.93 (dm, J = 17.5 Hz, 1 H), 3.05–3.12 (m, 1 H), 3.67 (q, J =
6.7 Hz, 1 H), 5.50–5.55 (m, 1 H), 5.61–5.67 (m, 1 H), 7.18 (tt, J =
6.4, 1.4 Hz, 1 H), 7.26 (td, J = 6.4, 1.0 Hz, 2 H), 7.35 (d, J = 7.5,
1.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.5 (p), 20.1
(s), 20.9 (p), 27.9 (s), 28.5 (s), 45.2 (s), 51.2 (t), 60.3 (t), 123.5 (t),
125.5 (t), 126.6 (t), 127.4 (t), 128.2 (t), 146.4 (q) ppm. HRMS:
calcd. for C16H24N [M + H]+ 230.19087; found 230.1909. C16H23N
(229.36): calcd. C 83.79, H 10.11, N 6.11; found C 82.97, H 10.04,
N 6.05.
(1ЈR,2R)-(–)-1-(1-Phenylethyl)-2-methylpiperidine [(–)-12a]: A low-
pressure hydrogenator (50 mL) was charged with MeOH (30 mL),
tetrahydropyridine (+)-10a (2.23 g, 11.07 mmol), and chlorotris(tri- ganic phase was dried with MgSO4 and concentrated, and the resi-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O30595
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Pages: 12
J.-P. Hurvois et al.
FULL PAPER
due was transferred to a chromatographic column (20ϫ2.0 cm,
prepared with 10 g of silica, diethyl ether/petroleum ether, 60:40).
The combined fractions were evaporated to yield (–)-14a (0.37 g,
93%) as a colorless oil; Rf = 0.6 (diethyl ether/petroleum ether,
(400 MHz, CDCl3): δ = 0.88 (t, J = 7.2 Hz, 3 H), 1.23 (d, J =
6.7 Hz, 3 H), 1.20–1.33 (m, 19 H), 1.46 (s, 9 H), 1.40–1.56 (m, 2
H), 1.57–1.70 (m, 3 H), 1.71–1.90 (m, 2 H), 3.75–3.82 (m, 1 H),
3.87–3.95 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.9
(s), 14.1 (p), 20.9 (p), 22.7 (s), 23.3 (s), 27.0 (s), 27.2 (s), 28.6 (p),
60:40). [α]2D2 = –47 (c = 1.2, CHCl3); ref.[36] [α]2D2 = –51 (c = 0.83,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.11 (d, J = 6.9 Hz, 3 29.4 (s), 29.63 (s), 29.66 (s), 29.69 (s), 29.70 (s), 29.73 (s), 31.9 (s),
H), 1.30–1.50 (m, 2 H), 1.45 (s, 9 H), 1.50–1.65 (m, 4 H), 2.80 (td,
J = 13.0, 2.7 Hz, 1 H) 3.90 (dm, J = 13.0 Hz, 1 H), 4.32–4.41 (m,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.7 (p), 18.7 (s),
25.7 (s), 28.5 (p), 30.1 (s), 38.7 (t), 46.1 (t), 79.0 (q), 155.0 (q) ppm.
HRMS: calcd. for C11H21NO2Na [M + Na]+ 222.1470; found
222.1469. C11H21NO2 (199.28): calcd. C 66.29, H 10.62, N 7.03;
found C 66.20, H 10.20, N 7.00.
34.4 (s), 47.0 (t), 51.73 (t), 78.7 (q), 155.3 (q) ppm. HRMS: calcd.
for C22H43NO2Na [M
+
Na]+ 376.31915; found 376.3193.
C22H43NO2 (353.58): calcd. C 74.73, H 12.26, N 3.96; found C
75.00, H 12.10, N 3.80.
(2R,6R)-(–)-2-Methyl-6-undecyl-piperidine [(–)-Solenopsin A, (–)-2]:
An oven-dried, one-necked Schlenk tube (50 mL) was successively
charged with compound (–)-16 (0.5 g, 1.41 mmol) and dry Et2O
(10 mL). Then, dry Et2O (10 mL) that was saturated with gaseous
HCl was added, and the resulting solution was stirred for 12 h. The
solvents were removed, and the resulting white powder was stirred
in NaOH (1 m solution) to yield a crude oil, which was purified by
a silica gel column (Et2O saturated with gaseous ammonia) to af-
ford (–)-solenopsin A (0.28 g, 80%) as a colorless oil; Rf = 0.80
(diethyl ether saturated with gaseous ammonia). [α]2D2 = –1.2 (c =
1.0, CHCl3); ref.[39] [α]2D2 = –1.3 (c = 0.94, CH3OH). 1H NMR
(400 MHz, CDCl3): δ = 0.87 (t, J = 6.7 Hz, 3 H), 1.07 (d, J =
6.5 Hz, 3 H); 1.20–1.65 (m, 26 H), 2.83–2.91 (m, 1 H), 3.00–3.10
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.2 (p), 19.6 (s),
21.3 (p), 22.7 (s), 26.5 (s), 29.4 (s), 29.66 (s), 29.69 (s), 29.8 (s), 30.8
(s), 31.9 (s), 33.0 (s), 34.1 (s), 45.9 (t), 50.9 (t) ppm.
tert-Butyl (2R)-(–)-Propyl-piperidine-1-carboxylate [(–)-14b]: The
synthesis was as reported for (–)-14a, but with (–)-12b (1.80 g,
7.78 mmol) to afford (R)-(–)-coniine·(S)-(+)-mandelic acid salt
[(+)-13b, 2.06 g, 95% from (–)-12b, Ͼ98:2 dr] as a white solid, m.p.
125 °C; ref.[23] m.p. 117 °C. [α]2D2 = +45 (c = 0.97, EtOH); ref.[23]
[α]2D2 = +49 (c = 0.6, MeOH). 1H NMR (400 MHz, CDCl3): δ =
0.84 (t, J = 7.0 Hz, 3 H), 1.03–1.15 (m, 1 H), 1.16–1.32 (m, 4 H),
1.40–1.76 (m, 5 H), 2.20 (td, J = 12.5, 5.4 Hz, 1 H), 2.50–2.60 (m,
1 H), 2.97 (d, J = 12.5 Hz, 1 H), 3.60–4.50 (br. s, 1 H), 4.84 (s, 1
H), 7.20 (t, J = 7.1 Hz, 1 H), 7.26 (t, J = 7.1 Hz, 2 H), 7.44 (d, J
= 7.1 Hz, 2 H), 8.00–10.00 (br. s, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 13.8 (p), 18.3 (s), 22.1 (s), 22.5 (s), 27.9 (s), 35.4 (t),
44.1 (s), 56.2 (t), 74.5 (t), 126.7 (t), 127.0 (t), 128.0 (t), 142.7 (q),
178.1 (q) ppm. HRMS: calcd. for C8H18N [M]+ 128.14392; found
128.14392. C16H25NO3 (279.37): calcd. C 68.79, H 9.02, N 5.01;
found C 68.38, H 8.96, N 5.01. The synthesis of (R)-(–)-N-Boc-
coniine [(–)-14b, 93%] was as reported for (–)-14a, but with man-
delate salt (+)-13b (0.50 g). Colorless oil; Rf = 0.6 (diethyl ether/
petroleum ether, 60:40). [α]2D2 = –32.5 (c = 1.34, CHCl3); ref.[37]
(R)-(–)-Coniine·(+)-22: Mandelate salt (+)-13b (45 mg, 160 μmol,
Ͼ99:1 dr) and its optical antipode (–)-13b (5.0 mg, 18 μmol, Ͼ99:1
dr) were mixed (5 min) in 5% NaOH (1 mL). The aqueous phase
was extracted with diethyl ether (5 mL), and the organic phase was
washed with water until the pH was neutral and then dried with
MgSO4. Then, (R)-(+)-tert-butylphenylphosphanylthioic acid (+)-
22 (0.04 g, 186 μmol, γ = 1.15, Ͼ99:1 er) was added to the ethereal
phase, and the solvent was evaporated to afford (R)-(–)-coniine·(+)-
22, (0.063 g, 99%, 90:10 dr). This salt was diluted with CDCl3
(0.5 mL) in a 5 mm NMR tube. 1H NMR [400 MHz, CDCl3, split-
ting signals are indicated by an asterisk (*)]: δ = 0.75 (t, J = 7.4 Hz,
[α]2D2 = –28.4 (c = 1.36, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
0.92 (t, J = 7.2 Hz, 3 H), 1.20–1.41 (m, 4 H), 1.45 (s, 9 H), 1.50–
1.70 (m, 6 H), 2.77 (t, J = 14.0 Hz, 1 H) 3.96 (d, J = 12.0 Hz, 1
H), 4.20 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.1 (p),
19.1 (s), 19.5 (s), 25.7 (s), 28.5 (p), 31.9 (s), 38.7 (br. s), 50.1 (br. t),
78.9 (q), 155.2 (q) ppm. HRMS: calcd. for C13H25NO2Na [M +
Na]+ 250.17830; found 250.1782. C13H25NO2 (227.34): calcd. C
68.68, H 11.08, N 6.16; found C 68.34, H 10.48, N 5.97.
3
0.38 H), 0.79 (t, J = 7.4 Hz, 3 H)*, 1.11 (d, JH,P = 16.0 Hz, 9 H),
1.20–1.50 (m, 5 H), 1.61–1.85 (m, 5 H), 2.70 (td, J = 12.6, 3.2 Hz,
1 H), 2.81 (td, J = 12.6, 3.2 Hz, 0.1 H)*, 2.84–2.93 (m, 1 H), 3.30
(dm, J = 12.6 Hz, 1 H), 7.33–7.40 (m, 3 H), 7.90–7.98 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = [13.67 (p), 13.68 (p)]*,
[18.48 (s), 18.56 (s)]*, 22.4 (s), 22.5 (s), 25.2 (p), 28.2 (s), [35.41 (s),
tert-Butyl (2R,6R)-(–)-2-Methyl-6-undecyl-piperidine-1-carboxylate
[(–)-16]: An oven-dried, one-necked Schlenk tube (200 mL), which
was fitted with a magnetic stirring bar and connected to an argon
inlet, was flushed with argon. The flask was then cooled to –80 °C,
and a solution of compound (–)-14a (1.00 g, 5.02 mmol) in dry
Et2O (40 mL) was added. To this solution was added TMEDA
(1.26 mL, 0.97 g, 8.35 mmol). A solution of sBuLi (1.4 m in cyclo-
hexane, 5.60 mL, 7.84 mmol, 1.56 equiv.) was then added dropwise.
The resulting solution was stirred between –80 and –65 °C for 3 h
and was then cooled to –80 °C. A solution of the complex
CuCN·2LiCl [prepared from CuCN (0.70 g, 7.81 mmol) and LiCl
(0.66 g, 15.57 mmol)] in THF (20 mL) was added dropwise, and the
reaction mixture was stirred between –80 °C and –60 °C for 2 h.
The solution was then cooled to –80 °C, and 1-iodoundecane
(2.19 g, 1.80 mL, 7.76 mmol, 1.5 equiv.) was added. The reaction
mixture was warmed to room temperature over a 12 h period and
then poured into water (50 mL). The organic phase was dried with
MgSO4 and concentrated, and the resulting residue was transferred
to a chromatographic column (20ϫ2.0 cm, prepared with 10 g of
silica, diethyl ether/petroleum ether, 10:90). The combined fractions
were evaporated to yield (–)-16 (1.12 g, 65%) as a colorless oil; Rf
= 0.42 (diethyl ether/petroleum ether, 10:90). [α]2D2 = –29 (c = 1.20,
CHCl3); ref.[38] [α]2D2 = –26.3 (c = 1.58, CHCl3). 1H NMR
1
35.49 (s)]*, 36.3 [q, (d, JC,P = 73.5 Hz)], [44.51 (s), 44.55 (s)]*,
[56.55 (s), 56.59 (s)]*, 126.9 [(t), d, JC,P = 11.0 Hz], 129.4 [(t), d,
1
JC,P = 2.5 Hz], 132.7 [(t), d, JP,H = 8.8 Hz], 139.2 [q, d, JP,H
=
88.0 Hz] ppm.
1-Benzyl-pyridinium Hexafluorophosphate (17)
Alkylation: In a Schlenk tube (200 mL), which was fitted with a
magnetic stirring bar and connected to an argon inlet and a
bubbler, was placed dry pyridine (8.70 g, 110 mmol). The flask was
flushed with argon, and degassed acetone (20 mL) was added. The
solution was cooled to 0 °C, and benzyl bromide (11.89 mL,
17.10 g, 100 mmol) was added by a syringe. The solution was
stirred at that temperature for 4 h, and the stirring was continued
at room temperature overnight. The solvent was removed by can-
nulation, and the solvents were evaporated in vacuo under argon
to afford 1-benzyl-pyridinium bromide (22.50 g, 90%) as a highly
hygroscopic white powder, which could be stored for one month
under argon without any loss of quality.
Anion
Exchange:
1-Benzyl-pyridinium
bromide
(2.50 g,
10.00 mmol) was dissolved in water (15 mL), and to this clear solu-
8
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Asymmetric Syntheses of (–)-Coniine and (–)-Solenopsin A
tion was added KPF6 (2.00 g, 10.86 mmol). The hexafluorophos-
phate pyridinium salt precipitated immediately as a white solid, and
the resulting suspension was stirred at room temperature for 24 h.
The content of the flask was poured into a sintered-glass funnel,
and the solvents were removed by filtration to yield a white powder,
which was rinsed with cold ethanol (2ϫ20 mL) to afford pyridin-
ium salt 17 (3.0 g, 95%) as a white powder; m.p. 150–152 °C (eth-
calcd. for C13H14N2Na [M + Na]+ 221.10547; found 221.1055;
calcd. for C12H13NNa [M – HCN + Na]+ 194.09457; found
194.0957. C13H14N2 (198.26): calcd. C 78.75, H 7.12, N 14.13;
found C 78.86, H 7.12, N 14.00.
1-Benzyl-2-propyl-1,2,3,6-tetrahydropyridine-2-carbonitrile (19): An
oven-dried, one-necked Schlenk tube (200 mL), which was fitted
with a magnetic stirring bar and connected to an argon inlet, was
flushed with argon. The flask was then cooled to –80 °C, and dry
THF (5 mL) and diisopropylamine (1.45 mL, 1.03 g, 10.18 mmol)
were added followed by the dropwise addition of n-butyllithium
(2.5 m solution in hexane, 3.60 mL, 9.0 mmol, 1.5 equiv.). The stir-
ring was continued for 30 min, and the solution was warmed to
0 °C over a 1 h period. This solution was then added dropwise to
a Schlenk tube (200 mL) that was cooled to –80 °C and contained
a suspension of α-amino nitrile 18 (1.20 g, 6.05 mmol) in dry THF
(5 mL). The solution rapidly turned deep red in color to yield a
homogeneous anion mixture, which was warmed to 0 °C over 2.0 h
and then cooled to –80 °C. 1-Iodopropane (0.90 mL, 1.56 g,
9.22 mmol, 1.5 equiv.) was added dropwise, and the reaction mix-
ture was warmed to –10 °C for 2 h and was then quenched by the
addition of ethanol (2 mL). Workup was carried out under argon.
A degassed mixture of diethyl ether (100 mL) and water (15 mL)
that contained NaCN (0.15 g) was added to the reaction mixture.
The ethereal layer was separated, dried with MgSO4, and concen-
trated at a temperature ranging between 5 and 10 °C to yield a
crude oil (1.30 g), which was dissolved in dichloromethane. The
1
anol). H NMR (500 MHz, [D6]DMSO): δ = 5.86 (s, 2 H), 7.40–
7.50 (m, 3 H), 7.52–7.56 (m, 2 H), 8.18 (t, J = 7.4 Hz, 2 H), 8.62
(t, J = 7.0 Hz, 1 H), 9.19 (d, J = 5.5 Hz, 2 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 63.3 (s), 128.4 (t), 128.7 (t), 129.1 (t),
129.3 (t), 134.1 (q), 144.7 (t), 145.9 (t) ppm. HRMS: calcd for
C12H12N [M]+ 170.09697; found 170.0970; calcd. for C24H24N2F6P
[2M + PF6]+ 485.158313; found 485.1578.
1-Benzyl-1,2,3,6-tetrahydro-pyridine-2-carbonitrile (18)
Synthesis: Caution: Because of the possible emission of toxic HCN,
the preparation of the HCN/NaCN buffer should be carried out
under a well-ventilated hood. An oven-dried, one-necked Schlenk
tube (200 mL), which was fitted with a magnetic stirring bar and
connected to an argon inlet, was charged with pyridinium salt 17
(2.0 g, 6.34 mmol) and dry THF (20 mL). The resulting suspension
was cooled to –70 °C, and lithium triethylborohydride (1.0 m solu-
tion in THF, 7.0 mL, 7.0 mmol, 1.1 equiv.) was added dropwise by
a syringe. The solution rapidly turned yellow, and the clear homo-
geneous reaction mixture was warmed to 0 °C over a 1 h period.
Then, an aqueous HCN/NaCN buffer solution [20 mL, prepared
from the addition of 10% HCl solution (4 mL) to a solution of
NaCN (1.90 g, 38.80 mmol, 6.0 equiv.) dissolved in water (16 mL)]
was added at that temperature over a period of 15 min. The stirring
was continued overnight at 0 °C, and water (25 mL) was added to
the reaction solution. The mixture was covered by a layer of diethyl
ether (75 mL), and the biphasic system was vigorously stirred for
5 min. The aqueous layer was discarded, and the cyanide anions
were oxidized with an excess amount of KMnO4. The organic layer
was washed with water until the aqueous phase remained neutral
to litmus paper, and it was then dried with MgSO4 and concen-
trated to afford a slightly yellowish solid (1.17 g). This crude mate-
rial was dissolved in dichloromethane, and the resulting solution
was transferred to a chromatographic column (30ϫ3.5 cm, pre-
pared with 20 g of silica, diethyl ether/petroleum ether, 20:80). The
combined fractions were evaporated to yield α-amino nitrile 18
(1.14 g, 91%) as a viscous oil that solidified upon cooling. A slow
crystallization in ethanol yielded single crystals, which were ana-
lyzed by X-ray diffraction.
solution was transferred to
a
chromatographic column
(30ϫ3.5 cm, prepared with 20 g of silica, diethyl ether/petroleum
ether, 25:75). The combined fractions were evaporated to yield α-
amino nitrile 19 (1.28 g, 88%) as slightly yellow viscous oil; Rf =
0.5 (diethyl ether/petroleum ether, 20:80). 1H NMR (400 MHz,
CDCl3) δ = 0.99 (t, J = 7.3 Hz, 3 H), 1.53–1.65 (m, 2 H), 1.80–
1.88 (m, 1 H), 1.93–2.01 (m, 1 H), 2.37 (dm, JAB = 17.0 Hz, 1 H),
2.49 (dm, JAB = 17.0 Hz, 1 H), 2.84 (dm, JAB = 17.8 Hz, 1 H), 3.14
(dm, JAB = 17.8 Hz, 1 H), 3.18 (d, JAB = 13.0 Hz, 1 H), 4.20 (dm,
JAB = 13.0 Hz, 1 H), 5.60–5.68 (m, 2 H), 7.22–7.34 (m, 5 H) ppm.
13C NMR (100 MHz, CDCl3) δ = 14.2 (p), 16.6 (s), 35.0 (s), 39.5
(s), 49.4 (s), 55.1 (s), 58.6 (q), 119.1 (q), 121.2 (t), 125.1 (t), 127.3
(t), 128.5 (t), 128.6 (t), 138.0 (q) ppm. HRMS: calcd. for
C16H20N2Na [M + Na]+ 263.15242; found 263.1522. C16H20N2
(240.34): calcd. C 79.96, H 8.39, N 11.66; found C 80.58, H 8.44,
N 11.57.
1-Benzyl-2-propyl-1,2,3,6-tetrahydropyridine (20):
A one-necked
flask (50 mL), which was equipped with a rubber septum, was
charged with ethanol (10 mL) and α-amino nitrile 19 (2.60 g,
10.80 mmol). The solution was cooled to 0 °C, and NaBH4 (1.75 g,
46.26 mmol, 4.3 equiv.) was added in portions. The stirring was
continued for 48 h at that temperature, and the solvent was evapo-
rated under reduced pressure. The crude material was dissolved in
a 15% ammonia solution (20 mL), and the aqueous layer was ex-
tracted with dichloromethane (2ϫ25 mL). The combined organic
Recrystallization. α-Amino nitrile 18 (21.5 g) was dissolved in boil-
ing ethanol (25 mL). After the solid had precipitated, the mixture
was kept at –20 °C for 24 h. The precipitate was filtered through a
sintered-glass funnel to give a light yellow powder (20.0 g, 93%);
m.p. 74–76 °C (ethanol); Rf = 0.2 (diethyl ether/petroleum ether,
20:80). 1H NMR (400 MHz, CDCl3): δ = 2.26 (dm, J = 16.5 Hz, 1
H), 2.53–2.62 (m, 1 H), 3.07 (dm, J = 17.0 Hz, 1 H), 3.20 (dm, J layers were washed with water (25 mL), dried with anhydrous so-
= 17.0 Hz, 1 H), 3.55 (d, JAB = 13.1 Hz, 1 H), 3.78 (d, JAB dium sulfate, and concentrated on a rotary evaporator. The crude
=
13.1 Hz, 1 H), 3.80 (dd, J = 6.2, 1.6 Hz, 1 H), 5.67–5.79 (m, 2 H), oily residue (2.26 g) was diluted with dichloromethane (2 mL), and
7.26–7.37 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 29.4
the resulting solution was transferred to a chromatographic column
(s), 48.2 (t), 49.1 (s), 60.1 (s), 116.5 (q), 121.3 (t), 125.5 (t), 127.8
(50ϫ2.5 cm, prepared with 30 g of silica, diethyl ether/petroleum
(t), 128.5 (t), 129.0 (t), 136.5 (q) ppm. 1H NMR (400 MHz, C6D6): ether, 50:50). The combined fractions were evaporated to afford
δ = 1.64 (dm, J = 16.5 Hz, 1 H), 2.01 (dm, J = 16.5 Hz, 1 H), 2.80–
2.93 (m, 2 H), 3.26 (dd, J = 6.2, 1.6 Hz, 1 H), 3.31 (d, JAB
tetrahydropyridine 20 (1.86 g, 80%) as a colorless oil; Rf = 0.5 (di-
ethyl ether/petroleum ether, 50:50). H NMR (500 MHz, CDCl3) δ
1
=
13.2 Hz, 1 H), 3.43 (d, JAB = 13.2 Hz, 1 H), 5.27–5.32 (m, 1 H),
5.35–5.40 (m, 1 H), 7.06–7.20 (m, 5 H) ppm. 13C NMR (100 MHz,
C6D6): δ = 29.5 (s), 48.4 (t), 49.0 (s), 60.2 (s), 116.2 (q), 121.4 (t),
125.7 (t), 127.9 (t), 128.3 (t), 128.8 (t), 137.3 (q) ppm. HRMS:
= 0.90 (t, J = 7.1 Hz, 3 H), 1.30–1.42 (m, 3 H), 1.57–1.64 (m, 1
H), 1.91 (dm, JAB = 14.7 Hz, 1 H), 2.23 (dm, JAB = 14.7 Hz, 1 H),
2.77–2.82 (m, 1 H), 2.98 (dm, JAB = 17.5 Hz, 1 H), 3.06 (dm, JAB
= 17.5 Hz, 1 H), 3.60 (d, JAB = 13.3 Hz, 1 H), 3.68 (d, JAB
=
Eur. J. Org. Chem. 0000, 0–0
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J.-P. Hurvois et al.
FULL PAPER
13.3 Hz, 1 H), 5.56–5.60 (m, 1 H), 5.70–5.74 (m, 1 H), 7.21 (t, J =
7.0 Hz, 1 H), 7.28 (t, J = 7.0 Hz, 2 H), 7.34 (d, J = 7.0 Hz, 2
H) ppm. 13C NMR (125 MHz, CDCl3) δ = 14.4 (p), 19.8 (s), 28.0
(s), 31.4 (s), 48.3 (s), 55.6 (t), 56.2 (s), 124.5 (t), 125.1 (t), 126.7 (t),
(2ϫ20 mL). The diethyl ether extracts were combined and washed
with water until the pH was neutral, and then it was dried with
magnesium sulfate. (R)-(–)-mandelic acid (0.34 g) was added to the
resulting ethereal solution, which was stirred for 25 h at room tem-
128.2 (t), 128.8 (t), 139.9 (q) ppm. HRMS: calcd. for C15H22N [M perature. The precipitate was filtered to afford the (S)-(+)-
+ H]+ 216.17522; found 216.1753; calcd. for C15H21NNa [M +
Na]+ 238.15717; found 238.1581. C15H21N (215.33): calcd. C 83.67,
H 9.83, N 6.50; found C 83.27, H 9.71, N 6.51.
coniine·(R)-(–)-mandelic acid salt [(–)-13b, 0.35 g, 52% based on
isomer content] as a single diastereoisomer; m.p. 125 °C. [α]2D2
–46 (c = 1.07, EtOH); (S,R)/(R,R), Ն98:2 dr.
=
1-Benzyl-2-propyl-piperidine (21): A low-pressure hydrogenator
(50 mL) was charged with THF (25 mL), tetrahydropyridine 20
(1.10 g, 5.10 mmol), and chlorotris(triphenylphosphane)rhodium(I)
(Wilkinson’s catalyst, 0.05 g, 5% by mass). Air was removed from
the reactor by alternately filling it with hydrogen and venting it
(3ϫ). Hydrogen pressure (3.75ϫ103 Torr, 5 bars) was applied, and
the homogeneous solution was stirred for 72 h at room tempera-
ture. The solution was concentrated under reduced pressure to af-
ford a crude oily residue, which was diluted with dichloromethane
(2 mL). The resulting solution was transferred to a chromato-
graphic column (20ϫ2.0 cm, prepared with 10 g of silica, diethyl
ether/petroleum ether, 50:50). The combined fractions were evapo-
rated to afford piperidine 21 (0.90 g, 81%) as a colorless viscous
oil; Rf = 0.5 (diethyl ether/petroleum ether, 50:50). 1H NMR
(400 MHz, CDCl3) δ = 0.90 (t, J = 7.3 Hz, 3 H), 1.25–1.70 (m, 10
H), 1.98–2.05 (m, 1 H), 2.23–2.30 (m, 1 H), 2.72 (dt, J = 11.7,
4.2 Hz, 1 H), 3.21 (d, JAB = 13.5 Hz, 1 H), 3.96 (d, JAB = 13.5 Hz,
1 H), 7.18–7.23 (m, 1 H), 7.25–7.34 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3) δ = 14.6 (p), 18.8 (s), 23.7 (s), 25.2 (s), 30.3 (s),
34.1 (t), 51.7 (s), 57.6 (s), 60.7 (t), 126.5 (t), 128.1 (t), 128.9 (t),
140.1 (q) ppm. HRMS: calcd. for C15H24N [M + H]+ 218.19087;
found 218.1909. C15H23N (217.35): calcd. C 82.89, H 10.67, N 6.44;
found C 82.10, H 10.50, N 6.40.
Single-Crystal X-ray Analysis of (–)-5-A and 18: The structures
were solved by direct methods with SIR-97,[40] which revealed the
non-hydrogen atoms of the molecules. Refinement was performed
by full-matrix least-square techniques based on F2 with SHELXL-
97[41] with the aid of the WINGX[42] program. All non-hydrogen
atoms were refined with anisotropic thermal parameters. H atoms
were finally included in their calculated positions. Figures were
drawn with ORTEP-3 for Windows®. CCDC-910514 [for (–)-5-A]
and -910515 (for 18) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Crystal Data, X-ray Data Collection and Refinement Results of α-
Amino Nitrile (–)-5-A: C14H16N2, M = 212.29, monoclinic, space
group C2, a = 24.798(4) Å, b = 5.4404(8) Å, c = 8.9506(16) Å, α =
90°, β = 93.766(8)°, γ = 90°, V = 1204.9(3) Å3, Z = 4, DX
=
1.17 Mgm–3, µ = 0.70 cm–1, λ(Mo-Kα) = 0.71073 Å, F(000) = 456,
T = 150(2) K. The sample (0.60ϫ0.13ϫ0.13 mm) was studied with
a diffractometer with graphite-monochromatized Mo-Kα radiation.
The data collection (θmax = 27.45°, range of hkl: h –31Ǟ32, k
–6Ǟ6, l –11Ǟ11) gave 4727 reflections with 1511 unique reflections
from which 1346 with I Ͼ 2.0σ(I).
Crystal Data, X-ray Data Collection and Refinement Results of α-
Amino Nitrile 18: C13H14N2, M = 198.26, monoclinic, space group
C2/c, a = 20.2826(9) Å, b = 6.2838(3) Å, c = 17.6042(10) Å, α =
Optical Resolution of rac-Coniine to (R)-(–)-Coniine·(S)-(+)-
Mandelic Acid [(+)-13b]: A low-pressure hydrogenator (50 mL) was
charged with methanol (20 mL), piperidine 21 (1.0 g, 4.60 mmol),
and 20% Pd(OH)2 (Pearlman’s catalyst, 0.1 g, 10% by mass). Air
was removed from the reactor by alternately filling it with hydrogen
and venting it (3ϫ). Hydrogen pressure (3.75ϫ103 Torr, 5 bars)
was applied, and the homogeneous solution was stirred for 72 h at
room temperature. The suspension was filtered through a short pad
of Celite, and the vessel was washed with methanol. Then, (S)-
(+)-mandelic acid (0.70 g, 4.60 mmol) was added to the methanolic
solution, and the resulting solution was concentrated on a rotary
evaporator to afford rac-coniine·(S)-(+)-mandelic acid (1.30 g) as a
white solid. This solid was dissolved in diethyl ether (30 mL), and
the solution was stirred at room temperature for 12 h. The precipi-
tate was filtered, and the mother liquor was saved for the recovery
of the (S)-(+)-coniine (vide infra). The white solid was washed with
diethyl ether (10 mL) to give the (R)-(–)-coniine·(S)-(+)-mandelic
acid salt (0.62 g, mixture of diastereoisomers, 75:25 dr); m.p.
115 °C. [α]2D2 = +46 (c = 0.94, EtOH); (R,S)/(S,S), 75:25 dr. This
process was repeated (2ϫ) using diethyl ether (2ϫ20 mL) to give
the (R)-(–)-coniine·(S)-(+)-mandelic acid salt (0.39 g, 60% based
on isomer content, mixture of diastereoisomers, 92:8 dr); m.p.
122 °C. [α]2D2 = +46 (c = 0.94, EtOH); (R,S)/(S,S), 92:8 dr. This
ratio was determined by proton NMR spectroscopy. This solid
(0.28 g) was dissolved in methanol (1.5 mL) followed by the ad-
dition of diethyl ether (20 mL). The resulting solution was kept at
0 °C for 24 h, and the (R)-(–)-coniine·(S)-(+)-mandelic acid salt
[(+)-13b, 0.21 g, 75%] was recovered as a single diastereoisomer
[(R,S)/(S,S), Ն98:2 dr]. The mother liquor from the initial resolu-
tion procedure was cooled to 0 °C and stirred for 10 min with the
addition of water (15 mL) that contained NaOH (0.5 g). The aque-
ous layer was separated and extracted with diethyl ether
90°, β = 97.730(2)°, γ = 90°, V = 2223.30(19) Å3, Z = 8, DX
=
1.185 Mgm–3, µ = 0.71 cm–1, λ(Mo-Kα) = 0.71073 Å, F(000) = 848,
T = 150(2) K. The sample (0.60ϫ0.50ϫ0.30 mm) was studied with
a diffractometer with graphite-monochromatized Mo-Kα radiation.
The data collection (θmax = 27.52°, range of hkl: h –25Ǟ26, k
–8Ǟ8, l –22Ǟ22) gave 8487 reflections with 2524 unique reflections
from which 2110 with I Ͼ 2.0σ(I).
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of derivatives 1–21 and additional
X-ray crystallographic data and ORTEP plots of (–)-5-A and 18.
Acknowledgments
V. H. V. is grateful to the Ministry of Education and Training of
the Socialist Republic of Vietnam for a three-year doctoral fellow-
ship. A. C. is grateful for financial support by the Région Bretagne
(BIPICAT project).
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10
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Asymmetric Syntheses of (–)-Coniine and (–)-Solenopsin A
[2]
[15]
For a detailed investigation of the borohydride reduction of a
pyridinium salt to the corresponding tetrahydropyridine, see:
a) I. S. Young, A. Ortiz, J. R. Sawyer, D. A. Conlon, F. G.
Buono, S. W. Leung, J. L. Burt, E. W. Sortore, Org. Process
Res. Dev. 2012, 16, 1558; in the former reaction, the intermedi-
ary 1,2-dihydropyridine is protonated at C-3, and we do believe
that a similar process occurred in 4b during the formation of
α-amino nitrile 5. For a recent study of the protonation of 1,2-
dihydropyridines, see: b) S. Duttwyler, S. Chen, M. K. Takase,
K. B. Wiberg, R. G. Bergman, J. A. Ellman, Science 2013, 339,
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C. Patrascu, C. Sugisaki, C. Mingotaud, J.-C. Marty, Y. Génis-
son, N. Lauth-de Viguerie, Heterocycles 2004, 63, 2033.
The remarkable efficiency of this reaction sequence suggests
that 1,2-dihydropyridine 4b is stable in THF at temperatures
ranging from –50 to 0 °C. For the dimerization of 1,2-dihy-
dropyridine systems, see: a) K. Jakubowicz, Y.-S. Wong, A.
Chiaroni, M. Bénéchie, C. Marazano, J. Org. Chem. 2005, 70,
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Org. Chem. 2012, 77, 780; b) G. Satyalakshmi, K. Suneel, D. B.
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Ren, W. D. Wulff, J. Am. Chem. Soc. 2011, 133, 5656; d) K.
Damodar, M. Lingaiah, N. Bhunia, B. Das, Synthesis 2011, 15,
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Xu, R. Li, Y. Hu, J. Org. Chem. 2005, 70, 1897; j) Y. Yamashita,
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J. A. Bull, J. J. Mousseau, G. Pelletier, A. B. Charrette, Chem.
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[16]
[17]
[3]
For the cyclization of allylic alcohols, see: a) P. Mukherjee,
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N. Kawai, J. I. Uenishi, J. Org. Chem. 2009, 74, 244; for the
hydroamination/cyclization method, see: S. Hong, A. M. Ka-
waoka, T. J. Marks, J. Am. Chem. Soc. 2003, 125, 15878.
[18]
[19]
The optical rotation of (–)-5-A was also recorded in EtOH and
was found to be [α]2D2 = +5.0 (c = 1.0, EtOH). Because of an
epimerization process in this solvent, this optical rotation grad-
ually changed to the equilibrium value of [α]2D2 = +56 (c = 1.0,
EtOH).
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11

Job/Unit: O30595
/KAP1
Date: 10-07-13 15:45:58
Pages: 12
J.-P. Hurvois et al.
FULL PAPER
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Received: April 24, 2013
Published Online: ᭿
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12
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Eur. J. Org. Chem. 0000, 0–0