Formal Synthesis of (–)-Perhydrohistrionicotoxin Using a Thorpe-Ziegler Cyclization Approach. Synthesis of Functionalized Aza-Spirocycles

Article abstract of DOI:10.1002/ejoc.201801604

The formal synthesis of (–)-PHTX is described. Our approach was based on the anodic cyanation of (S)-1-(1-phenylethyl)-piperidine (–)-1 to afford α-aminonitrile 2 in 85 % yield in a 53:47 dr. The presence of the α-phenylethyl group as the chiral auxiliary

Full text of DOI:10.1002/ejoc.201801604

A Journal of
Accepted Article
Title: Formal Synthesis of (–)-Perhydrohistrionicotoxin Using a Thorpe-
Ziegler Cyclization Approach. Synthesis of Functionalized Aza-
Spirocycles.
Authors: Van Ha Vu, Christelle Bouvry, Thierry Roisnel, Stéphane
Golhen, and Jean-Pierre Hurvois
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801604
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10.1002/ejoc.201801604
European Journal of Organic Chemistry
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Formal Synthesis of (–)-Perhydrohistrionicotoxin Using a Thorpe-
Ziegler Cyclization Approach. Synthesis of Functionalized Aza-
Spirocycles.
Dr. Van Ha Vu,[b] Christelle Bouvry,[a] Dr. Thierry Roisnel,[a] Dr. Stéphane Golhen,[a] Prof. Dr. Jean-
Pierre Hurvois *[a]
Abstract: The formal synthesis of (–)-PHTX is described. Our
approach was based on the anodic cyanation of (S)-1-(1-phenylethyl)-
piperidine (–)-1 to afford -aminonitrile 2 in 85% yield in a 53:47 dr.
The presence of the -phenylethyl group as the chiral auxiliary
ensured the control of the absolute configuration of the future C6
spiro-center during the alkylation step of 2, which was carried out with
Several studies have shown that natural histrionicotoxins,
and their more potent synthetic analogues, such as
perhydrohistrionicotoxin (PHTX), are non-competitive blockers of
the nicotinic acetyl choline receptor (nAChR).[5]
1-bromo-4-chlorobutane.
Next,
elaboration
of
the
1-
azaspiro[5,5]undecane-7-one ring system was achieved in a two-step
sequence, involving (a) a Thorpe-Ziegler annulation, and (b) the
hydrolysis–decarboxylation of enaminonitrile (–)-5 to afford
spiroketone (+)-6 in >99:1 dr. Finally, the incorporation of the future
C7 butyl chain was carried out stereoselectively through a new
reaction sequence which involved the synthesis of tricyclic
oxazolidinone (–)-11 and alkylation of the intermediary syn-
fluorohydrin (+)-13 with nBuMgCl to form oxazolidinone (+)-15 in an
overall 19% yield from (–)-1.
Figure 1. Representation of (–)-HTX-283A and its saturated analogue (–)-PHTX.
These interesting biological properties coupled with the
construction of the unusual heterocyclic core of these alkaloids
has provided a sustained interest in the community of organic
chemists.[6] In the last decade, total or formal syntheses of
members of the histrionicotoxin family have been achieved by the
application of well-designed methodologies, such as: SmI2-
induced ring expansion,[7] cross-methathesis-hydrogenation,[8]
free-radical induced cyclizations,[9] intramolecular nitrone
cycloaddition,[10] dienyne metathesis,[11] and rearrangement of
deprotonated aziridines.[12]
Introduction
Histrionicotoxin (HTX-283A, figure 1) was isolated in 1971
by Daly and co-workers from the skin extracts of 800 specimens
of poison frogs belonging to the neotropical family Dendrobatidae.
The 1-azaspiro-[5,5]-undecan-8-ol structure and the absolute
configuration of this new alkaloid were elucidated by an X-ray
diffraction study.[1]
To date, approximately 20 new alkaloids have been isolated
from dendrobatid frogs, all of which share the same spiro-ring
system substituted at the C2 and C7 positions by unsaturated
alkyl chains.[2,3] Recently, methanol extracts of ants of the species
Carabella bicolor were found to contain histrionicotoxins
indicating that alkaloids accumulated in the skin of amphibians
arise from a dietary source.[4]
[a]
[b]
ISCR (Institut des Sciences Chimiques de Rennes) - UMR 6226
Université de Rennes, CNRS
F-35000 Rennes, France
E-mail: jean-pierre.hurvois@univ-rennes1.fr
Homepage:
Laboratory of Organic Chemistry
Vietnam Institute of Industrial Chemistry
2 Pham Ngu Lao - Hoan Kiem Dist. - Hanoi, Vietnam
Scheme 1. Retrosynthetic analysis of (–)-PHTX from -aminonitrile 2.
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In this contribution, we wish to present a new route to chiral
spiro-piperidine (+)-9, a known intermediate to unnatural (–)-
PHTX.[13] The retrosynthetic analysis is presented in scheme 1
and is based on the electrochemical synthesis of -aminonitrile 2,
while an asymmetric alkylation would control the absolute
configuration of the future C6 atom. We also hypothesized, that a
Thorpe-Ziegler annulation sequence could be efficient for the
formation of the C7-C8 bond of the 1-azaspiro-[5,5]undecane
heterocyclic system.
aminonitrile
diastereoisomers.
2
in 85% yield as
a
mixture (53:47) of
The quaternary -aminonitrile (+)-3 was synthesized in two
steps: the deprotonation of 2 and alkylation of the resulting -
cyano-carbanion (Scheme 3). Treatment of an epimeric mixture
(53:47) of -aminonitrile 2 with 1.4 equivalents of LDA produced
the intermediary red anion solution. Addition of 1-bromo-4-
chlorobutane gave -aminonitrile (+)-3 in 90% yield after
chromatographic purification. Of note, quaternary -aminonitriles
of the type of (+)-3 proved to be unstable when exposed to a mild
acidic medium. Therefore, to avoid a Retro-Strecker type
decomposition, the purification step and characterization should
be carried out with care.[16] The reaction sequence provided two
diastereoisomers which could be differentiated by distinct
resonance signals of the benzylic protons of the -PEA group.
This signal resonated in the major diastereoisomer as a quartet (J
= 6.8 Hz) at  = 4.45. Hence, comparison of the relative
integrations of these two diagnostic protons indicated an
alkylation event with a 90:10 dr.
Results and Discussion
This work began with the synthesis of -aminonitrile 2
according to a reaction sequence described previously (Scheme
2).[14] Thus, heating (–)--phenylethylamine (-PEA) with 1.2
equivalents of 1,5-dibromopentane in DMSO for 4 h in the
presence of an excess of K2CO3, provided (–)-1 in 89% yield. We
then carried out an analytical study to determine the best
conditions for the electrochemical synthesis by dissolving
piperidine (–)-1 in methanol in the presence of LiClO4•3H2O as
the supporting electrolyte and 2.5 equivalents of NaCN.[15]
Figure 2. Cyclic Voltammogram of piperidine (–)-1 (15 mmol).
MeOH/LiClO4•3H2O (0.1 M), glassy carbon electrode,  = 0.05 Vs–1, NaCN (35
mmol).
Scheme 2. Anodic cyanation of piperidine (–)-1. Reagents and conditions: (a)
(S)-(–)--PEA, 1,5-dibromopentane, K2CO3, DMSO, 50 °C, 2 h, then 100 °C, 2
h. (b) MeOH/LiClO4, NaCN, Ep = 1.0 V (ECS).
The dinitrile (+)-4 was synthesized by prolonged
treatment of (+)-3 with NaCN in DMSO for 72 h in the presence of
catalytic amounts of Bu4NI. Substitution of the terminal chlorine
atom proceeded well, providing dinitrile (+)-4 in 95% yield in a
90:10 dr which could be improved to >99:1 dr by a slow
crystallization in diethyl ether at –20 °C. A single crystal X-ray
analysis, revealed the absolute configuration of the newly created
chiral center to be S (Figure 3).
The cyclic voltammogram (Figure 2) was carried out
using a vitreous carbon electrode at a scan rate of 0.05 V.s–1, and
potentials were recorded versus a saturated calomel electrode
(SCE). As is typical for tertiary amines, an irreversible bielectronic
system was recorded at Ep1 = +1.0 V corresponding to the
oxidation of (–)-1 to iminium cation A which was directly converted
into -aminonitrile 2 upon condensation with cyanide anions at
the anode surface. Under these conditions, a macroscale
electrolysis of (–)-1 was carried out on a 10 g scale in an undivided
cell equipped with a glassy carbon electrode (diameter = 10 cm)
as anode and a carbon rod as cathode at a controlled potential of
+ 1.0 V. After consumption of 2.1 Faradays per mole of substrate,
the electrolysis was stopped. Aqueous work-up and purification of
the crude reaction mixture on a silica column afforded -
Next, we investigated the formation of the C7-C8 bond
through
a
Thorpe-Ziegler annulation sequence. This
transformation is typically accomplished in the presence of
various organic or mineral bases such as: tBuOK,[17]
morpholine,[18] K2CO3,[19] sodium methyl phenyl amide,[20]
LiHMDS,[21] NaNH2,[22] while Murahashi accomplished this
cyclization under base-free conditions by iridium hydride complex
catalysis.[23] However, based on our previous experiments, we
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10.1002/ejoc.201801604
European Journal of Organic Chemistry
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believed that LDA should remain the base of choice to perform
the reaction under non-epimerizing conditions.[24]
Figure 3. ORTEP view of derivative (+)-4. Thermal ellipsoid plots are drawn at
40% probability.
Thus, the addition of 1.3 equivalents of LDA onto a THF
solution of dinitrile (+)-4 cooled to –80 °C and stirring the solution
at 0 °C for 12 h, resulted in the formation of enaminonitrile (–)-5
in 90% yield after filtration on a chromatography column. The
spectroscopic data of (–)-5 (1H and 13C NMR) were consistent with
the formation of a single diastereoisomer providing evidence that
cyclization occurred without epimerization at the future C6 carbon.
In addition, the high-resolution mass spectrum supported the
molecular formula C19H25N3Na through a signal at m/z 318.1946
(M + Na)+.
Scheme 3. Formal synthesis of (–)-HTX. reagents and conditions: (a) LDA,
THF, –80 °C to 0 °C, 2 h, then 1-bromo-4-chlorobutane, –80 °C to rt. (b) NaCN,
Bu4NI (10% mol), DMSO, 72 h, rt. (c) LDA, THF, –80 °C to 0 °C, 12 h. (d)
Toluene, HCl 35%, reflux, 15 h. (e) 10% Pd/C, MeOH, H2 (1 bar), 20 °C, 24 h.
(f) BnBr, DMSO, Na2CO3, 72 h, 20 °C.
Having secured the absolute configuration of the C6 spiro-
center, we set ketone (+)-6 as the next synthetic target. We were
inspired by a protocol previously proposed by Piers and
Abeysekera aiming to perform hydrolysis-decarboxylation of
enaminonitrile (–)-5 in the same flask.[17b] Heating our sample in a
1:10 mixture of phosphoric acid in glacial acetic acid, resulted in
poor conversion (<30%) and formation of unidentified products
presumably through a polymerization process. Neither alteration
of the reaction parameters nor varying the medium composition
impacted significantly the overall yield and the reaction rate. To
get more insight into this process, we sought to isolate the
intermediate -keto-nitrile derived from (–)-5. Scrutinizing the
literature data revealed that such derivatives could be obtained
from acid hydrolysis of enaminonitriles.[25] Our first experiments
were carried out by stirring enaminonitrile (–)-5 for 16 h at room
temperature, in a two-phase system consisting of a mixture of
37% hydrochloric acid and toluene. Unfortunately, no reaction
occurred under these conditions, and we reasoned that
significantly higher yields should be obtained at a more elevated
temperature. Indeed, heating the medium for 2 h at 100-110 °C
cleanly produced ketone (+)-6 (30% yield) together with
unreacted enaminonitrile (–)-5. On increasing the reaction time to
15 h, the ketone (+)-6 was recovered as the sole product in 80%
yield after chromatographic purification.
Structural determination was straightforward. In the 13C
NMR spectrum, the C7 quaternary carbon gives a resonance
signal at  = 216.2 ppm and both 1H and 13C NMR analysis
suggested product formation without erosion of chirality. Taken
together, these results indicated that protonation of the
enaminonitrile is slow and that decarboxylation of the
intermediary -keto-acid occurred at high temperature.
Further optimization provided more information about the
reactivity of spiroketone (+)-6 under acidic conditions. Close
examination of the 1H NMR spectrum of the crude reaction
mixture revealed the presence of an additional ethylenic doublet
of doublet (3J = 4.8, 3.2 Hz) signal at  = 6.10 ppm corresponding
to the vinylic proton of more polar hexahydrophenanthridine (–)-7
(Scheme 3) which was isolated in 5% yield after purification by
column chromatography (dichloromethane/methanol 7:3). To
determine the origin of this unexpected compound, a control
experiment with spiroketone (+)-6 was conducted (15 h, 110 °C)
as synthesis of (+)-6. Indeed, the hexahydrophenanthridine (–)-7
was obtained in 30% yield, together with unreacted starting
material, providing evidence of an intramolecular Friedel-Crafts
type process.
All that remained to carry out the formal synthesis of (–
)-PHTX was to replace the -PEA group by a benzyl substituent
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(Scheme 3). Gratifyingly, removal of the chiral appendage was
easily carried out in the presence of 10% Pd/C in methanol under
a hydrogen pressure of 1 bar. The expected spiropiperidine was
obtained as its mandelate salt (–)-8 (m.p. = 141-142 °C) in nearly
quantitative yield. Due to a strong steric hindrance around the
nitrogen atom, the alkylation step necessitated a prolonged
reaction time. Nevertheless, treatment of the mandelate salt (–)-8
with an excess (2 equiv.) of benzylbromide in DMSO for 72 h
afforded spiropiperidine (+)-9 in 85% yield after chromatographic
purification. The optical rotation of our sample was recorded in
piperidine (+)-10 in 93% yield. We found only a few reports in the
literature where transfer of two chlorine atom takes place at the
carbonyl group. Our preliminary experiments which were carried
out with traditional chlorinating reagents such as PCl5, proved to
be problematic and afforded a mixture of products.[28] We also
explored
the
chlorination
of
(+)-10
with
dichlorotriphenylphosphorane (Ph3PCl2) as an alternative to the
previous method.[29,30] The reaction was carried out in the
presence of TMEDA as the base and afforded oxazolidinone (–)-
11 as the sole product. A detailed examination of the spectrum of
(–)-11 confirmed the proposed structure. The downfield value (
= 5.14 ppm) for the resonance signal of 1-H coupled with a
chloroform ([]22 = +15.0, c 1.0, CHCl3) and proved to be
D
identical to that reported in the literature ([]22 = +15.0, c 2.06,
D
CHCl3).[26]
characteristic J value of 3.7 Hz confirmed the presence of an
3
With an efficient stereoselective route to enantiopure
spiropiperidine (–)-8 in hand, we sought to develop a new and
reliable route for the introduction of the butyl chain at the future
C7 position (Scheme 4). With this purpose in mind, we turned to
recent studies devoted to the Cu-catalyzed cross-coupling
condensation between alkyl-chlorides and Grignard reagents.[27]
Therefore, we screened several reagents that were expected to
perform the chlorination of (+)-10. Access to the starting material
was straightforward.
ethylenic double bond. The 13C NMR spectrum contained also two
characteristic signals resonance lines at  = 99.7 and 150.1 which
could be easily attributed to the C7 and C8 carbon atoms,
respectively. This cyclization process could be explained as
follows (Scheme 5). First, treatment of (+)-10 with
Ph3PCl2/TMEDA activates the C7 carbon through the probable
formation of vinyloxyphosphorane B which is in equilibrium with
the cationic intermediate C.[31] Second, the presence of a highly
electrophilic carbon in close proximity of the carbonyl group,
induced a cyclization process to form intermediate D which
decomposed into oxazolidinone E with loss of isobutylene and
OPPh3.[32] Finally, elimination of HCl from E, leads to
oxazolidinone (–)-11.
Scheme 5. Proposed mechanism for the cyclization of (+)-10.
Scheme 4. Synthesis of oxazolidinone (+)-15. Reagents and conditions (a)
Boc2O, DIPEA, acetonitrile, reflux, 3 h. (b) TMEDA, Ph3PCl2, acetonitrile, rt, 4 h.
(c) Oxone, Na2B4O7•10H2O, acetone, CH2Cl2, 0 °C, 4 h. (d) BF3•Et2O, Et2O, 0 °C,
1 h. (e) nBuMgBr, CuCl2 (5 mol%), THF, rt, 2 h. (f) NaH, MOMCl, NaI (10 mol%),
THF, rt, 16 h.
With this unexpected derivative in hand, we set epoxide (–)-
12 as the next synthetic target. The reaction was best achieved
by stirring (–)-11 in a mixture of dichloromethane, acetone and
Oxone, while the pH of the reaction medium was maintained at
ca. 9–10 by the continuous addition of an aqueous solution of
sodium tetraborate.[33] Under these in situ conditions, epoxide (–)-
12 was isolated (95%) as a colorless solid (m.p. = 110-111 °C)
Refluxing the mandelate salt (–)-8 in acetonitrile for 3 h
in the presence of Boc2O and an excess of DIPEA afforded
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with >92:8 dr. A single crystal X-ray study revealed the
stereochemical outcome of the epoxidation process. The ORTEP
view (Figure 4) indicated that addition of the assumed
dimethyldioxirane intermediate occurred on the less hindered Re
face of oxazolidinone (–)-11. With epoxide (–)-12 available in
good yield, several attempts were made to install the future C7
alkyl chain with concomitant epoxide ring opening. Unfortunately,
reacting (–)-12 with an excess of nBuLi (2 equiv.) in the presence
of BF3•Et2O (5 equiv.) as the Lewis acid met with failure, with no
perceptible formation of the expected product probably due to the
sensitivity of the oxazolidine ring to these reaction conditions.[34]
The relative syn-configuration within (+)-13 was established from
an X-ray analysis (Figure 5) performed on one single crystal
obtained from a slow crystallization of (+)-13 in a mixture of diethyl
ether and petroleum ether.[36] In the penultimate step, the butyl
chain was introduced by modifying the protocol developed by
Terao and Kambe.[35] Indeed, we rapidly observed that an efficient
coupling could be achieved between (+)-13 and a Grignard
reagent. Thus, the addition of two equivalents of nBuMgCl to a
THF solution of (+)-13 containing a catalytic amount of CuCl2 (5
mol%) resulted in the isolation of (+)-14 (95%) whose absolute
configuration probably corresponds to that drawn in scheme 4.
Evidence for the presence of the butyl chain in (+)-15 was
1
provided by H and 13C NMR techniques and high-resolution
mass spectra with [M + Na]+ at 290.1735. Finally, and for our
further chemical purposes, the protection of the secondary
alcohol function was carried out in the presence of MOMCl to
provide (+)-15 as a single diastereoisomer after purification on a
chromatography column.
Conclusions
In summary, anodic cyanation and Thorpe-Ziegler
annulation proved to be an efficient combination to construct in a
stereoselective fashion the 1-azaspiro[5.5]undecane ring system
of the histrionicotoxin alkaloids. Apart from the generally high
yields in each individual step, we present an efficient and scalable
synthesis of oxazolidinone (+)-15 which may serve as an
advanced precursor to the synthesis of (–)-PHTX. This work is
currently under investigation in the laboratory and will be reported
in due course.
Figure 4. ORTEP view of epoxide (–)-12. Thermal ellipsoid plots are drawn at
40% probability.
Experimental Section
The search for a more robust method led to consider the
coupling between an alkyl fluoride and a Grignard reagent.[35]
Thus, treatment of epoxide (–)-12 in diethyl ether with 2.2
equivalents of BF3•Et2O as the nucleophilic fluoride source, gave
fluorohydrin (+)-13 as a colorless solid (m.p. = 113–114 °C) in
75% yield and >98:2 dr.
Experimental section
General Techniques: Purification by chromatography column was
performed with 70–230 mesh silica gel. TLC analyses were carried out on
alumina sheets precoated with silica gel 60 F254; Rf values are given for
1
guidance. The H NMR spectra were recorded with a 400 MHz or a 300
MHz spectrometer. The 13C NMR spectra were recorded with a 100 MHz
or a 75 MHz spectrometer. Positive-ion mass spectra were recorded on an
orthogonal acceleration quadrupole time-of-flight mass spectrometer
equipped with a standard electrospray probe. Melting points were
measured on a Kofler apparatus, the values reported in °C, and were
uncorrected. Optical rotations were recorded at 20 °C in a 1 dm cell. For
air-sensitive reactions, the glassware was oven-dried (90 °C) for 24 h and
cooled under a stream of argon before use. All commercially available
reagents were used as supplied and THF was distilled over sodium
benzophenone ketyl. Diisopropylamine was distilled from solid potassium
hydroxide.
Electrochemical techniques. Cyclic voltammetry experiments
were carried out on a potentiostat using a three-electrode device with a
glassy carbon (GCE, diameter = 2 mm) as the working electrode, a
saturated calomel electrode (SCE) as the reference and a platinum wire
as the auxiliary electrode. The experiments were carried out in methanol
containing LiClO4•3H2O (0.1 mol L–1) as the supporting electrolyte.
Figure 5. ORTEP view of syn-fluorohydrin (+)-13. Thermal ellipsoid plots are
drawn at 40% probability.
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Preparative electrolysis was carried out at controlled potential in a single
compartment cell. The solution was stirred with a magnetic stirring bar and
the electrolysis was stopped after the consumption of 2.1 F/mole.
continued at 0 °C for 30 minutes and the LDA solution was transferred (via
a cannula) into a 200-mL Schlenk tube cooled to –80 °C, containing 3.35
g (15.63 mmol) of a mixture (53:47 dr) of -aminonitrile 2 dissolved in 10
mL of dry THF. The solution turned rapidly red and was warmed to 0 °C
for 2.0 h and then was cooled to –80 °C. Then, 2.33 mL (3.47 g, 20.22
mmol, 1.29 equiv.) of 1-bromo-4-chlorobutane were added dropwise and
the reaction mixture was warmed to 0 °C and was stirred at that
temperature for 12 h. The solvents were evaporated under reduced
pressure, and the crude material was taken-up with 20 mL of water. The
aqueous layer was extracted with 2 × 25 mL of diethyl ether and the
organic phases were dried over MgSO4 and concentrated. The crude oily
residue (5.40 g) was poured into a chromatography column prepared with
20 g of silica and 1:2 diethyl ether/petroleum ether. The combined fractions
were concentrated to afford 4.28 g (90%) of -aminonitrile (+)-3 as a
(S)-(–)-1-(1-phenylethyl)-piperidine, (–)-1. To
a
solution of (S)-
phenylethylamine (4.14 mL, 3.99 g, 33.00 mmol) in DMSO (20 mL) was
added 1,5-dibromopentane (5.39 mL, 9.10 g, 39.67 mmol, 1.20 equiv.) and
powdered K2CO3 (10.00 g, 72.36 mmol, 2.19 equiv.). The reaction mixture
was heated at 50 °C for 2 hours and then at 100 °C for an additional 2
hours period. After cooling, the reaction mixture was poured over 50 mL of
brine and the resulting mixture was extracted with 30 mL of
dichloromethane (x 3). The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure to afford a crude oil
which was transferred to
a
chromatography column (diethyl
mixture [90 (S,R):10 (S,S) dr] of diastereoisomers. Colorless oil. []22
=
D
ether/petroleum ether, 1:1). The combined fractions were evaporated to
+2.8 (c 1.0, C6H6). Rf = 0.30 (petroleum ether/diethyl ether, 95:5). 1H NMR
(isomeric mixture, 90 (S,R):10 (S,S) dr, major diastereoisomer, CDCl3, 400
MHz)  = 1.20–1.40 (m, 1 H), 1.55 (d, J = 6.8 Hz, 3 H), 1.64–2.04 (m, 11
H), 2.55–2.65 (m, 2 H), 3.55 (t, J = 6.1 Hz, 2 H), 4.44 (q, J = 6.8 Hz, 1 H),
7.25 (t, J = 5.2 Hz, 1 H), 7.35 (t, J = 6.0 Hz, 2 H), 7.44 (d, J = 7.0 Hz, 2 H).
IR (film, cm–1): 2937, 2214, 1493, 1444, 1119, 698.13C NMR (CDCl3, 100
MHz)  = 11.5 (p), 20.8 (s), 22. 2 (s), 25.4 (s), 32.5 (s), 36.2 (s), 37.3 (s),
42.9 (s), 44.4 (s), 53.8 (t), 59.7 (q), 121.8 (q), 126.6 (t), 128.1 (t), 144.1 (q).
HRMS (ESI+, CH3OH, C18H25ClN2Na [M + Na]+) calcd for 327.1604, found
327.1601. Anal. Calcd for C18H25ClN2 (304.8): C, 70.92; H, 8.27; N, 9.19.
Found C, 70.78; H, 8.30; N, 9.16.
afford piperidine (–)-1 (5.60 g, 90%). Colorless oil. []22 = –27.3 (c 1.2,
D
CHCl3). Rf = 0.5 (diethyl ether/petroleum ether, 1:1). 1H NMR (CDCl3, 400
MHz)  = 1.36 (d, J = 6.8 Hz, 3 H); 1.32–1.41 (m, 2 H); 1.50–1.57 (m, 4 H);
2.30–2.44 (m, 4 H); 3.39 (q, J = 6.8 Hz, 1 H); 7.20–7.25 (m, 1 H); 7.27–
7.33 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz)  = 19.4 (p); 24.6 (s); 26.3
(s); 51.5 (s); 65.2 (t); 126.6 (t); 127.8 (t); 128.0 (t); 144.0 (q). IR (film, cm–
1): 2970, 2930, 2751, 1490, 1450, 1372, 939, 698. HRMS (ESI+, CH3OH,
C13H20N [M + H]+) calcd for 190.1595, found 190.1594. Anal. Calcd for
C13H19N (189.3): C, 82.48; H, 10.12; N, 7.40. Found: C, 82.20; H, 10.10;
N, 7.39.
1-((S)-1-phenylethyl)-piperidine-2-carbonitrile, 2. A 1000 mL undivided
electrolysis cell fitted with a vitreous carbon anode (diameter = 100 mm)
and a magnetic stirrer, was successively charged with 300 mL of methanol,
9.90 g (52.34 mmol) of piperidine (–)-1, 4.90 g of LiClO4•3H2O, and 6.40 g
(130.60 mmol, 2.48 equiv.) of NaCN. The working potential is adjusted to
+ 1.00 V/SCE and after the consumption of 10 600 C (2.10 F/mol), the
electrolysis was stopped. Then, 1000 mL of brine were added to the
electrolysis solution and the reaction mixture was extracted with 2 × 200
mL of diethyl ether. The combined organic layers were dried over MgSO4
and concentrated to afford 10.5 g of a crude oil which was poured into a
chromatography column (50 × 5.0 cm, ethyl acetate/pentane, 10:90). The
combined fractions were evaporated to afford to -aminonitrile 2 (9.59 g,
85%) as a mixture (53:47) of diastereoisomers. Yellow oil. Rf = 0.45 (ethyl
acetate/pentane, 10:90). Caution: LiClO4 may lead to severe explosions
when the material is evaporated to dryness. The excess of NaCN was
destroyed by the addition of KMnO4 onto the resulting aqueous phase. Due
to the possible release of HCN, the electrolysis should be carried out under
a well-ventilated hood. 1H NMR (CDCl3, 400 MHz)  = 1.33 (d, J = 6.6 Hz,
1.41 H), 1.37 (d, J = 6.6 Hz, 1.59 H), 1.32–1.45 (m, 1 H), 1.50–1.79 (m,
4.06 H); 1.87 (tt, J = 12.0, 4.2 Hz, 0.47 H), 1.95–2.02 (m, 0.47 H), 2.16 (td,
J = 12.2, 2.8 Hz, 0.47 H), 2.35 (td, J = 11.6, 2.9 Hz, 0.53 H), 2.60 (dm, J =
11.0 Hz, 0.47 H), 3.20 (dm, J = 11.8 Hz, 0.53 H), 3.47 (q, J = 6.6 Hz, 0.53
H); 3.52 (q, J = 6.6 Hz, 0.47 H), 3.59 (t, J = 3.0 Hz, 0.53 H), 4.24 (t, J = 3.3
Hz, 0.47 H), 7.21–7.37 (m, 5 H). 13C NMR (CDCl3, 100 MHz)  = 20.5 (s),
20.7 (s), 21.0 (p), 21.5 (p), 25.1 (s), 25.3 (s), 28.9 (s), 29.2 (s), 45.6 (s),
48.2 (s), 49.7 (t), 51.7 (t), 63.1 (t), 63.2 (t), 117.0 (q), 117.2 (q), 127.2 (t),
127.3 (t), 127.5 (t), 128.5 (t), 128.8 (t), 143.9 (q), 144.7 (q). IR (film, cm–1):
2973, 2938, 2214, 1491, 1452, 1124, 939, 700. HRMS (ESI+, CH3OH,
C14H18N2Na [M + Na+]) calcd for 237.1367, found 237.1367. Anal. Calcd
for C14H18N2 (214.3): C, 78.46; H, 8.47; N, 13.07. Found: C, 78.75; H, 8.46;
N, 13.00.
(S)-2-(4-cyanobutyl)-1-((S)-1-phenylethyl)-piperidine-2-carbonitrile, (+)-4.
-Aminonitrile (+)-3 (3.04 g, 9.97 mmol) was dissolved in 25 ml DMSO in
the presence of 1.40 g (28.57 mmol, 2.86 equiv.) of NaCN and 0.30 g (0.81
mmol, 0.08 equiv.) of nBu4NI. The reaction mixture was stirred at room
temperature for 72 h and was poured onto 200 ml of water. The products
were extracted with 100 mL of diethyl ether (x 3) and the combined organic
phases were washed with water, dried over MgSO4 and concentrated. The
crude oily residue was poured into a chromatography column prepared
with 20 g of silica diethyl ether. The fractions were concentrated to afford
a highly viscous oil which was dissolved in a minimum of diethyl ether and
was kept at –20 °C for 24 h. The precipitate was filtered on a sintered-
glass funnel to afford 2.67 g (91%) of -aminonitrile (+)-4 as a single
diastereoisomer. Rf = 0.42 (diethyl ether). Slightly brown flakes. []22
=
D
+7.2 (c 1.0, C6H6). Mp = 79–80°C. 1H NMR (C6D6, 400 MHz)  = 0.70–0.80
(m, 2 H), 1.00–1.20 (m, 5 H), 1.26 (t, J = 7.3 Hz, 2 H), 1.30–1.45 (m, 4 H),
1.41 (d, J = 6.8 Hz, 3 H), 1.51 (tt, J = 13.0, 3.8 Hz, 1 H), 2.35 (dm, J = 12.2
Hz, 1 H), 2.48 (td, J = 12.2, 2.7 Hz, 1 H), 4.12 (q, J = 6.8 Hz, 1 H), 7.10
(tm, J = 6.0 Hz, 1 H), 7.21 (tt, J = 6.0, 2.2 Hz, 2 H), 7.27 (dm, J = 6.0 Hz,
2 H). 13C NMR (C6D6, 100 MHz,)  = 11.3 (p), 16.1 (s), 22.0 (s), 22.2 (s),
25.1 (s), 25.2 (s), 35.7 (s), 36.9 (s), 42.7 (s), 53.6 (t), 59.1 (q), 118.6 (q),
121.0 (q), 126.6 (t), 126.9 (t), 128.1 (t), 144.2 (q). 1H NMR (CDCl3, 400
MHz)  = 1.30–1.42 (m, 1 H), 1.54 (d, J = 6.8 Hz, 3 H), 1.57–1.85 (m, 8 H),
1.90–2.39 (m, 3 H), 2.36 (t, J = 6.6 Hz, 2 H), 2.59–2.67 (m, 2 H), 4.41 (q,
J = 6.8 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 2 H), 7.42 (d,
J = 8.0 Hz, 2 H). 13C NMR (CDCl3, 100 MHz,)  = 11.7 (p), 17.1 (s), 22.1
(s), 22.6 (s), 25.4 (s), 25.5 (s), 36.2 (s), 37.3 (s), 43.0 (s), 53.9 (t), 59.7 (q),
119.2 (q), 122.0 (q), 126.6 (t), 126.9 (t), 128.2 (t), 144.1 (q). IR (film, cm–
1): 2967, 2860, 2245, 2210, 1443, 1071, 699. HRMS (ESI+, CH3CN/CH3OH,
C18H25N2 [M – HCN + H]+ calcd for 269.2017, found 269.2017. Anal. Calcd
for C19H25N3 (295.4): C, 77.25; H, 8.53; N, 14.22. Found C, 77.46; H, 8.50;
N, 14.20.
(R)-2-(4-chlorobutyl)-1-((S)-1-phenylethyl)-piperidine-2-carbonitrile, (+)-3.
An oven dried, 200-mL, one-necked Schlenk tube, fitted with a magnetic
stirring bar, was flushed with argon and was charged with 15 mL of dry
THF and 3.75 mL (2.69 g, 26.57 mmol, 1.70 equiv.) of diisopropylamine.
The solution was cooled to –80 °C before the addition of 8.76 mL (21.90
mmol, 1.40 equiv.) of n-butyllithium (2.5 M solution in hexane). Stirring was
(S)-7-amino-1-((S)-1-phenylethyl)-1-azaspiro[5.5]undec-7-ene-8-
carbonitrile, (–)-5. An oven dried, 200-mL, one-necked Schlenk tube, fitted
with a magnetic stirring bar, was flushed with argon, and was successively
charged with 20 mL of dry THF and 2.41 mL (1.72 g, 17.10 mmol, 1.4
equiv.) of diisopropylamine. The flask was cooled to –80 °C and 6.34 mL
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801604
European Journal of Organic Chemistry
FULL PAPER
(15.85 mmol, 1.3 equiv.) of n-butyllithium (2.5 M solution in hexane) were
added to the previous solution. Stirring was continued for 30 min at 0 °C
and the resulting LDA solution was then added dropwise into a 200-mL
Schlenk tube cooled to –80 °C containing 3.60 g (12.20 mmol) of -
aminonitrile (+)-4 dissolved in 50 mL of dry THF. The solution was warmed
to 0 °C and stirring was continued at that temperature for 12 h. The
solvents were evaporated under reduced pressure, and the crude material
was taken-up with 20 mL of water. The aqueous layer was extracted with
50 mL of diethyl ether (x 2) and the organic phases were dried over MgSO4
and concentrated. The crude oily residue is poured into a chromatography
column containing 40 g of silica and 1:2 petroleum ether/diethyl ether. The
fractions were collected and concentrated to afford 3.24 g (90%) of
enaminonitrile (–)-5 as a single diastereoisomer. Vitreous solid. Rf = 0.30
(petroleum ether/diethyl ether, 7:3). []22D = –200.7 (c 0.9, CHCl3).1H NMR
(CDCl3, 400 MHz)  = 1.36 (d, J = 6.8 Hz, 3 H), 1.39–1.85 (m, 10 H), 2.10–
2.28 (m, 2 H), 2.37 (td, J = 11.8, 2.8 Hz, 1 H), 3.20 (dm, J = 11.8 Hz, 1 H),
3.83 (q, J = 6.8 Hz, 1 H), 5.01 (s, 2 H), 7.20–7.31 (m, 5 H). 13C NMR (CDCl3,
100 MHz)  = 19.8 (s), 20.0 (s), 21.9 (p), 22.8 (s), 24.4 (s), 26.7 (s), 35.3
(s), 42.0 (s), 59.6 (t), 61.1 (q), 74.8 (q), 121.1 (q), 126.9 (t), 128.2 (t), 128.8
(t), 148.8 (q), 162.3 (q). IR (film, cm–1): 3468, 3361, 2930, 2181, 1615,
1573. HRMS (ESI+, CH3OH, C19H25N3Na [M + Na]+) calcd for 318.1946,
found 318.1944. Anal. Calcd for C19H25N3 (295.4): C, 77.25; H, 8.53; N,
14.22. Found C, 77.00; H, 8.55; N, 14.17.
4.0 Hz, 1 H), 2.10–2.31 (m, 1 H), 2.69 (dd, J = 10.4, 4.4 Hz, 1 H), 2.82 (dm,
J = 14.5 Hz, 1 H), 3.28 (ddd, J = 14.5, 12.7, 3.2 Hz, 1 H), 4.10 (q, J = 6.8
Hz, 1 H), 6.10 (dd, J = 4.8, 3.2 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 7.11–
7.20 (m, 2 H), 7.32 (dd, J = 7.3, 1.2 Hz, 1 H). 13C NMR (CDCl3, 100 MHz)
 = 18.1 (s), 19.2 (s), 19.6 (s), 26.06 (p), 26.09 (s), 27.8 (s), 32.1 (s), 44.2
(s), 53.2 (t), 53.9 (q), 125.2 (t), 125.0 (t), 126.0 (t), 126.3 (t), 126.5 (t),133.3
(q), 138.9 (q), 139.0 (q). HRMS (ESI+, CH3OH, C18H24N [M + H]+) calcd for
254.1908, found 254.1910. Anal. Calcd for C18H23N (253.4): C, 85.32; H,
9.15; N, 5.53. Found C, 85.46; H, 9.13; N, 5.55.
(S)-1-azaspiro[5.5]undecan-7-one•(R)-mandelic acid, (–)-8. A 100-mL
low-pressure hydrogenator was charged with 60 mL of methanol, 3.0 g
(11.05 mmol) of spiropiperidine (+)-6 and 0.3 g (10% in mass) of 10% Pd/C.
Air was removed from the reactor by alternately venting it three times with
argon and filling it with hydrogen. The pressure (7.5 × 102 Torr, 1 bar) was
applied, and the solution was stirred for 24 h at room temperature. The
suspension was filtered over a short pad of Celite and the vessel was
washed with methanol. Then, 1.68 g (11.04 mmol) of (R)-(–)-mandelic acid
were added to the methanolic solution which was concentrated on a rotary
evaporator to afford 3.34 g (95%) of mandelate salt (–)-8 as a white solid.
Mp: 141–142 °C. []22D = –13.4 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz)
 = 1.20–1.31 (m, 1 H), 1.48–1.71 (m, 7 H), 1.76 (td, J = 12.4, 4.4 Hz, 1 H),
1.86–1.95 (m, 1 H), 1.96–2.03 (m, 1 H), 2.12 (dm, J = 12.8 Hz, 1 H), 2.35–
2.45 (m, 2 H), 2.87–3.01 (m, 1 H), 3.30–3.40 (m, 1 H), 4.91 (s, 1 H), 7.19
(tt, J = 6.4, 1.0 Hz, 1 H), 7.24–7.30 (m, 3 H), 7.48 (d, J = 7.0 Hz, 2 H), 6.5–
8.5 (s, br. 2 H). 13C NMR (CDCl3, 400 MHz)  = 18.6 (s), 20.6 (s), 21.7 (s),
27.3 (s), 29.1 (s), 35.3 (s), 38.2 (s), 40.6 (s), 65.3 (q), 74.2 (t), 126.6 (t),
126.8 (t), 127.8 (t), 142.4 (q), 177.7 (q), 207.9 (q). IR (neat, cm–1): 3157,
3060, 1724, 1606, 1584, 724. HRMS (ESI+, CH3OH, C10H18NO [M]+) calcd
for 168.1388, found 168.1388. Anal. C18H24NO4 (319.4): C, 67.69; H, 7.89;
N, 4.39. Found C, 67.94; H, 7.90; N, 4.33.
(S)-1-((1S)-1-phenylethyl-1-azaspiro[5.5]undecan-7-one, (+)-6. To
a
solution of enaminonitrile (–)-5 (4.00 g, 13.54 mmol) in toluene (60 mL)
were added 10 ml of 37% hydrochloric acid. The resulting biphasic system
was refluxed for 15 h and was poured onto a 10% Na2CO3 solution (150
mL). The solution was stirred for 1 h while maintaining the pH of the
aqueous phase at 12. The organic phase was discarded and the aqueous
layer was extracted with 50 mL of diethyl ether (x 2). The combined organic
phases (toluene plus diethyl ether) were washed with water, dried over
MgSO4 and concentrated. The crude oil was poured on a chromatography
column containing 40 g of a slurry of silica gel and 7:3 pentane/diethyl
ether. The combined fractions were concentrated to give 3.30 g (90%) of
spiropiperidine (+)-6. Colorless oil. Rf = 0.30 (petroleum ether/diethyl ether,
(S)-1-benzyl-1-azaspiro[5.5]undecan-7-one, (+)-9. To
a solution of
mandelate salt (–)-8 (0.32 g, 1.0 mmol) in DMSO (3 mL) were successively
added 0.150 g (1.41 mmol, 1.40 equiv.) of Na2CO3 and 0.342 g (2.0 mmol,
2.0 equiv.) of benzyl bromide. The reaction mixture was stirred at room
temperature for 72 h and was poured onto 50 ml of water. The products
were extracted with 150 mL diethyl ether (x 2) and the combined organic
phases were washed with water, dried over MgSO4 and concentrated. The
crude reaction mixture was poured on a chromatography column prepared
with 20 g of silica and 6:4 petroleum ether/diethyl ether. The combined
fractions were concentrated to afford 0.220 g (85%) of piperidine (+)-9.
1
7:3). []22D = +47.3 (c 1.0, CHCl3). H NMR (CDCl3, 400 MHz)  = 1.18–
1.29 (m, 1 H), 1.36–1.50 (m, 1 H), 1.49 (d, J = 6.8 Hz, 3 H), 1.51–1.80 (m,
7 H), 1.90–2.00 (m, 1 H), 2.06 (ddd, J = 16.3, 11.9, 4.3 Hz, 1 H), 2.24 (dm,
J = 13.1 Hz, 1 H), 2.36 (dm, J = 14.5 Hz, 1 H), 2.44 (ddd, J = 18.5, 14.5,
6.3 Hz, 1 H), 2.71 (dt, J = 11.9, 4.4 Hz, 1 H), 3.21 (ddd, J = 11.9, 10.6, 3.4
Hz, 1 H), 4.15 (q, J = 6.8 Hz, 1 H), 7.14 (t, J = 7.2, Hz, 1 H), 7.27 (t, J = 7.8
Hz, 2 H), 7.37 (dm, J = 7.2 Hz, 2 H). 13C NMR (CDCl3, 100 MHz)  = 20.1
(p), 20.9 (s), 21.6 (s), 26.3 (s), 27.1 (s), 35.7 (s), 37.8 (s), 40.5 (s), 43.2 (s),
56.5 (t), 69.3 (q), 125.8 (t), 126.8 (t), 128.0 (t), 148.6 (q), 216.2 (q). IR (film,
cm–1): 2928, 2858, 1705, 1445. HRMS (ESI+, CH3OH, C18H26NO [M + H]+)
calcd for 272.2014, found 272.2010. Anal. Calcd for C18H25NO (271.4): C,
79.66; H, 9.28; N, 5.16. Found C, 79.70; H, 9.24; N, 5.13.
Colorless oil. Rf = 0.30 (petroleum ether/diethyl ether, 60:40). []22 = +
D
1
15.0 (c 1.0, CHCl3). H NMR (CDCl3, 400 MHz)  = 1.42–1.49 (m, 2 H),
1.51–1.74 (m, 5 H), 1.84–1.91 (m, 2 H), 1.92–2.03 (m, 2 H), 2.23 (ddd, J
= 12.9, 9.0, 3.4 Hz, 1 H), 2.36 (dt, J = 13.7, 7.1 Hz, 1 H), 2.62–2.80 (m, 2
H), 2.77 (dt, J = 13.7, 6.8 Hz, 1 H); 3.60 (d, J = 14.5 Hz, 1 H), 3.85 (d, J =
14.5 Hz, 1 H), 7.24 (tt, J = 7.2, 1.0 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 2 H), 7.43
(dm, J = 7.2 Hz, 2 H). 13C NMR (CDCl3, 100 MHz)  = 20.4 (s), 20.9 (s),
21.9 (s), 28.1 (s), 30.1 (s), 36.0 (s), 39.5 (s), 45.9 (s), 52.7 (s), 68.3 (q),
126.6 (t), 128.1 (t), 128.2 (t), 140.8 (q), 215.9 (q). IR (film, cm–1): 2939,
1732, 1494.8, 1447, 740, 699.0. HRMS (ESI+, CH3OH, C17H24NO [M + H]+)
calcd for 258.1858, found 258.1858. Anal. Calcd for C17H23NO (257.4): C,
79.33; H, 9.01; N, 5.44. Found C, 79.25; H, 8.95; N, 5.40.
(4aS,10S)-10-methyl-2,3,4,5,6,7,8,10-octahydropyrido[2,1-
e]phenanthridine, (–)-7. To a solution of spiropiperidine (+)-6 (0.50 g, 1.84
mmol) in toluene (20 mL) were added 2 ml of 37% HCl. The resulting
biphasic system was refluxed for 15 h and poured onto a 10% Na2CO3
solution (50 ml) while maintaining the pH of the aqueous phase at 12. The
organic phase was separated, and the aqueous layer was extracted with
50 mL of diethyl ether (x 2). The combined organic phases (toluene plus
diethyl ether) were washed with water, dried over MgSO4 and
concentrated. The crude oil was poured on a chromatography column
containing 10 g of silica and 7:3 of dichloromethane/ methanol. Unreacted
piperidine (+)-6 (0.35 g) was eluted first, followed by the more polar
hexahydrophenanthridine (–)-7 (0.14 g, 30%). Colorless oil. Rf = 0.30
(dichloromethane/methanol, 7:3). []22D = –159.3 (c 1.37, CHCl3). 1H NMR
(CDCl3, 400 MHz)  = 1.17–1.25 (m, 1 H), 1.32 (d, J = 6.8 Hz, 3 H), 1.33–
1.37 (m, 2 H), 1.43–1.58 (m, 3 H), 1.66–1.85 (m, 3 H), 2.14 (dt, J = 17.0,
tert-Butyl-(S)-7-oxo-1-azaspiro[5.5]undecane-1-carboxylate, (+)-10. To a
suspension of mandelate salt (–)-8 (0.40 g, 1.25 mmol) in acetonitrile (25
mL) were successively added 0.273 g (1.23 mmol, 1.0 equiv.) of Boc2O
and 0.88 mL (0.65 g, 5.05 mmol, 4.04 equiv.) of DIPEA. The reaction
mixture was refluxed for 3 h and was poured onto 50 ml of brine. The
products were extracted with 50 mL diethyl ether (x 2) and the combined
organic phases were washed with water, dried over MgSO4 and
concentrated. The crude reaction mixture was poured on
a
chromatography column prepared with 20 of silica and 4:1
g
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801604
European Journal of Organic Chemistry
FULL PAPER
dichloromethane/diethyl ether. The combined fractions were concentrated
3.20 mmol (46.5% BF3 basis), 2.24 equiv.] of freshly distilled BF3•Et2O
were slowly added to the previous solution. Stirring was continued for 1 h
and the reaction mixture was poured onto a biphasic system constituted
by 50 mL of Et2O and 50 mL of a 0.05 M ammonium chloride–ammonium
hydroxide buffer. The organic layer was separated, washed with water,
dried over MgSO4 and concentrated to yield to give 0.250 g of a crude
residue with was poured on a chromatography column prepared with 15 g
of silica and 7:3 diethyl ether/petroleum ether. The combined fractions
were concentrated to afford 0.245 g (75%) of syn-fluorohydrin-(+)-13.
White solid, m.p. = 113–114 °C. Rf = 0.25 (diethyl ether/ petroleum ether,
7:3). []22D = +49 (c 0.8, CHCl3). 1H NMR (CDCl3, 400 MHz)  = 1.20–1.32
(m, 1 H), 1.37–1.64 (m, 3 H), 1.66–1.94 (m, 6 H), 1.96–2.03 (m, 1 H), 2.32–
2.40 (m, 2 H), 2.90 (td, J = 12.9, 3.5 Hz, 1 H), 3.75 (dt, J = 12.9, 1.4 Hz, 1
H), 4.25–4.29 (m, 1 H). 13C NMR (CDCl3, 100 MHz)  = 14.3 (s), 19.0 (s),
23.7 (s), 25.6 [d, 3JCF = 8.8 Hz), (s)], 28.5 [(d, 3JCF = 4.7 Hz), (s)], 31.5 [(d,
to afford 0.31 g (93%) of carbamate (+)-10. White solid, m.p. = 110–111 °C.
Rf = 0.77 (dichloromethane/diethyl ether, 4:1). []22 = + 60.2 (c 0.93,
D
CHCl3). 1H NMR (CDCl3, 300 MHz)  = 1.42 (s, 9 H), 1.45–2.00 (m, 11 H),
2.25–2.42 (m, 2 H), 2.65 (ddd, J = 13.5, 9.1, 6.0 Hz, 1 H), 3.00 (tm, J =
14.0 Hz, 1 H), 3.85 (d, J = 13.5 Hz, 1 H). 13C NMR (CDCl3, 75 MHz)  =
18.5 (s), 21.0 (s), 24.1 (s), 26.7 (s), 28.4 (p), 29.7 (s), 33.8 (s), 39.4 (s),
41.2 (s), 65.3 (q), 80.9 (q), 156.1 (q), 209.2 (q). IR (neat, cm–1): 2930, 1705,
1679, 1486, 1380, 1014. HRMS (ESI+, CH3OH, C15H25NO3Na [M + Na]+)
calcd for 290.1732, found 290.1731. Anal. Calcd for C15H25NO3 (267.4): C,
67.38; H, 9.43; N, 5.24. Found C, 67.31; H, 9.41; N, 5.23.
(S)-2,3,8,9,10,11-hexahydro-1H,6H-benzo[4,5]oxazolo[3,4-a]pyridin-6-
one, (–)-11. To a solution of carbamate (+)-10 (0.35 g, 1.31 mmol) in
anhydrous acetonitrile (15 mL) were successively added 0.78 mL (0.60 g,
5.20 mmol, 4.0 equiv.) of TMEDA and 0.87 g, 2.61 mmol, 2.0 equiv.) of
dichlorotriphenylphosphorane. The reaction mixture was stirred under an
argon atmosphere for 4 h and was poured onto 50 ml of brine. The
products were extracted with 50 mL dichloromethane (x 2) and the
combined organic phases were washed with water, dried over MgSO4 and
2
2
3JCF = 4.5 Hz), (s)], 38.1 (s), 61.5 [d, JCF = 22.8 Hz), (q)], 67.5 [d, JCF
=
1
24.9 Hz, (q)], 113.5 [d, JCF = 240.0 Hz, (q)], 152.9 (q). IR (neat, cm–1):
3450, 2950, 2872, 1752, 1415, 937. HRMS (ESI+, CH3OH, C11H16NO3FNa
[M + Na]+) calcd for 252.10112, found 252.1008. Anal. Calcd for
C11H16FNO3 (229.2): C, 57.63; H, 7.04; N, 6.11. Found C, 57.60; H, 7.05;
N, 6.00.
concentrated. The crude reaction mixture was poured on
a
chromatography column prepared with 20 g of silica and 1:1 petroleum
ether/diethyl ether. The combined fractions were concentrated to afford
0.19 g (75%) of oxazolidinone (–)-11. Colorless oil. Rf = 0.5 (petroleum
(4R,4aR,11aR)-4a-butyl-4-hydroxy-octahydro-1H,6H-
benzo[4,5]oxazolo[3,4-a]pyridin-6-one, (+)-14. An oven dried, 100-mL,
one-necked Schlenk tube, fitted with a magnetic stirring bar, was flushed
with argon and was successively charged with 20 mL of dry THF, 0.27 g
(1.17 mmol) of syn-fluorohydrin-(+)-13 and 8 mg (0.05 equiv.) of CuCl2.
The solution was cooled to 0 °C and 1.70 mL (3.40 mmol, 2.0 equiv.) of a
2 M solution of BuMgCl in THF were slowly added. Stirring was continued
for 2 h at room temperature and the reaction mixture was poured onto 50
mL a 5% aqueous ammonium hydroxide solution and 100 mL of a mixture
of diethyl ether and dichloromethane (9:1). The organic layer was
separated, washed with water, dried over MgSO4 and concentrated to yield
to give a crude residue with was poured on a chromatography column
prepared with 15 g of silica and 4:1 pentane/acetone. The combined
fractions were concentrated to afford 0.30 g (96%) of (+)-14. Colorless oil.
ether/diethyl ether, 1:1). []22 = –202 (c 0.67, CHCl3). 1H NMR (CDCl3,
D
400 MHz)  = 1.40–1.70 (m, 6 H), 1.71–1.90 (m, 3 H), 2.14–2.20 (m, 2 H),
2.27 (dt, J = 12.0, 3.4 Hz, 1 H), 2.86 (ddd, J = 15.0, 11.9, 4.0 Hz, 1 H), 3.80
(dm, J = 15.0 Hz, 1 H), 5.14 (t, J = 3.7 Hz, 1 H). 13C NMR (CDCl3, 100
MHz)  = 17.9 (s), 20.0 (s), 21.7 (s), 24.3 (s), 27.6 (s), 30.5 (s), 39.7 (s),
59.2 (q), 99.7 (t), 150.0 (q), 155.6 (q). IR (neat, cm–1): 2941, 2864, 1770,
1706, 1087, 1005. HRMS (ESI+, CH3OH, C11H15NO2Na [M + Na]+) calcd
for 216.1000, found 216.1000. Anal. Calcd for C11H15NO2 (193.2): C,
68.37; H, 7.82; N, 7.25. Found C, 68.60; H, 7.83; N, 7.25.
(3aS,4aS,11aS)-octahydro-6H-
oxireno[2”,3”:2’,3’]benzo[1’,2’:4,5]oxazolo[3,4-a]pyridine-6-one, (–)-12. To
a 250 mL three necked flask, were successively added 30 mL of acetone,
15 mL of dichloromethane, a 0.05 M solution of Na2B4O7•10H2O in water
(100 mL) and 0.79 g (4.08 mmol) of oxazolidinone (–)-11. The resulting
biphasic system was cooled to 0°C with an ice bath. A solution of Oxone
(15.0 g, 24.43 mmol, 6.0 equiv.) in water (30 mL) and a solution of
Na2B4O7•10H2O (6.04 g, 15.84 mmol, 3.9 equiv.) in water (30 mL) were
added separately over a 1 h period. Stirring was continued for 3 h, and 50
mL of dichloromethane were added to the reaction mixture. The organic
layer was separated, washed with water, dried over MgSO4 and
concentrated to yield to give 0.918 g of a crude oil with was poured on a
chromatography column prepared with 15 g of silica and 3:2 diethyl
ether/dichloromethane. The combined fractions were concentrated to
afford 0.81 g (95%) of epoxide (–)-12. White solid, m.p. = 96–97 °C. Rf =
0.5 (diethyl ether/dichloromethane, 3:2). []22D = –34 (c 1.3, C6H6). 1H NMR
(C6D6, 400 MHz)  = 0.54 (tdd, J = 12.9, 3.8, 1.6 Hz, 1 H), 0.69–1.16 (m,
7 H), 1.29–1.47 (m, 4 H), 2.26 (ddd, J = 14.0, 12.5, 3.2 Hz, 1 H), 3.08 (t, J
= 1.5 Hz, 1 H), 3.78 (dm, J = 14.0 Hz, 1 H). 13C NMR (C6D6, 100 MHz)  =
14.7 (s), 18.8 (s), 23.8 (s), 24.0 (s), 25.8 (s), 27.3 (s), 38.7 (s), 56.2 (q),
57.2 (t), 88.1 (q), 153.6 (q). IR (neat, cm–1): 2930, 1762, 1747, 1000, 754.
HRMS (ESI+, CH3OH, C11H15NO3Na [M + Na]+) calcd for 232.0949, found
232.0949. Anal. Calcd for C11H15NO3 (209.2): C, 63.14; H, 7.23; N, 6.69.
Found C, 63.00; H, 7.21; N, 6.65.
Rf = 0.5 (pentane/acetone, 4:1). []22 = +5 (c 0.54, CHCl3). 1H NMR
D
(CHCl3, 400 MHz)  = 0.92 (t, J = 7.0 Hz, 3 H), 1.24–1.84 (m, 17 H), 2.11
(dm, J = 12.3 Hz, 1 H), 2.26 (dm, J = 12.3 Hz, 1 H), 2.81–2.90 (m, 1 H),
3.87 (s, 1 H), 3.73 (dd, J = 13.5, 4 Hz, 1 H). 13C NMR (CHCl3, 100 MHz) 
= 14.0 (p), 18.9 (s), 20.3 (s), 23.1 (s), 23.6 (s), 25.1 (s), 26.7 (s), 30.3 (s),
35.5 (s), 40.6 (s), 40.8 (s), 63.2 (q), 72.2 (q), 86.3 (t), 159.3 (q). IR (neat,
cm–1): 3421, 2943, 1748, 1277, 1011. HRMS (ESI+, CH3OH, C15H25NO3Na
[M + Na]+) calcd for 290.1732, found 290.1735. Anal. Calcd for C15H25NO3
(267.3): C, 67.38; H, 9.42; N, 5.24. Found C, 67.60; H, 9.41; N, 5.24.
(4a,4aR,11aR)-4a-butyl-4-(methoxymethoxy)octahydro-1H,6H-
benzo[4,5]oxazolo[3,4-a]pyridine-6-one, (+)-15. An oven dried, 100-mL,
one-necked Schlenk tube, fitted with a magnetic stirring bar, was flushed
with argon and was successively charged with 20 mL of dry THF, 0.30 g
(1.12 mmol) of oxazolidinone-(+)-14, and 16 mg (0.1 equiv.) of NaI. The
solution was cooled to 0 °C, and 0.22 g (4.9 equiv.) of NaH (60% in mineral
oil) were slowly added followed by the addition of 0.34 mL (0.36 g, 4.47
mmol, 4.0 equiv.) of MOMCl. Stirring was continued for 16 h at room
temperature and the reaction mixture was poured onto a 1:1 water/diethyl
ether biphasic system (50 mL). The organic layer was separated, washed
with water, dried over MgSO4 and concentrated to yield to give a crude
residue with was poured on a chromatography column prepared with 15 g
of silica and 7:3 petroleum ether/diethyl ether. The combined fractions
were concentrated to afford 0.29 g (83%) of (+)-15. Colorless oil. Rf = 0.5
(petroleum ether/diethyl ether, 7:3). []22D = +26 (c 0.78, CHCl3). 1H NMR
(CHCl3, 400 MHz)  = 0.93 (t, J = 7.0 Hz, 3 H), 1.26–1.90 (m, 15 H), 1.95
(dm, J = 14.3 Hz, 1 H), 2.07 (dm, J = 10.7 Hz, 1 H), 2.26 (dt, J = 12.5, 2.8
Hz, 1 H), 2.80–2.90 (m, 1 H), 3.38 (s, 3 H), 3.70 (s, 1 H), 3.74 (dd, J = 13.6,
(4R,4aS,11aR)-4a-fluoro-4-hydroxyoctahydro-1H,6H-
benzo[4,5]oxazolo[3,4-a]pyridin-6-one, (+)-13. An oven dried, 100-mL,
one-necked Schlenk tube, fitted with a magnetic stirring bar, was flushed
with argon and was charged with 30 mL of dry Et2O and 0.30 g (1.43 mmol)
of epoxide (–)-12. The solution was cooled to 0 °C and 0.85 mL [0.98 g,
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10.1002/ejoc.201801604
European Journal of Organic Chemistry
FULL PAPER
4.0 Hz, 1 H), 4.58 (d, JAB = 7.0 Hz, 1 H), 4.99 (d, JAB = 7.0 Hz, 1 H). 13C
NMR (CHCl3, 100 MHz)  = 14.0 (p), 18.8 (s), 20.3 (s), 23.2 (s), 23.7 (s),
25.5 (s), 26.6 (s), 30.5 (s), 34.6 (s), 35.8 (s), 40.7 (s), 55.8 (t), 63.1 (q),
86.8 (t), 92.2 (s), 159.0 (q). IR (neat, cm–1): 2940, 1750, 1280, 998. HRMS
(ESI+, CH3OH, C17H29NO4Na [M + Na]+) calcd for 334.1994, found
334.1989. Anal. Calcd for C17H29NO4 (311.4): C, 65.57; H, 9.39; N, 4.50.
Found C, 65.78; H, 9.35; N, 4.48.
Keywords: Alkaloids• Spiro compounds • Alkylation • Nitrogen
heterocycles• Asymmetric Synthesis•
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supplementary crystallographic data for this paper. These data can be
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P21, P21, a = 8.6755(3), b = 9.1517(3), c = 22.2914(7) Å,  = 90°,  = 90°,
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Crystal data, X-ray data collection and refinement results of
derivative (–)-12: C11H15NO3, M = 209.24, monoclinic, space group P21,
a = 8.6960(9), b = 6.4354(8), c = 9.48(10) Å,  = 90°,  = 101.882°,  =
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V. H. V. is grateful to the Ministry of Education and Training of the
Socialist Republic of Vietnam for a PhD funding. We also thank
Dr Saurabh Shahane for manuscript preparation. The author
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FULL PAPER
Alkaloid Synthesis
The stereoselective synthesis of
spiropiperidone (+)-9, a known
intermediate to PHTX, has been
achieved in an overall 66% yield
from 2. The introduction of the
future C7 butyl chain of the title
alkaloid has been achieved by
condensing the fluorohydrin (+)-13
with the corresponding Grignard
reagent.
Van Ha Vu, Thierry Roisnel, Stéphane
Golhen, Christelle Bouvry, Jean-Pierre
Hurvois *
Page No. – Page No.
Formal Synthesis of (–)-
Perhydrohistrionicotoxin Using a
Thorpe-Ziegler Cyclization
Approach. Synthesis of
Functionalized Aza-Spirocycles.
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