Electrochemical access to 8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5] decane-7-carbonitrile. Application to the asymmetric syntheses of (+)-myrtine and alkaloid (+)-241D

Article abstract of DOI:10.1021/jo500104c

The total syntheses of both enantiomers of trans-quinolizidine (+)-myrtine and cis-2,4,6-trisubstituted piperidine alkaloid (+)-241D are reported here. Our approach was based on the N-Boc-directed metalation of enantiopure 4-piperidone (-)-11, which was prepared in four steps from α-amino nitrile 6 through a stereoselective alkylation-reduction decyanation process. α-Amino nitrile 6 was prepared at the anode through electrochemical oxidation of 4-piperidone (+)-5. In our study, α-phenylethylamine (α-PEA) allowed an efficient 1-3 stereoinduction, and an orthogonal cleavage of the N-Boc protecting group in piperidone derivatives was carried out by stirring them in a suspension of SnCl₄·(Et₂O)₂ complex in diethyl ether. When appropriate, the ers were determined by proton and carbon NMR spectroscopy utilizing (+)-tert-butylphenylphosphinothioic acid and (+)-DBTA as chiral solvating agents.

Full text of DOI:10.1021/jo500104c

Article
pubs.acs.org/joc
Electrochemical Access to 8‑(1-Phenyl-ethyl)-1,4-dioxa-8-aza-
spiro[4.5]decane-7-carbonitrile. Application to the Asymmetric
Syntheses of (+)-Myrtine and Alkaloid (+)-241D
Van Ha Vu,† Fadila Louafi,‡ Nicolas Girard,§ Ronan Marion,∥ Thierry Roisnel,∥ Vincent Dorcet,∥
and Jean-Pierre Hurvois*,†
†Sciences Chimiques de Rennes, UMR 6226, CNRS−Universite
‡Unite
de Recherche CHEMS, Faculte des Sciences Exactes, Universite
Algerie
§Faculte
́
de Pharmacie, Universite de Strasbourg UMR 7200 CNRS/UDS, 74 Route du Rhin, 67401 Illkirch Graffenstaden, France
́
de Rennes 1, 2 Avenue Leon Bernard, 35043 Rennes Cedex, France
Constantine1, Route de Ain El Bey, 25000 Constantine,
́
́
́
́
́
∥Sciences Chimiques de Rennes, UMR 6226, CNRS−Universite
́ ́ ́
de Rennes 1, Campus de Beaulieu, Avenue du general Leclerc, 35042
Rennes Cedex, France
S
* Supporting Information
ABSTRACT: The total syntheses of both enantiomers of trans-quinolizidine (+)-myrtine and cis-2,4,6-trisubstituted piperidine
alkaloid (+)-241D are reported here. Our approach was based on the N-Boc-directed metalation of enantiopure 4-piperidone
(−)-11, which was prepared in four steps from α-amino nitrile 6 through a stereoselective alkylation−reduction decyanation
process. α-Amino nitrile 6 was prepared at the anode through electrochemical oxidation of 4-piperidone (+)-5. In our study, α-
phenylethylamine (α-PEA) allowed an efficient 1−3 stereoinduction, and an orthogonal cleavage of the N-Boc protecting group
in piperidone derivatives was carried out by stirring them in a suspension of SnCl4·(Et2O)2 complex in diethyl ether. When
appropriate, the er’s were determined by proton and carbon NMR spectroscopy utilizing (+)-tert-butylphenylphosphinothioic
acid and (+)-DBTA as chiral solvating agents.
INTRODUCTION
■
Piperidine derivatives are part of a large group of substances
that are found in Nature and in pharmaceuticals.1 As a result of
their various biological properties, these compounds and their
structural analogues have been the subject of numerous
synthetic approaches devoted to the construction of their
heterocyclic core.2 Because of our interest in the development
of new methodologies for the stereoselective synthesis of α-
and α,α′-disubstituted piperidine alkaloids,3 we wished to
synthesize more substituted derivatives bearing an additional
substituent at the γ position to the nitrogen atom.
As shown in Figure 1, two representative examples of our
synthetic targets include (+)-myrtine and the alkaloid
(+)-241D. (+)-Myrtine is a member of the trans-4,9a-
quinolizidin-2-one family which was isolated from Vaccinium
myrtillis (Ericaceae), a shrub indigenous to Europe and to the
western United States.4 Its absolute configuration was
Figure 1. Structures and absolute configurations of (+)-myrtine and
alkaloid (+)-241D.
skin extracts of the Panamanian poison frog Dendrobates
speciosus.5 Recently, several approaches based on the utilization
of chiral catalysts have led to the asymmetric synthesis of
alkaloids 1 and 2 with enantiomeric ratios greater than 98:2.6
Successful syntheses of 1 and 2 have also been carried out
through well-established diastereoselective approaches includ-
ing condensation of Grignard reagents to chiral pyridinium
salts,7 cyclization of allylsilane onto N-acyliminium ion,8
́
determined by Slosse and Hootele and was found to be
(4R,9aS).4b Alkaloid (+)-241D belongs to a subclass of all-cis 4-
hydroxy-2,6-disubstituted piperidines and was extracted in
minute quantities by Edwards and Daly from the methanolic
Received: January 16, 2014
Published: March 26, 2014
© 2014 American Chemical Society
3358
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
addition on chiral N-sulfinyl derivatives,9 Michael- and
Mannich-type cyclizations,10 chemical manipulations of enan-
tiopure amino acids,11 and more recently diastereodivergent
intramolecular nitrone cycloaddition.12
In light of our previous experience in alkaloid chemistry, we
sought a new synthetic route to 1 and 2. Our approach was
based on the elaboration of α-amino nitrile 6, which could be
prepared by electrochemical means (Scheme 1).13−17 The final
As is typical of this series, a single bielectronic irreversible
system is recorded at Ep = +1.10 V indicating that electron
transfer involved the amine moiety. The addition of
incremental amounts of sodium cyanide to the previous
solution (Scheme 3, γ = 1−3) caused an increase of the
anodic current. As shown previously in our laboratory, we
attribute this behavior to the presence of a homogeneous
electron transfer process between the nitrogen-centered
aminium radical cation A and the cyanide anion.13a The ip/ip
0
ratio (where ip and ip0 are the anodic currents with and without
sodium cyanide) reflects the overall redox process in which the
aminium radical cation A returned to its initial neutral state.20
From these results, one could expect Coulombic excesses from
the electrolysis of (+)-5.21 Nevertheless, when the concen-
Scheme 1. Retrosynthetic Analysis of (+)-Myrtine and
Alkaloid (+)-241D
0
tration of sodium cyanide ranged from 50 to 75 mM, the ip/ip
ratio was 2.28 and 2.34, respectively. This observation indicated
that, at these concentrations, the cyanide anion acted as a base
to produce the α-amino radical B, which is readily oxidized at
the anode to form the iminium ion C, which on trapping with
cyanide anion afforded α-amino nitrile 6.22 Thus, the
controlled-potential oxidation of (+)-5 was carried out in an
undivided cell at a glassy carbon electrode at Ep = +1.10 V in
the presence of 2 equiv of sodium cyanide. The current
dropped from 500 to ca. 5 mA over a 12 h period, and after the
consumption of 2.9 F per mole of substrate, the voltammogram
recorded on the resulting solution showed the quasi
disappearance of the oxidation peak.
stereochemical approach was to use Beak’s lithiation-alkylation
sequence of 4-piperidone (−)-11 to control the trans or the cis
relationship between the α and the α′ substituents that we hope
to establish for the synthesis of 1 and 2, respectively.
RESULTS AND DISCUSSION
■
Synthesis of 4-Piperidone (+)-5. The transamination
process between a primary amine and quaternary ammonium
salt 3 allows for the efficient synthesis of the corresponding N-
substituted 4-piperidone derivative.18
After aqueous workup (see the details in the Experimental
Section) and a rapid chromatography purification over a silica
gel column, α-amino nitrile 6 was obtained in an overall 81%
yield as a ca. 50/50 mixture of diastereoisomers. By fractional
crystallization in a mixture of diethyl ether and petroleum ether,
pure diastereomers (+)-6-A and (+)-6-B could be isolated,
Thus, the synthesis of chiral 4-piperidone (+)-4 was carried
out according to the protocol reported by Pawłowska and
Czarnocki by heating iodide 3 in a mixture of H2O/EtOH/
K2CO3 in the presence of 1 equiv of (+)-1-phenylethylamine
[(+)-α-PEA] with distillation to remove dimethylamine.19 The
carbonyl group was next protected as its 1,3-dioxolane
derivative by a prolonged heating of (+)-4 in toluene at reflux
in the presence of an excess of ethylene glycol and a catalytic
amount of p-TsOH. After basification, the crude reaction
mixture was purified by column chromatography to afford
protected 4-piperidone (+)-5 in 75% yield (Scheme 2).
respectively. A single crystal of (+)-6-B {mp 114 °C, [α]22
D
+87.7 (c 1.0, CHCl3)} was suitable for X-ray crystallography,
and the ORTEP view is shown in Figure S21 in the Supporting
Information. As the absolute configuration of the benzylic
carbon atom is known, the R configuration of the newly created
stereogenic center at C-7 is simply deduced from the X-ray
structure. With α-amino nitrile 6 in hand, we first explored the
synthesis of both enantiomers of 7-methyl-4-piperidone 11.
Synthesis of 7-Methyl-4-piperidone (+)-11 and Its
Enantiomer. It is known that lithiated α-amino nitriles can
react in high yield with a large set of electrophiles.23 To
introduce the requisite methyl group at C-7, the deprotonation
of an epimeric mixture (ca. 50:50) of α-amino nitriles (+)-6-A-
B was carried out at −80 °C in THF by the slow addition of an
LDA solution. The treatment of the resulting orange anion
solution with an excess of iodomethane and treatment of the
crude reaction mixture in diethyl ether gave the bifunctional α-
amino nitrile (−)-7 (90%) as a white powder {[α]22D −60.6 (c
1.0, C6H6), mp 136 °C} (Scheme 4). This derivative was stable
enough for spectroscopic characterization, and the proton
NMR spectrum of (−)-7 was recorded within 5 min in CDCl3,
attesting to the presence of one isomer. Nevertheless, a slow
epimerization took place in this solvent, providing a set of
additional resonances signals that were easily attributed to the
alternate (11R,7S) diastereoisomer. From the X-ray structure
analysis of (−)-7 (Figure S31 in the Supporting Information),
we were able to determine the absolute configuration of the C-
7 quaternary carbon atom as R.
a
Scheme 2. Synthesis of 4-Piperidone (+)-5
a
Reagents and conditions: (a) (+)-1-phenylethylamine, H2O/EtOH/
K2CO3, reflux, 3 h; (b) ethylene glycol, p-TsOH, toluene, reflux, 48 h.
Electrochemical Synthesis of α-Amino Nitrile (+)-6. To
determine the best conditions for electrosynthesis, an analytical
study was carried out at a vitreous carbon electrode in a
methanolic solution of (+)-5 in the presence of LiClO4 (0.2 M)
as the supporting electrolyte. The electrochemical behavior of
(+)-5 was studied in the absence (γ = 0) and in the presence (γ
= 1−3) of sodium cyanide, and the cyclic voltammograms are
collected in Scheme 3.
In the next step, the reductive decyanation of α-amino nitrile
(−)-7 was carried out at 0 °C in ethanol with 4 equiv of sodium
3359
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
Scheme 3. (Top) Proton Transfer or Homogeneous Redox Options for Radical Cation A. (Bottom) Cyclic Voltammograms of
a
4-Piperidone (+)-5 in the Absence (γ = 0) and in the Presence (γ = 1−3) of Sodium Cyanide
a
Conditions: MeOH/LiClO4·3H2O (0.2 M), glassy carbon electrode, v = 0.05 V s−1. γ = 0: (+)-5 (25 mM) alone. γ = 1: plus NaCN (25 mM). γ =
2: plus NaCN (50 mM). γ = 3: plus NaCN (75 mM).
borohydride to provide 7-methyl-4-piperidone (−)-8-A along
with its stereoisomer (+)-8-B {(−)-8-A/(+)-8-B, 87:13)} in a
combined yield of 91%. Gratifyingly, the major diastereoisomer
(−)-8-A could be easily obtained as a sole product after
chromatographic purification. The well resolved proton NMR
spectrum of (−)-8-A is consistent with the proposed structure,
and a most salient feature was the presence of an additional
doublet signal (J = 6.4 Hz, 3 H) at δ 1.18 ppm corresponding
to the 7-CH3 group. The stereochemical outcome of the
reductive decyanation process can be explained by the
formation of iminium species D on which the incorporation
of the hydride on the si face tended to produce the R,R absolute
configuration.24,25
(−)-8-A. The optical rotation of our sample of N-Boc-4-
piperidone (−)-11 {[α]22 −29.1 (c 1.2, CHCl3)} matched in
D
all aspects those reported by Pizzutti and Feringa {[α]22D −28.4
[c 0.92, CHCl3]}.6c
Complementing the synthetic efforts mentioned above,
enantiomeric 4-piperidone (−)-9 was also obtained from a
similar reaction pathway but involving (−)-α-PEA as a nitrogen
source. As a result, the enantiomeric ratios of both enantiomers
of 4-piperidone 9 could be determined by proton and carbon
spectroscopy utilizing (−)-tert-butylphenylphosphinothioic acid
[(−)-10] as the chiral solvating agent.26 The full details of this
study are provided in the Supporting Information, and from
examination of the spectral data one can deduce that both
samples displayed >99:1 er’s.
In the next step, the chiral auxiliary was easily removed from
derivative (−)-8-A with 20% Pd(OH)2 as catalyst to afford 4-
piperidone (+)-9, which was heated at reflux in acetonitrile in
At this point, the absolute configuration of 4-piperidone
(+)-9 had to be determined. To this end, a screening of
enantiopure chiral carboxylic acids that would hopefully form
single crystals of diastereomeric salts was undertaken.
the presence of Hunig’s base and (Boc) O to afford N-Boc-
̈
2
protected 4-piperidone (−)-11 in an overall 93% yield from
3360
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
a
Scheme 4. Synthesis of 4-Piperidone (−)-11 and Its Enantiomer
a
Reagents and conditions: (a) LDA, THF, −80 to 0 °C, 2 h, then iodomethane, −80 to −10 °C; (b) NaBH4, EtOH, 0 to 20 °C, 12 h; (c) 20% Pd/
C, H (5 bar), MeOH, 72 h; (d) (Boc) O, Hunig’s base, acetonitrile, reflux, 4 h.
̈
2
2
a
Table 1. Synthesis of 4-Piperidones rac-14a−d
entry
no.
R1
yield (%)
entry
no.
yield (%)
1
2
3
4
rac-13a
rac-13b
rac-13c
rac-13d
C3H7
70
62
65
60
5
6
7
8
rac-14a
rac-14b
rac-14c
rac-14d
97
97
98
97
C5H11
C7H15
C11H23
a
Reagents and conditions: (a) Procedure A: sBuLi (1.5 equiv), TMEDA (1.5 equiv), Et2O, −80 to −70 °C, 2 h; (b) CuCN·LiCl (1.5 equiv, THF)
−80 to −60 °C, 2 h; (c) R1I (2.5 equiv), −80 °C to rt, 12 h. (d) Procedure B: SnCl4·(Et2O)2, 0 °C, Et2O, 12 h, then NaOH 2 M, 24 h, rt.
Unfortunately, all attempts met with failure. Nonetheless, a
single crystal was obtained from a slow crystallization of a
stoichiometric mixture of (−)-9 and rac-tert-butylphenylphos-
phinothioic acid [(−)-9·rac-10, Scheme 4] in chloroform. The
ORTEP view (Figure S61 in the Supporting Information) is in
keeping with the proposed structure and from determination of
Flack parameters values [−0.01 (4)] calculated from Friedel
pair reflections for each structure, it became clear that the
absolute configuration of 4-piperidone (−)-9 was S and that
our previous assignments were correct.27 Thus, the heterocyclic
core of alkaloids (+)-1 and (+)-2 was synthesized in 7 steps and
30% overall yield from inexpensive and commercially available
(+)-α-PEA.
Synthesis of (+)-Myrtine and Its Unnatural (−)-Enan-
tiomer. With an efficient route to enantiopure 7-methyl-4-
piperidone 9 in hand, we attempted to develop a regio- and
3361
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
a
Scheme 5. Synthesis of Quinolizidine Alkaloid (+)-Myrtine and Its Enantiomer
a
Reagents and conditions: (a) procedure A but with 1-chloro-4-iodo-butane as the alkylating agent; (b) acetone, 5 M HCl, reflux, 12 h; then 5 M
NaHCO3, 0 °C, 12 h; (c) procedure A but with iodide 16 as the alkylating agent, (d) 10% Pd/C, H2 (5 bar), MeOH, rt, 24 h; (e) CBr4/PPh3,
CH2Cl2, rt, 24 h; (f) procedure B; (g) 5 M HCl, acetone, 4 h, reflux; (h) (+)-DBTA (0.5 equiv), Et2O, 1 h.
stereodefined procedure for the introduction of the second
alkyl chain into the piperidine ring system. As the C-9a
stereogenic center in (+)-myrtine displayed an absolute R
configuration, one should be able to place both the methyl
group and the future alkyl chain in a trans disposition. In a
recent paper, we noticed that the alkylation of N-Boc-piperidyl
cuprates with alkyl iodides proved to be the method of
choice.3,28,29 To gain further insight into this process, we set to
synthesize 7-alkyl-4-piperidones rac-13a−d, and the results are
collected in Table 1.
The lithiation of 4-piperidone 12 with sBuLi/TMEDA
followed by the addition of a THF solution of CuCN·LiCl at
−80 °C led to the formation of the intermediary cuprate E. The
addition of 1-iodopropane (entry 1) at −80 °C followed by 12
h of stirring at room temperature led to the formation of 7-
propyl-4-piperidone rac-13a (70%), which could be readily
separated by column chromatography from trace amounts (up
to 5%) of starting material. According to the same procedure, 7-
alkyl-4-piperidones rac-13b−c displaying an alkyl chain at C-7
with an increasing length were obtained as viscous oils in yields
ranging from 62% to 65% (entries 2 and 3). A prolonged
stirring at room temperature was however required to complete
the reaction with 1-iodoundecane (entry 4). It was also
necessary to remove the N-Boc group in a selective fashion. We
next screened several Lewis acids inert toward the 1,3-dioxolane
group, due to the challenging nature of this orthogonal
deprotection. Gratifyingly, when 4-piperidones rac-13a−d were
added to a suspension of SnCl4·(Et2O)2 (prepared from the
addition of a 1 M solution of SnCl4 in hexanes on an excess of
diethyl ether) in diethyl ether, the expected 4-piperidones rac-
14a−d (entries 5−8) were obtained as sole products in nearly
quantitative yield after basic treatment.30
We continued our study with inspiration from the synthetic
approach toward (+)-myrtine proposed by Pizzuti and
Feringa.6c We thus sought to introduce a four-carbon chain
tethered by a potential terminal leaving group to construct the
3362
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
indolizidine ring system. Thus, according to a slightly modified
procedure, the lithiation−transmetalation of an ethereal
solution of 4-piperidone (−)-11 was carried out according to
the procedure A to produce the intermediary configurationally
stable 7-methyl-9-piperidyl-cuprate F in which the methyl
group is axially oriented. The addition of 1-chloro-4-iodo-
butane afforded the expected 4-piperidone (+)-15 (86%) in a
>95:5 dr. The carbon NMR spectrum of (+)-15 contained one
set of signals indicating the formation of one isomer. Fifteen
carbon resonance lines were observed, two of which were due
to the C-7 and C-9 tertiary carbon atoms found at δ 46.2 and
50.6, respectively. Taken together, these observations indicated
that alkylation of 4-piperidone (−)-11 had occurred regio- and
stereoselectively at C-9. Deprotection of both the acetal and the
carbamate moieties in (+)-15 were routinely carried out by a
treatment in 5 M HCl to produce an intermediary hydro-
chloride salt that, upon stirring in a 5 M NaHCO3/diethyl ether
biphasic system for 12 h at 0 °C, afforded (+)-myrtine as a
colorless solid (mp = 50 °C) in 33% yield. Nevertheless,
spectral data and specific rotation {[α]22D +9.8 (c 1.2, CHCl3)}
of our synthetic sample of (+)-myrtine matched in all aspects
those reported in the literature.6a To improve the yield of
(+)-myrtine, we sought to incorporate a terminal bromine atom
into its precursor. Thus, 4-piperidone (−)-11 was alkylated
with iodide 16 to afford disubstituted 4-piperidone (+)-17 as a
single derivative (>99:1 dr) in 86% yield.31 Catalytic hydro-
genolysis of (+)-17 afforded alcohol (+)-18 as colorless single
crystals {mp = 95 °C; [α]22D +9.4 (c 1.0, CHCl3)} whose X-ray
analysis (Figure 117 in the Supporting Information) confirmed
the trans configuration of the diastereoisomer obtained in this
way.32 Halogenation of the pendant alcohol function was
carried out through the use of the Appel reaction by stirring
(+)-18 in dichloromethane at room temperature in the
presence of CBr4 and PPh3.33 The reaction proceeded well,
and after the addition of an excess of ethanol, the expected
bromide (+)-19 was obtained in 89% yield without a detectable
amount of phosphorus derivative. The penultimate step
consisted of the selective removal of the N-Boc group and
the construction of the quinolizidine ring system. Thus, the
treatment of bromide (+)-19 according to the protocol B
afforded the quinolizidine (+)-20 in nearly quantitative yield.
Structural determination of (+)-20 was straightforward. In the
carbon NMR spectrum, the C-2 and the C-3 carbon atoms of
the 1,3-dioxolane group gave resonance signals at δ 63.6 and
64.5 ppm, and in agreement with the formation of the new N-
5′−C-6′ bond, a secondary resonance signal was recorded at δ
51.4 ppm.
addition of 2 equiv of (+)-myrtine to 1 equiv of (+)-DBTA in
diethyl ether afforded the corresponding 2[(+)-myrtine]·
(+)-DBTA salt as a colorless solid that proved to be freely
soluble in CDCl3.34 Examination of the proton NMR spectrum
revealed that this tartrate salt had a 2:1 stoichiometry and that
our products have >99:1 er’s.
Total Synthesis of Dendrobate alkaloid (+)-241D.
According to the retrosynthetic analysis shown in Scheme 1, we
turned to the synthesis of alkaloid (+)-241D. Thus, a
stereodivergent construction of the 2,4,6-cis-piperidine ring
system from the same 4-piperidone (−)-11 was planned. Thus,
treatment of (−)-11 with sBuLi/TMEDA in diethyl ether at
−80 °C provided the intermediary 2-lithio derivative, which
was condensed with an excess of dimethylformamide (DMF) to
provide aldehyde 21 as a 75:25 mixture of trans and cis isomers
(Scheme 6). Taking advantage of the configurational instability
Scheme 6. Total Synthesis of the Dendrobate Alkaloid
a
(+)-241D
a
Reagents and conditions: (a) sBuLi (1.5 equiv), TMEDA (1.5 equiv),
Et2O, −80 to −65 °C, 3 h; then DMF (2.5 equiv), −80 °C to rt, 12 h;
(b) Et3N, silica gel, diethyl ether, 60 h, rt; (c) [nC8H17(Ph)3P]+·Br−,
nBuLi, THF, −40 to 0 °C, 2 h; then 21, −70 °C to rt, 3 h; (d) 20%
Pd/C, H2 (3 bar), MeOH, 72 h; (e) procedure B; (f) 5 M HCl,
acetone, 4 h, reflux; (g) NaBH4 (2.0 equiv), ethanol, 0 °C, 1 h.
Finally, deprotection of the acetal moiety in (+)-20 was
carried out by refluxing it in acetone in the presence of 5 M
HCl to afford (+)-myrtine in nearly quantitative yield as a
single stereoisomer (Scheme 5), and its optical rotation was
quasi similar to that reported above. Complementing the
previous approach, (−)-myrtine was obtained from 7-methyl-4-
piperidone (+)-11 in an overall 70% yield. The magnitude and
the sign of the optical rotation of this sample of unnatural
of the C-7 carbon atom, we sought to reverse the previous
diastereomeric ratio by stirring 21 in diethyl ether in the
presence of silica gel and triethylamine over a 60 h period.35
The reaction can be monitored by gas chromatography or by
proton NMR spectroscopy,36 and when the reaction was
judged to be complete, treatment of the reaction mixture
afforded aldehyde 21 in 83% yield with the cis isomer
predominating (80:20 dr). Elaboration of the nine carbon
alkyl chain was carried out by the Wittig olefination of aldehyde
21 with n-octyl-triphenyl-phosphonium bromide as the
phosphonium ylide source to produce an inseparable mixture
(75:25 dr) of Z-alkenes 22.
(−)-myrtine proved to be [α]22 −10.7 (c 1.0, CHCl3),
D
confirming the chiral conservation in both asymmetric
syntheses.
With enantiomers of myrtine in hand, we also found it
interesting to determine the optical purity of our samples of
synthetic (+)- and (−)-myrtine by proton and carbon NMR,
which could be best achieved with (+)-O,O′-dibenzoyl-L-
tartaric acid [(+)-DBTA] as the resolving agent. Indeed the
Next, saturation of the olefinic double bond was performed
by the catalytic hydrogenation of 22 in methanol in the
presence of 20% Pd(OH)2 under an hydrogen pressure of 3
3363
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
arrangement with a glassy carbon electrode (GCE, diameter = 2 mm)
as the working electrode, an SCE (saturated calomel electrode) as the
reference electrode, and a platinum wire as the counter electrode.
Cyclic voltammetry experiments were carried out in methanol
solutions containing LiClO4·3H2O (0.2 mol L−1) as supporting
electrolyte. Experiments were carried out at ambient temperature. All
potential values are referred versus SCE. Electrolyses were carried out
in a homemade undivided electrolysis cell (see the schematic diagram
in the Supporting Information).
bar. In this way cis-4-piperidone (−)-23-A was obtained as a
sole product in 71% yield after removal of its trans stereoisomer
(+)-23-B by column chromatography. Deprotection of the
carbamate moiety was carried out according to the procedure B
to liberate 4-piperidone (+)-24, which was treated with a 5 M
HCl solution to afford the unmasked 4-piperidone (−)-25 in an
overall 95% yield from (−)-23-A.37 Finally the hydride
reduction of the carbonyl function in (−)-25 was carried out
in ethanol at 0 °C in the presence of NaBH4 for 1 h. This latter
reaction gave the expected alkaloid (+)-241D in 80% yield with
its C-4 epimer (10%), which could be easily chromato-
graphically removed. It is also notable that this synthetic route
provided alkaloid (−)-241D from 4-piperidone (+)-11. The
optical rotations of our synthetic alkaloid 241D matched in all
aspects with those reported previously, and proton and carbon
NMR spectroscopy utilizing (+)-tert-butylphenylphosphino-
thioic acid (+)-10 as the chiral solvating agent indicated that
our samples have >99:1 er’s.11b
1,1-Dimethyl-4-oxopiperidinium Iodide 3.38 An oven-dried,
200-mL, one-necked Schlenk tube, fitted with a magnetic stirring bar,
connected to an argon inlet tube, was charged with 6.92 mL (6.78 g,
59.91 mmol) of 1-methyl-piperidine-4-one and 35 mL of dry acetone.
The resulting solution was cooled to 0 °C, and 4.09 mL of
iodomethane (9.34 g, 65.80 mmol, 1.10 equiv) was added slowly.
The solution was stirred for 24 h at ambient temperature, and the
solvent was removed by filtration under an atmosphere of argon. The
resulting powder was taken up (×2) with dry acetone and dried in
vacuo to afford 15.44 g (99%) of piperidinium iodide 3 as a white
1
hygroscopic powder. Mp = 250 °C (dec). H NMR (DMSO-d6, 400
MHz) δ 2.69 (t, J = 6.5 Hz, 4 H), 3.28 (s, 6 H), 3.76 (t, J = 6.6 Hz, 4
H). 13C NMR (DMSO-d6, 100 MHz) δ 35.1 (s), 50.9 (p), 60.0 (s),
201.4 (q). HRMS (ESI+): calcd for C7H14INO [C]+ 128.10754, found
128.1077. Anal. Calcd for C7H14INO (255.09): C 32.96, H 5.53, N
5.49. Found: C 32.81, H 5.44, N 5.57.
CONCLUSION
■
The syntheses of (+)-myrtine and alkaloid (+)-241D
demonstrated that the enantiopure 7-methyl-4-piperidone
ring system (or any related derivative) can be used as valuable
common precursor for the synthesis of either 2,6-trans-4-
piperidones or 2,4,6-cis-piperidine derivatives. Key steps in this
approach involved (a) the one-step electrochemical synthesis of
a new α-amino nitrile system displaying a masked carbonyl
function at C-4, (b) the stereodivergent second functionaliza-
tion at C-6 provided by the Beak’s methodology, and (c) the
selective removal of the N-Boc moiety with SnCl4·(Et2O)2
complex in the final derivatives.
(7R)-(+)-1-(1-Phenylethyl)-piperidin-4-one [(+)-4].19 A 200-
mL, two-necked Schlenk tube, fitted with a magnetic stirring bar, was
successively charged with 50 mL of water, 17.00 g of K2CO3, and 200
mL of ethanol containing 7.15 mL (6.79 g, 56.09 mmol) of (R)-(+)-1-
phenylethylamine. The resulting mixture was heated to reflux under
vigorous stirring, and 50 mL of water, containing 15.72 g (61.62
mmol) of 1,1-dimethyl-4-oxo-piperidinium 3, was added dropwise.
The mixture was refluxed over a 3 h period, and ethanol was
evaporated in vacuo. The resulting aqueous phase was extracted with
diethyl ether (2 × 100 mL), and the combined organic phases were
dried over anhydrous sodium sulfate, filtered, and concentrated on a
rotary evaporator to afford a yellowish oil, which was poured into a
chromatographic column (diameter = 5.0 cm) prepared with 150 g of
silica and diethyl ether. The combined fractions were evaporated, to
afford 8.70 g (76%) of 4-piperidone (+)-4 as yellowish oil. Rf = 0.43
(diethyl ether). [α]22D +13.4 (c 1.2, CHCl3), [lit.39 [α]22D +31.5 [c 1.0,
EXPERIMENTAL SECTION
General Techniques. Purification by column chromatography was
performed with 70−230 mesh silica gel (Merck). TLC analyses were
carried out on alumina sheets precoated with silica gel 60 F254 and
■
1
visualized with UV light; Rf values are given for guidance. The H
1
MeOH]. H NMR (CDCl3, 400 MHz) δ 1.40 (d, J = 6.8 Hz, 3 H),
NMR spectra were recorded with a 500 or 400 MHz spectrometer.
The 13C NMR spectra were recorded with a 125 or 100 MHz
spectrometer. Chemical shifts are expressed in ppm downfield from
TMS. Data are reported as follows: chemical shift [multiplicity (s,
singlet; d, doublet; dd, double doublet; ddd, double double doublet;
dm, double multiplet; d, double triplet; t, triplet; td, triple doublet; tm,
triple multiplet; tt, triple triplet; q, quartet; quint, quintuplet; m,
multiplet; br, broad), coupling constants (J) in hertz, integration].
Number of attached proton(s) in the 13C NMR spectra was elucidated
using DEPT and are described as (p) primary, RCH3; (s) secondary,
R2CH2; (t) tertiary, R3CH; (q) quaternary, R4C. Positive-ion mass
spectra were recorded with an orthogonal acceleration quadrupole
time-of-flight mass spectrometer that was equipped with a standard
electrospray probe. Elemental analyses are expressed as percentage
values with the abbreviation calcd designating calculated. Melting
points were measured on a Kofler apparatus, and the values are
reported in °C and are uncorrected. For air-sensitive reactions, all
glassware was oven-dried (100 °C) over a 24 h period and cooled
under a stream of argon. All commercially available reagents were used
as supplied. THF was distilled over sodium benzophenone ketyl and
stored under an atmosphere of argon. Diisopropylamine was distilled
from potassium hydroxide. Air-sensitive reagents were transferred by
syringe or with a double-ended needle. Yields refer to chromato-
graphically and spectroscopically (1H,13C) homogeneous material.
Optical rotations were recorded at 22 °C in a 1.0-dm cell. Enantiomer
ratios (er’s) were determined using (+)-,(−)-10 and (+)-DBTA as a
chiral solvating agents (CSA).
2.39 (t, J = 6.1 Hz, 4 H), 2.66−2.77 (m, 4 H), 3.61 (q, J = 6.8 Hz, 1
H), 7.20−7.35 (m, 5 H). 13C NMR (CDCl3, 100 MHz) δ 19.3 (p),
41.5 (s), 49.9 (s), 63.3 (t), 127.1 (t), 127.3 (t), 128.3 (t), 143.4 (q),
209.3 (q). IR (neat) ν = 1713 cm−1. HRMS (EI+): calcd for
C13H17NO (M•+) 203.13101, found 203.1304. Anal. Calcd for
C13H17NO (203.28): C 76.81, H 8.43, N 6.89. Found: C 76.91, H
8.50, N 6.91.
(7S)-(−)-1-(1-Phenylethyl)-piperidin-4-one [(−)-4]. The syn-
thesis was as reported for (+)-4 but with (S)-(−)-1-phenyl-ethylamine
to afford (−)-4 as a colorless oil. [α]22 −14.0 (c 1.2, CHCl3).
(11R)-(+)-8-(1-Phenyl-ethyl)-1,D4-dioxa-8-aza-spiro[4.5]-
decane [(+)-5], New Derivative. A 200-mL, two-necked Schlenk
tube, fitted with a magnetic stirring bar and a Dean−Stark apparatus,
was successively charged with 8.50 g (41.81 mmol) of 4-piperidone
(+)-4, 7.64 mL (8.50 g, 137.00 mmol) of ethylene glycol, 0.50 g (2.90
mmol) of p-TsOH, and 150 mL of toluene. The resulting solution was
heated under reflux for 48 h, and the reaction mixture was cooled and
stirred with 15 mL of a saturated NaHCO3 aqueous solution. The
organic solution was dried over anhydrous sodium sulfate, filtered, and
concentrated on a rotary evaporator to afford a yellowish oil, which
was poured into a chromatographic column (diameter = 5.0 cm)
prepared with 150 g of silica and diethyl ether. The combined fractions
were evaporated, to afford 7.75 g (75%) of 4-piperidone (+)-5 as
yellowish oil. Rf = 0.30 (diethyl ether/petroleum ether, 70:30). [α]22
D
+25.5 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 1.36 (d, J = 6.8
Hz, 3 H), 1.70 (t, J = 5.8 Hz, 4 H), 2.43−2.49 (m, 2 H), 2.51−2.60
(m, 2 H), 3.45 (q, J = 6.8 Hz, 1 H), 3.90 (s, 4 H), 7.20−7.32 (m, 5 H).
13C NMR (CDCl3, 100 MHz) δ 19.5 (p), 35.1 (s), 48.4 (s), 64.14 (s, 2
Electrochemical Procedure and Equipment. Cyclic voltamme-
try curves were carried out on a potentiostat using a three electrode
3364
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
C), 64.16 (t), 107.4 (q), 126.8 (t), 127.5 (t), 128.2 (t), 144.3 (q). IR
solution was allowed to warm to 0 °C over 2.0 h and then cooled to
−80 °C. Then, 0.38 mL (0.86 g, 6.10 mmol, 1.66 equiv) of
iodomethane was added dropwise, and the reaction mixture was
allowed to warm to −10 °C for 2 h. The reaction was stopped by the
addition of 20 mL of water, and the solvents were evaporated under
reduced pressure to yield a crude oil, which was extracted with 2 × 25
mL of dichloromethane. The organic phases were dried over MgSO4
and concentrated. The crude oily residue was taken up in diethyl ether
to afford 3.73 g of α-amino nitrile (−)-7 as white crystals. A slow
crystallization of (−)-7 in diethyl ether afforded single crystals, which
were analyzed by X-ray diffraction. Mp = 136 °C. [α]22D −57.0 (c 0.96,
CHCl3), {[α]22D −50.5 (c 0.96, CHCl3, after a 2 h standing at 22 °C},
[α]22D −61.2 (c 1.02, C6H6). 1H NMR (CDCl3, 400 MHz) δ 1.54 (d, J
= 6.8 Hz, 3 H), 1.55−1.65 (m, 2 H), 1.65 (s, 3 H), 1.84 (d, J = 13.4
Hz, 1 H), 2.04 (dd, J = 13.4, 2.6 Hz, 1 H), 2.61 (ddd, J = 12.5, 4.7, 2.8
Hz, 1 H), 2.84 (td, J = 12.5, 3.2 Hz, 1 H), 3.89−3.95 (m, 2 H), 3.98−
4.10 (m, 2 H), 4.46 (q, J = 6.8 Hz, 1 H), 7.23 (dm, J = 6.9 Hz, 1 H),
7.32 (tm, J = 6.9 Hz, 2 H), 7.40 (dm, J = 6.9 Hz, 2 H). 13C NMR
(CDCl3, 100 MHz) δ 11.8 (p), 27.8 (p), 35.4 (s), 40.4 (s), 47.2 (s),
54.1 (t), 54.2 (q), 64.3 (s), 64.7 (s), 105.9 (q), 122.2 (q), 126.7 (t),
127.0 (t), 128.1 (t), 144.2 (q). 1H NMR (C6D6, 400 MHz) δ 1.15 (s, 3
H), 1.41 (d, J = 6.8 Hz, 3 H), 1.44 (dq, J = 12.6, 3.0 Hz, 1 H), 1.50 (td,
J = 12.6, 4.5 Hz, 1 H), 1.59 (d, J = 13.4 Hz, 1 H), 1.80 (dd, J = 13.4,
3.0 Hz, 1 H), 2.39 (ddd, J = 12.5, 4.5, 3.0 Hz, 1 H), 2.91 (td, J = 12.3,
3.0 Hz, 1 H), 3.36−3.41 (m, 2 H), 3.45−3.50 (m, 1 H), 3.54−3.58 (m,
1 H), 4.16 (q, J = 6.8 Hz, 1 H), 7.07−7.11 (m, 1 H), 7.07−7.11 (m, 4
H). 13C NMR (C6D6, 100 MHz) δ 11.7 (p), 27.4 (p), 35.5 (s), 40.4
(s), 47.0 (s), 53.8 (q), 54.0 (t), 63.8 (s), 64.2 (s), 105.7 (q), 121.5 (q),
126.5 (t), 127.0 (t), 128.0 (t), 144.5 (q). IR (neat) ν = 1068, 2215,
(neat) ν = 1097, 2877, 3025 cm−1. HRMS (EI+): calcd for C14H18NO2
•
[(M − CH3 )+] 232.13375, found 232.1334. Anal. Calcd for
C15H21NO2 (247.33): C 72.84, H 8.56, N 5.66. Found: C 73.10, H
8.69, N 5.59.
(11S)-(−)-8-(1-Phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5]-
decane [(−)-5], New Derivative. The synthesis was as reported for
(+)-5 but with (−)-4 to afford (−)-5 as a colorless oil. [α]22D −21.0 (c
1.35, CHCl3).
(11R,7S)-(+)-8-(1-Phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5]-
decane-7-carbonitrile [(+)-6-A] and (11R,7R)-(+)-8-(1-Phenyl-
ethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-7-carbonitrile [(+)-6-
B], New Derivatives. Caution: Due the possible evolution of HCN
gas, this experiment should be carried out under a well ventilated hood. 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, 6.00 g of LiClO4, 2.30 g (46.92 mmol, 2.15
equiv) of NaCN, and 5.40 g (21.83 mmol) of (+)-3. The working
potential was adjusted to +0.95 V/SCE, and after the consumption of
6130 C (2.90 F/mol) 300 mL of water was added to the electrolysis
solution (Caution: LiClO4 may lead to severe explosions when the
material is evaporated to dryness). The reaction mixture was extracted
with 2 × 200 mL of diethyl ether, and the combined organic layers
were dried over anhydrous magnesium sulfate and concentrated to
afford 5.40 g of a crude oil, which was poured into a chromatographic
column (diameter = 5.0 cm) prepared with 150 g of silica and diethyl
ether to afford 4.80 g (81%) of α-amino nitriles (+)-6-A-B as a mixture
(ca. 50:50) of diastereoisomers, which could be obtained as sole
products from a fractional crystallization that was carried out in 20 mL
of a mixture (1:1) of diethyl ether and petroleum ether. α-Amino
nitrile (+)-6-A. Colorless plates. Mp = 130 °C (diethyl ether/
•
2833 cm−1. HRMS (ESI+): calcd for C16H19N2O2 [(M − CH3 )+]
271.14465, found 271.1453. Anal. Calcd for C17H22N2O2 (286.37): C
71.30, H 7.74, N 9.78. Found: C 71.38, H 7.76, N 9.79.
(11S,7S)-(+)-7-Methyl-8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-
spiro[4.5]decane-7-carbonitrile [(+)-7], New Derivative. The
synthesis was as reported for (−)-7 but with α-amino nitriles (−)-6-A-
B to afford α-amino nitrile (+)-7. Mp = 136 °C. [α]22D +61.0 (c 1.53,
C6H6).
petroleum ether). Rf = 0.67 (diethyl ether). [α]22 +78.0 (c 1.0,
D
CHCl3), [α]22D +142.0 (c 1.0, C6H6). 1H NMR (CDCl3, 400 MHz) δ
1.36 (d, J = 6.6 Hz, 3 H), 1.56 (dq, J = 13.1, 2.9 Hz, 1 H), 1.67 (td, J =
13.0, 4.7 Hz, 1 H), 2.22−2.12 (m, 2 H), 2.47 (td, J = 12.2, 2.9 Hz, 1
H), 2.62 (dm, J = 12.3 Hz, 1 H), 3.61 (q, J = 6.6 Hz, 1 H), 3.90−4.07
(m, 4 H), 4.29−4.33 (m, 1 H), 7.23−7.36 (m, 5 H). 13C NMR
(CDCl3, 100 MHz) δ 20.9 (p), 34.7 (s), 36.9 (s), 45.7 (s), 48.0 (t),
62.2 (t), 64.4 (s), 64.6 (s), 105.4 (q), 117.0 (q), 127.0 (t), 127.3 (t),
128.6 (t), 144.5 (q). IR (neat) ν = 1083, 2225, 2822 cm−1. HRMS
(EI+): calcd for C16H20N2O2 (M•+) 272.15248, found 272.1510. Anal.
Calcd for C16H20N2O2 (272.34): C 70.56, H 7.40, N 10.29. Found: C
70.33, H 7.50, N 10.33. α-Amino nitrile (+)-6-B. Colorless plates. Mp
(11R,7R)-(−)-7-Methyl-8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-
spiro[4.5]decane [(−)-8-A] and (11R,7S)-(−)-7-Methyl-8-(1-
phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5]decane [(+)-8-B], New
Derivatives. A 200-mL, one-necked Schlenk tube fitted with a
magnetic stirring bar was successively charged with 3.90 g (13.62
mmol) of α-amino nitrile (−)-7 and 45 mL of ethanol. The resulting
solution was cooled to 0 °C, 2.04 g (53.92 mmol, 4.0 equiv) of NaBH4
was added in portions, and stirring was continued for 6 h at that
temperature. The solvent was removed under reduced pressure, and
the crude material was taken up with a 15% ammonia solution (30
mL) and extracted with diethyl ether (3 × 50 mL). The combined
organic layers were dried over MgSO4 and concentrated under
reduced pressure to afford a crude residue, which was poured into a
chromatographic column (diameter = 2.5 cm) prepared with 40 g of
silica and diethyl ether to afford 3.38 g (95%) of 4-piperidones 8-A-B
as a mixture (85:15) of diastereoisomers. A subsequent careful
filtration of that mixture on silica gel utilizing a mixture (10:90) of
diethyl ether/petroleum ether as eluent afforded 2.80 g (79%) of 4-
piperidone (−)-8-A and 0.44 g (12%) of 4-piperidone (+)-8-B as
colorless oils. 4-Piperidone (−)-8-A. [α]22D −52.5 (c 1.0, CHCl3). Rf =
0.6 (diethyl ether). 1H NMR (CDCl3, 400 MHz) δ 1.18 (d, J = 6.4 Hz,
3 H), 1.27 (d, J = 6.4 Hz, 3 H), 1.50−1.55 (m, 2 H), 1.60 (dd, J = 12.9,
10.1 Hz, 1 H), 1.76 (dm, J = 12.9 Hz, 1 H), 2.29−2.36 (m, 1 H), 2.41
(dt, J = 11.7, 4.4 Hz, 1 H), 2.82−2.91 (m, 1 H), 3.89−3.96 (m, 4 H),
4.23 (q, J = 6.4 Hz, 1 H), 7.21 (tm, J = 7.4 Hz, 1 H), 7.31 (tm, J = 7.4
Hz, 2 H), 7.45 (dm, J = 7.4 Hz, 2 H). 13C NMR (CDCl3, 100 MHz) δ
10.2 (p), 19.4 (p), 35.2 (s), 42.0 (s), 43.8 (s), 50.9 (t), 54.8 (t), 64.10
(s), 64.16 (s), 108.0 (q), 126.3 (t), 127.6 (t), 127.9 (t), 145.0 (q). IR
(neat) ν = 1108, 2963 cm−1. HRMS (ESI+): calcd for C16H24NO2 [M
+ H]+ 262.1807, found 262.1810. Anal. Calcd for C16H23NO2
(261.36): C 73.53, H 8.87, N 5.36. Found: C 73.73, H 9.04, N
= 114 °C. Rf (diethyl ether) = 0.67. [α]22 +88.5 (c 1.0, CHCl3),
D
[α]22D +133.2 (c 1.0, C6H6). 1H NMR (CDCl3, 400 MHz) δ 1.41 (d, J
= 6.6 Hz, 3 H), 1.78−1.91 (m, 4 H), 2.66 (td, J = 12.2, 3.2 Hz, 1 H),
3.20 (dm, J = 11.9 Hz, 1 H), 3.63−3.65 (m, 1 H), 3.67 (q, J = 6.6 Hz,
1 H), 3.90−3.95 (m, 2 H), 4.00−4.04 (m, 2 H), 7.24−7.29 (m, 1 H),
7.30−7.38 (m, 4 H). 13C NMR (CDCl3, 100 MHz) δ 21.6 (p), 35.1
(s), 36.6 (s), 43.3 (s), 49.9 (t), 61.9 (t), 64.4 (s), 64.7 (s), 105.4 (q),
117.1 (q), 127.2 (t), 127.7 (t), 128.8 (t), 143.4 (q). IR (neat) ν = 2223
cm−1.
(11S,7R)-(−)-8-(1-Phenyl-ethyl)-1,4-dioxa-8-aza-spiro[4.5]-
decane-7-carbonitrile [(−)-6-A], New Derivative. The synthesis
was as reported for (+)-6-A but with 4-piperidone (−)-5 to afford
(−)-6-A as single crystals that were analyzed by X-ray diffraction. Mp
= 130 °C. [α]22 −76.0 (c 1.53, CHCl3), [α]22 −137.3 (c 0.98,
D
D
C6H6).
(11R,7R)-(−)-7-Methyl-8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-
spiro[4.5]decane-7-carbonitrile [(−)-7], New Derivative. An
oven-dried, 200-mL, one-necked Schlenk tube, fitted with a magnetic
stirring bar, and connected to an argon inlet tube, was flushed with
argon. The flask was cooled to −80 °C, and 15 mL of dry THF and
0.88 mL (0.63 g, 6.22 mmol, 1.70 equiv) of diisopropylamine were
added, followed by the dropwise addition of 2.20 mL (5.50 mmol) of
n-butyllithium (2.5 M solution in hexane). Stirring was continued for
30 min, and the solution was warmed to 0 °C over a 1 h period. This
solution was then added dropwise into a 200-mL Schlenk tube cooled
to −80 °C, containing 1.00 g (3.67 mmol) of a mixture (ca. 50:50) of
α-amino nitriles (+)-6-A-B dissolved in 5 mL of dry THF. The
5.47. 4-Piperidone (+)-8-B. [α]22 +44.2 (c 1.2, CHCl3). Rf = 0.35
D
(diethyl ether). 1H NMR (CDCl3, 400 MHz) δ 1.14 (d, J = 6.3 Hz, 3
3365
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
H), 1.44 (d, J = 6.4 Hz, 3 H), 1.55 (dd, J = 13.2, 9.6 Hz, 1 H), 1.64−
1.73 (m, 3 H), 2.19−2.26 (m, 1 H), 2.45−2.53 (m, 1 H), 2.95 (dt J =
11.6, 4.4 Hz, 1 H) 3.82−3.86 (m, 2 H), 3.87−3.91 (m, 2 H), 4.19 (q, J
= 6.4 Hz, 1 H), 7.21−7.32 (m, 5 H). 13C NMR (CDCl3, 100 MHz) δ
19.2 (p), 19.9 (p), 35.4 (s), 42.8 (s), 43.5 (s), 51.3 (t), 56.3 (t), 64.0
(s), 64.1 (s), 107.5 (q), 126.7 (t), 127.9 (t), 128.0 (t), 141.1 (q). IR
(neat) ν = 1097, 2963 cm−1. HRMS (ESI+): calcd for C16H24NO2 [M
+ H]+ 262.1807, found 262.1805. Anal. Calcd for C16H23NO2
(261.36): C 73.53, H 8.57, N 5.36. Found: C 73.13, H 8.95, N 5.44.
(11S,7S)-(+)-7-Methyl-8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-
spiro[4.5]decane [(+)-8-A], New Derivative. The synthesis was as
reported for (−)-8-A but with α-amino nitrile (+)-7 to afford
50.98 (t), 64.5 (s), 64.7 (s), 105.1 (q), 127.2 [(t), (d, 2JPH = 11.0 Hz)],
4
3
130.1 [(t), (d, JPH = 2.4 Hz)], 132.6 [(t), (d, JPH = 9.2 Hz)], 137.0
1
[(q), (d, JPH = 91.0 Hz)]. 31P NMR (CDCl3, 161 MHz) δ 81.82.
(7R)-(−)-7-Methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-car-
boxylic Acid tert-Butyl Ester [(−)-11].6c 4-Piperidone (+)-9 (0.80
g, 5.08 mmol) was dissolved in 20 mL of dry acetonitrile, and to the
resulting solution were successively added 2.05 mL (1.56 g, 12.05
mmol) of N,N-diisopropylethylamine (Hunig’s base) and 1.09 g (5.00
̈
mmol) of di-tert-butyldicarbonate (Boc2O). The reaction mixture was
refluxed for 4 h, and the solvent was evaporated. The residue was taken
up with 20 mL of water, and the aqueous phase was extracted with 50
mL of diethyl ether. The organic phase was dried over MgSO4,
concentrated, and poured into a chromatographic column (diameter =
2.0 cm) prepared with 10 g of silica and 60:40 diethyl ether/petroleum
ether. The combined fractions were evaporated to yield 1.20 g (95%)
of 4-piperidone (−)-11 as a colorless oil. [α]22D −29.1 (c 1.2, CHCl3),
[lit.6c [α]22D −28.4 [c 0.92, CHCl3]. Rf = 0.3 (diethyl ether/petroleum
derivative (+)-8-A as a colorless oil. [α]22 +50.0 (c 1.0, CHCl3).
D
[α]22 +43.0 (c 1.0, EtOH).
D
(11S,7R)-(−)-7-Methyl-8-(1-phenyl-ethyl)-1,4-dioxa-8-aza-
spiro[4.5]decane [(−)-8-B], New Derivative. The synthesis was as
reported for (+)-8-B but with α-amino nitrile (+)-7 to afford derivative
(−)-8-B as a colorless oil. [α]22 −38.0 (c 1.2, CHCl3).
1
ether, 50:50). H NMR (CDCl3, 400 MHz) δ 1.23 (d, J = 7.1 Hz, 3
(7R)-(+)-7-Methyl-1,4-dioxDa-8-aza-spiro[4.5]decane [(+)-9],
New Derivative. A 50-mL low-pressure hydrogenator was charged
with 30 mL of methanol, 1.40 g (5.35 mmol) of 4-piperidone (−)-8-A,
and 0.28 g (20% in mass) of 20% Pd(OH)2/C. The hydrogen pressure
(3.75 × 103 Torr, 5 bar) was applied, and the homogeneous solution
was stirred for 72 h at room temperature. The suspension was filtered
over a small pad of Celite, and the methanolic solution was
concentrated to afford 0.82 g (98%) of 4-piperidone (+)-9 as an
oily residue, which could be utilized in the next step without
purification. [α]22D +5.8 (c 1.0, EtOH). 1H NMR (CDCl3, 400 MHz)
δ 1.09 (d, J = 6.4 Hz, 3 H), 1.30 (t, J = 12.6 Hz, 1 H), 1.58 (td, J =
12.5, 4.9 Hz, 1 H), 1.65−1.75 (m, 2 H), 1.65−1.70 (br., 1 H), 2.81−
2.90 (m, 2 H), 3.05 (ddd, J = 12.3, 7.2, 2.3 Hz, 1 H), 3.93−3.97 (m, 4
H). 13C NMR (CDCl3, 100 MHz) δ 22.5 (p), 35.4 (s), 43.86 (s),
43.92 (s), 50.0 (t), 64.1 (s), 64.2 (s), 107.9 (q). HRMS (ESI+): calcd
for C8H16NO2 [M + H]+ 158.1181, found 158.1180.
H), 1.42 (s, 9 H), 1.55−1.65 (m, 3 H), 1.87 (dd, J = 13.6, 6.6 Hz, 1
H), 3.07 (ddd, J = 16.1, 11.8, 4.4 Hz, 1 H), 3.88−4.02 (m, 5 H), 4.46
(quint. J = 7.0 Hz, 1 H). 13C NMR (CDCl3, 100 MHz) δ 17.4 (p),
28.5 (p), 34.6 (s), 36.7 (s), 38.4 (s), 46.5 (t), 63.7 (s), 64.6 (s), 79.4
(q), 107.4 (q), 154.6 (q). IR (neat) ν = 1115, 1687, 2970 cm−1.
HRMS (ESI+): calcd for C13H23NO4Na [M + Na]+ 280.15193, found
280.1520. Anal. Calcd for C13H23NO4 (257.32): C 60.68, H 9.01, N
5.44. Found: C 60.48, H 8.93, N 5.53.
(7S)-(+)-7-Methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-car-
boxylic Acid tert-Butyl Ester [(+)-11], New Derivative. The
synthesis was as reported for (−)-11 but with 4-piperidone (−)-9 to
afford derivative (+)-11 as a colorless oil. [α]22D +28.2 (c 1.3, CHCl3).
1,4-Dioxa-8-aza-spiro[4.5]decane-8-carboxylic Acid tert-
Butyl Ester (12).40 1,4-Dioxa-8-aza-spiro[4.5]decane (1.45 g, 10.12
mmol) was dissolved in 25 mL of dry acetonitrile, and to the resulting
solution were successively added 4.21 mL (3.20 g, 24.76 mmol) of
N,N-diisopropylethylamine and 2.18 g (10.00 mmol) of di-tert-
butyldicarbonate. The reaction mixture was refluxed for 4 h, and the
solvent was evaporated. The residue was taken up with 20 mL of
water, and the organic phase was extracted with 50 mL of diethyl
ether. The organic phase was dried over MgSO4, concentrated, and
poured into a chromatographic column (diameter = 2.0 cm) prepared
with 10 g of silica and 60:40 diethyl ether/petroleum ether. The
combined fractions were evaporated to yield 2.40 g (97%) of 4-
piperidone 12 as white flakes. Mp = 55 °C. Rf = 0.30 (diethyl ether/
petroleum ether, 50:50). 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 9 H),
1.64 (t, J = 6.0 Hz, 4 H), 3.49 (t, J = 6.0 Hz, 4 H), 3.96 (s, 4 H). 13C
NMR (CDCl3, 100 MHz) δ 28.5 (p), 35.0 (s), 42.0 (s), 64.5 (s), 79.6
(q), 107.2 (q), 154.7 (q). HRMS (ESI+): calcd for C12H21NO4Na [M
+ Na]+ 266.13683, found 266.1366. Anal. Calcd for C12H21NO4
(243.29): C 59.24, H 8.70, N 5.76. Found: C 59.33, H 8.63, N 5.74.
Procedure A . Lithiation of 4-piperidone 12 and synthesis of
derivatives rac-13a−d.
7-Propyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic
Acid tert-Butyl Ester (rac-13a).41 An oven-dried, 200-mL, one-
necked Schlenk tube, fitted with a magnetic stirring bar, containing 40
mL of dry Et2O, and connected to an argon inlet tube, was flushed
with argon and was cooled to −80 °C. Then, 0.50 g (2.05 mmol) of 4-
piperidone 12 and 0.46 mL of TMEDA (0.35 g, 3.07 mmol, 1.50
equiv) were successively added. A solution of s-BuLi (2.18 mL, 3.05
mmol, 1.48 equiv, 1.4 M in cyclohexane) was added dropwise. The
resulting solution was stirred between −80 and −65 °C for 3 h and
was cooled to −80 °C. Then, a THF (20 mL) solution of the complex
CuCN·LiCl {prepared from CuCN (0.27 g, 3.01 mmol, 1.47 equiv)
and LiCl (0.13 g, 3.07 mmol, 1.50 equiv} was added dropwise, and the
reaction mixture was stirred between −80 and −60 °C for 2 h. The
solution was then cooled to −80 °C, and 0.48 mL (0.84 g, 4.94 mmol,
2.40 equiv) of 1-iodopropane was added. The reaction mixture was
warmed to room temperature over a 12 h period and then poured in
50 mL of water. The organic phase was dried over MgSO4,
concentrated, and poured into a chromatographic column (diameter
= 2.0 cm) prepared with 10 g of silica and 10:90 diethyl ether/
(7S)-(−)-7-Methyl-1,4-dioxa-8-aza-spiro[4.5]decane [(−)-9],
New Derivative. The synthesis was as reported for (+)-9 but with
4-piperidone (+)-8-A to afford derivative (−)-9 as a colorless oil.
[α]22 −7.3 (c 1.2, EtOH).
D
(7R)-7-Methyl-1,4-dioxa-8-aza-spiro[4.5]decane (>99:1 er)·
(−)-10. 4-Piperidone (+)-9 (21.5 mg, 137 μmol, >99:1 er) and
CDCl3 (0.7 mL) were added in a 5-mm NMR tube, and 45.7 mg (213
μmol, γ = 1.55) of (−)-tert-butyl-phenylphosphinothioic acid [(−)-10]
was added to it. 1H NMR (CDCl3, 400 MHz, 300 K, transients = 64) δ
1.11 (d, 3JPH = 16.5 Hz, 14 H), 1.26 (d, J = 6.6 Hz, 3 H), 1.55 (dq, J =
13.9, 2.6 Hz,1 H), 1.74 (dt, J = 13.9, 3.0 Hz,1 H), 1.87 (t, J = 12.7 Hz,
1 H), 1.92 (td, J = 13.7, 5.1 Hz, 1 H), 3.01 (td, J = 13.0, 3.3 Hz, 1 H),
3.11 (ddd, J = 13.0, 5.1, 2.2 Hz, 1 H), 3.27−3.37 (m, 1 H), 3.85−3.95
(m, 4 H), 7.35−7.45 (m, 4.6 H), 7.92−7.99 (m, 3.1 H). 13C NMR
2
(CDCl3, 100 MHz, transients = 256) δ 18.9 (p), 24.8 [(p), d, JPH
=
2.0 Hz)], 31.3 (s), 36.3 [(q), d, 1JPH = 75.0 Hz], 40.1 (s), 41.8 (s), 51.1
(t), 64.5 (s), 64.7 (s), 105.0 (q), 127.2 [(t), (d, 2JPH = 11.0 Hz)], 130.3
[(t), (d, 4JPH = 2.4 Hz)], 132.6 [(t), (d, 3JPH = 9.2 Hz)], 136.1 [(q), (d,
1JPH = 90.0 Hz)]. 31P NMR (CDCl3, 161 MHz) δ 82.37.
(7R)-7-Methyl-1,4-dioxa-8-aza-spiro[4.5]decane (80:20 er)·
(−)-10. 4-Piperidones (+)-9 (21.5 mg, 137 μmol, >99:1 er) and
(−)-9 (6.0 mg, 38 μmol, >99:1 er) were mixed in CDCl3 (0.7 mL) in a
5-mm NMR tube, and 45.7 mg (213 μmol, γ = 1.20) of (S)-tert-butyl-
phenyl-phosphinothioic acid [(−)-10] was added to it. Signals
attributed to the salt (−)-9·(−)-10 are indicated with a hash (#).
1H NMR (CDCl3, 400 MHz, 300 K, transients = 64) δ 1.11 (d, 3JPH
=
16.5 Hz, 14 H), 1.22 (d, J = 6.6 Hz, 0.7 H)#, 1.27 (d, J = 6.6 Hz, 3 H),
1.54 (dq, J = 13.9, 2.6 Hz, 1 H), 1.63 (dq, J = 13.9, 2.6 Hz, 0.2 H)#,
1.72 (dt, J = 13.9, 3.0 Hz, 1.2 H), 1.82 (t, J = 12.4 Hz, 0.2 H)#, 1.91 (t,
J = 12.7 Hz, 1 H), 1.95 (td, J = 13.8, 5.1 Hz, 1 H), 2.10 (td, J = 13.8,
5.1 Hz, 0.2 H)#, 2.90 (td, J = 13.0, 3.3 Hz, 0.2 H)#, 3.00 (td, J = 13.0,
3.3 Hz, 1 H), 3.12 (ddd, J = 13.0, 5.1, 2.2 Hz, 1.2 H), 3.20−3.33 (m,
1.2 H), 3.85−3.95 (m, 4.8 H), 7.35−7.45 (m, 5 H), 7.92−7.99 (m, 3.3
H). 13C NMR (CDCl3, 100 MHz, transients = 1185) δ 18.7 (s)#, 18.9
(s), 24.9 [(p), d, 2JPH = 2.0 Hz)], 31.2 (s), 31.3 (s)#, 36.3 [(q), d, 1JPH
= 75.0 Hz], 39.89 (s)#, 39.97 (s), 41.85 (s), 41.90 (s)#, 50.90 (t)#,
3366
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
petroleum ether. The combined fractions were evaporated to yield
0.41 g (70%) of 4-piperidone rac-13a as a colorless oil. Rf = 0.3
(petroleum ether/diethyl ether, 70:30). Rf = 0.9 (petroleum ether/
extracted with 2 × 50 mL of diethyl ether, and the organic phase was
dried over MgSO4 and concentrated to afford 0.55 g (97%) of 4-
piperidone rac-14a as a colorless oil. H NMR (CDCl3, 400 MHz) δ
1
1
diethyl ether, 70:30). H NMR (CDCl3, 400 MHz) δ 0.91 (t, J = 7.0
0.89 (t, J = 7.0 Hz, 3 H), 1.25−1.45 (m, 5 H), 1.61 (td, J = 12.9, 5.0
Hz, 1 H), 1.66−1.77 (m, 2 H), 1.80−1.90 (s, br. One H), 2.70−2.77
(m, 1 H), 2.83 (td, J = 12.5, 3.2 Hz, 1 H), 3.07 (ddd, J = 12.5, 5.0, 2.3
Hz, 1 H), 3.94−3.98 (m, 4 H). 13C NMR (CDCl3, 100 MHz) δ 14.2
(p), 19.0 (s), 35.8 (s), 39.1 (s), 42.2 (s), 43.9 (s), 54.2 (t), 64.1 (s),
64.3 (s), 108.0 (q). IR (neat) ν = 1071, 2926, 3318 cm−1. HRMS
(ESI+): calcd for C10H20NO2) [M + H]+ 186.1494, found 186.1491.
Anal. Calcd for C10H19NO2 (185.26): C 64.83, H 10.34, N 7.56.
Found: C 64.70, H 10.28, N 7.40.
Hz, 3 H), 1.21−1.32 (m, 2 H), 1.45 (s, 9 H), 1.44−1.52 (m, 1 H),
1.60−1.68 (m, 3 H), 1.75−1.85 (m, 2 H), 3.00 (ddd, J = 16.1, 11.8, 4.4
Hz, 1 H), 3.88−4.00 (m, 4 H), 4.05 (dm, J = 13.2 Hz, 1 H), 4.32 (q. J
= 7.5 Hz, 1 H). 13C NMR (CDCl3, 100 MHz) δ 14.0 (p), 19.8 (s),
28.5 (p), 33.4 (s), 34.7 (s), 36.6 (s), 37.0 (s), 50.5 (t), 63.8 (s), 64.6
(s), 79.4 (q), 107.5 (q), 154.9 (q). IR (neat) ν = 1110, 1685, 2922
cm−1. HRMS (ESI+): calcd for C15H27NO4Na [M + Na]+ 308.18378,
found 308.1837. Anal. Calcd for C15H27NO4 (285.37): C 63.13, H
9.54, N 4.91. Found: C 62.94, H 9.69, N 4.96.
7-Pentyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic Acid
tert-Butyl Ester (rac-13b), New Derivative. The synthesis of 4-
piperidone rac-13b (62%) was carried out according to procedure A,
but with 0.40 mL (0.60 g, 3.05 mmol) of 1-iodopentane as the
alkylating agent. Colorless oil. Rf = 0.35 (petroleum ether/diethyl
ether, 60:40). 1H NMR (CDCl3, 400 MHz) δ 0.88 (t, J = 7.0 Hz, 3 H),
1.15−1.35 (m, 6 H), 1.45 (s, 9 H), 1.44−1.55 (m, 1 H), 1.60−1.68
(m, 3 H), 1.75−1.85 (m, 2 H), 2.99 (ddd, J = 16.1, 11.8, 4.4 Hz, 1 H),
3.88−4.00 (m, 4 H), 4.05 (dm, J = 13.2 Hz, 1 H), 4.32 (q. J = 7.5 Hz,
1 H). 13C NMR (CDCl3, 100 MHz) δ 14.0 (p), 22.7 (s), 26.3 (s), 28.5
(p), 31.1 (s), 31.6 (s), 34.7 (s), 36.6 (s), 36.9 (s), 50.8 (t), 63.7 (s),
64.7 (s), 79.4 (q), 107.5 (q), 154.9 (q). IR (neat) ν = 1111, 1687,
2925 cm−1. HRMS (ESI+): calcd for C17H31NO4Na) [M + Na]+
336.21453, found 336.2149. Anal. Calcd for C17H31NO4 (313.43): C
65.14, H 9.97, N 4.47. Found: C 65.03, H 9.95, N 4.47.
7-Pentyl-1,4-dioxa-8-aza-spiro[4.5]decane (rac-14b), New
Derivative. The synthesis of 0.50 g (97%) of 4-piperidone rac-14b
1
was carried out according to procedure B. Colorless oil. H NMR
(CDCl3, 400 MHz) δ 0.88 (t, J = 7.0 Hz, 3 H), 1.25−1.45 (m, 9 H),
1.45−1.55 (s, br. One H), 1.61 (td, J = 12.9, 5.0 Hz, 1 H), 1.66−1.77
(m, 2 H), 2.67−2.75 (m, 1 H), 2.83 (td, J = 12.5, 3.2 Hz, 1 H), 3.07
(ddd, J = 12.5, 5.0, 2.3 Hz, 1 H), 3.94−3.98 (m, 4 H). 13C NMR
(CDCl3, 100 MHz) δ 14.0 (p), 22.6 (s), 25.5 (s), 32.0 (s), 35.8 (s),
37.0 (s), 42.3 (s), 44.0 (s), 54.5 (t), 64.1 (s), 64.3 (s), 108.0 (q). IR
(neat) ν = 1146, 2952, 3320 cm−1 HRMS (ESI+): calcd for
C12H24NO2) [M + H]+ 214.1807, found 214.1805. Anal. Calcd for
C12H23NO2 (213.31): C 67.57, H 10.87, N 6.57. Found: C 67.45, H
10.43, N 6.40.
7-Heptyl-1,4-dioxa-8-aza-spiro[4.5]decane (rac-14c), New
Derivative. The synthesis of 0.45 g (98%) of 4-piperidone rac-14c
1
was carried out according to procedure B. Colorless oil. H NMR
(CDCl3, 400 MHz) δ 0.87 (t, J = 7.0 Hz, 3 H), 1.25−1.45 (m, 13 H),
1.40−1.50 (s, br. One H), 1.61 (td, J = 12.9, 5.0 Hz, 1 H), 1.66−1.77
(m, 2 H), 2.67−2.75 (m, 1 H), 2.82 (td, J = 12.5, 3.2 Hz, 1 H), 3.07
(ddd, J = 12.5, 5.0, 2.3 Hz, 1 H), 3.94−3.98 (m, 4 H). 13C NMR
(CDCl3, 100 MHz) δ 14.1 (p), 22.7 (s), 25.9 (s), 25.2 (s), 29.7 (s),
31.8 (s), 35.8 (s), 37.0 (s), 42.3 (s), 44.0 (s), 54.6 (t), 64.1 (s), 64.3
(s), 108.0 (q). IR (neat) ν = 1146, 2923, 3200 cm−1. HRMS (ESI+):
calcd for C14H28NO2) [M + H]+ 242.2120, found 242.2121. Anal.
Calcd for C14H27NO2 (241.36): C 69.66, H 11.27, N 5.80. Found: C
69.56, H 11.26, N 5.74.
7-Heptyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic
Acid tert-Butyl Ester (rac-13c), New Derivative. The synthesis of
4-piperidone rac-13c (65%) was carried out according to procedure A,
but with 0.50 mL (0.69 g, 3.05 mmol) of 1-iodoheptane as the
alkylating agent. Colorless oil. Rf = 0.35 (petroleum ether/diethyl
ether, 60:40). 1H NMR (CDCl3, 400 MHz) δ 0.88 (t, J = 7.0 Hz, 3 H),
1.15−1.35 (m, 10 H), 1.45 (s, 9 H), 1.44−1.55 (m, 1 H), 1.60−1.68
(m, 3 H), 1.75−1.85 (m, 2 H), 2.99 (ddd, J = 16.1, 11.8, 4.4 Hz, 1 H),
3.88−4.00 (m, 4 H), 4.05 (dm, J = 13.2 Hz, 1 H), 4.32 (q. J = 7.5 Hz,
1 H). 13C NMR (CDCl3, 100 MHz) δ 14.1 (p), 22.7 (s), 26.7 (s), 28.5
(p), 29.3 (s), 29.4 (s), 31.2 (s), 31.8 (s), 34.7 (s), 36.7 (s), 36.9 (s),
50.8 (t), 63.7 (s), 64.7 (s), 79.4 (q), 107.5 (q), 154.9 (q). IR (neat) ν
= 1120, 1686, 2918 cm−1. HRMS (ESI+): calcd for C19H35NO4Na [M
+ Na]+ 364.24638, found 364.2462. Anal. Calcd for C19H35NO4
(341.48): C 66.83, H 10.33, N 4.10. Found: C 66.42, H 10.32, N 4.14.
7-Undecyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic
Acid tert-Butyl Ester (rac-13d), New Derivative. The synthesis of
4-piperidone rac-13d (60%) was carried out according to procedure A
but with 0.71 mL (0.86 g, 3.07 mmol) of 1-iodoundecane as the
alkylating agent. Colorless oil. Rf = 0.50 (petroleum ether/diethyl
ether, 50:50). 1H NMR (CDCl3, 400 MHz) δ 0.88 (t, J = 7.0 Hz, 3 H),
1.15−1.35 (m, 18 H), 1.45 (s, 9 H), 1.44−1.55 (m, 1 H), 1.60−1.68
(m, 3 H), 1.75−1.85 (m, 2 H), 2.99 (ddd, J = 16.1, 11.8, 4.4 Hz, 1 H),
3.88−4.00 (m, 4 H), 4.05 (dm, J = 13.2 Hz, 1 H), 4.32 (q. J = 7.5 Hz,
1 H). 13C NMR (CDCl3, 100 MHz) δ 14.1 (p), 22.7 (s), 26.7 (s), 28.5
(p), 29.3 (s), 29.5 (s), 29.63 (s), 29.65 (s), 29.69 (s), 31.1 (s), 31.9
(s), 34.7 (s), 36.7 (s), 36.9 (s), 50.8 (t), 63.7 (s), 64.7 (s), 79.4 (q),
107.5 (q), 154.9 (q). IR (neat) ν = 1119, 1685, 2916 cm−1. HRMS
(ESI+): calcd for C23H43NO4Na [M + Na]+ 420.30898, found
420.3089. Anal. Calcd for C23H43NO4 (397.59): C 69.48, H 10.90,
N 3.52. Found: C 69.56, H 10.98, N 3.54.
7-Undecyl-1,4-dioxa-8-aza-spiro[4.5]decane (rac-14d), New
Derivative. The synthesis of 0.65 g (97%) of 4-piperidone rac-14d
1
was carried out according to procedure B. Colorless oil. H NMR
(CDCl3, 400 MHz) δ 0.87 (t, J = 7.0 Hz, 3 H), 1.25−1.45 (m, 21 H),
1.40−1.50 (s, br. One H), 1.60 (td, J = 12.9, 5.0 Hz, 1 H), 1.66−1.77
(m, 2 H), 2.67−2.75 (m, 1 H), 2.82 (td, J = 12.5, 3.2 Hz, 1 H), 3.07
(ddd, J = 12.5, 5.0, 2.3 Hz, 1 H), 3.94−3.98 (m, 4 H). 13C NMR
(CDCl3, 100 MHz) δ 14.1 (p), 22.7 (s), 25.9 (s), 29.3 (s), 29.58 (s, 2
C), 29.64 (s), 29.66 (s), 29.8 (s), 31.9 (s), 35.8 (s), 37.0 (s), 42.3 (s),
44.0 (s), 54.6 (t), 64.1 (s), 64.3 (s), 108.0 (q). IR (neat) ν = 1145,
2921, 3319 cm−1 HRMS (ESI+): calcd for C18H36NO2) [M + H]+
298.2746, found 298.2743. Anal. Calcd for C18H35NO2 (297.47): C
72.68, H 11.86, N 4.71. Found: C 72.22, H 11.96, N 4.72.
(7R,9R)-7-(4-Chloro-butyl)-9-methyl-1,4-dioxa-8-aza-spiro-
[4.5]decane-8-carboxylic Acid tert-Butyl Ester [(+)-15].6c The
synthesis of 4-piperidone (+)-15 (86%, 98:2 dr) was carried out
according to procedure A, but with 0.75 g (2.91 mmol) of 4-
piperidone (−)-11 and 0.50 mL (0.89 g, 4.08 mmol) of 1-chloro-4-
iodobutane as the alkylating agent. [α]22D +10.6 (c 1.3, CHCl3), [lit.6c
[α]22 +8.2 [c 0.49, CHCl3]. Colorless oil. Rf = 0.67 (dichloro-
D
methane/ethyl acetate 90:10). 1H NMR (CDCl3, 400 MHz) δ 1.28 (d,
J = 7.0 Hz, 3 H), 1.35−1.55 (m, 3 H), 1.45 (s, 9 H), 1.56−1.85 (m, 4
H), 1.95 (dd, J = 14.8, 3.3 Hz, 1 H), 2.05 (dd, J = 14.8, 5.1 Hz, 1 H),
2.12 (dd, J = 14.6, 5.3 Hz, 1 H), 3.54 (t, J = 6.8 Hz, 2 H), 3.82−4.06
(m, 6 H). 13C NMR (CDCl3, 100 MHz) δ 20.9 (p), 24.0 (s), 28.5 (p),
32.3 (s), 33.3 (s), 35.8 (s), 39.6 (s), 45.0 (s), 46.2 (t), 50.6 (t), 63.78
(s), 63.87 (s), 79.3 (q), 106.6 (q), 155.0 (q). IR (neat) ν = 1123, 1682,
2971 cm−1. HRMS (ESI+): calcd for C17H30ClNO4Na) [M + Na]+
370.17556, found 370.1754. Anal. Calcd for C17H30ClNO4 (347.87):
C 58.69, H 8.69, N 4.03. Found: C 58.52, H 8.76, N 3.99.
Procedure B. N-Boc cleavage in derivatives rac-13a−d.
7-Propyl-1,4-dioxa-8-aza-spiro[4.5]decane (rac-14a), New
Derivative. A 200-mL, one-necked Schlenk tube fitted with a
magnetic stirring bar and cooled to 0 °C was charged with 30 mL of
anhydrous diethyl ether and 14.01 mL (14.00 mmol) of a 1 M solution
of SnCl4 in hexanes. The SnCl4·(Et2O)2 complex precipitated as a
white solid, 1.00 g (3.50 mmol) of 4-piperidone rac-13a was added,
stirring was continued at ambient temperature for 12 h, and the
reaction mixture was cooled to 0 °C. Then, 35 mL of a 2 M NaOH
aqueous solution were added at that temperature, and stirring was
continued for 12 h at ambient temperature. The aqueous layer was
(4-Iodo-butoxymethyl)-benzene (16).42 To a suspension of
2.88 g of NaH (120.00 mmol, 60% in mineral oil) in dry THF was
3367
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
added 8.91 mL (9.00 g, 100.00 mmol) of 1,4-butanediol. The resulting
solution was stirred for 1 h at room temperature, and 12.00 mL (17.16
g, 100.0 mmol) of benzyl bromide was slowly added by syringe. After
12 h of stirring, 50 mL of water was added to the reaction mixture, and
the crude material was extracted by 2 × 75 mL of diethyl ether. The
organic phase was dried over MgSO4, concentrated, and poured into a
chromatographic column (diameter = 5.0 cm) prepared with 30 g of
silica and 65:35 pentane/ethyl acetate. The combined fractions were
evaporated to yield 12.25 g (68%) of 4-benzyloxy-1-butanol [Rf = 0.38
(pentane/ethyl acetate, 65:35)] as a colorless oil. This oil (6.00 g,
33.28 mmol) was dissolved in 150 mL of dichloromethane. Then, 4.65
g (68.30 mmol) of imidazole, 15.70 g (59.85 mmol) of
triphenylphosphine, and 16.05 g (63.68 mmol) of iodine were
successively added, and the resulting solution was stirred at 0 °C for 5
min and at ambient temperature for 45 min. The reaction was
quenched with 100 mL of a 2 M aqueous solution of sodium bisulfite.
The organic layer was separated, washed with water, dried over MgSO4
and concentrated to yield a crude oil, which was poured into a
chromatographic column (diameter = 5.0 cm) prepared with 30 g of
silica and 90:10 petroleum ether/diethyl ether. The combined
fractions were evaporated to yield 8.00 g (83%) of (4-iodo-butoxy-
methyl)-benzene (16) as a colorless oil, which could be stored at −20
°C for several months without loss of quality. Rf = 0.48 (90:10
1.75 (m, 5 H), 1.82 (dd, J = 14.6, 3.7 Hz, 1 H), 1.98 (dd, J = 14.7, 3.3
Hz, 1 H), 2.07 (dd, J = 14.7, 5.2 Hz, 1 H), 2.14 (dd, J = 14.6, 5.3 Hz, 1
H), 3.60−3.70 (m, 2 H), 3.82−3.93 (m, 3 H), 3.94−4.00 (m, 2 H),
4.01−4.06 (m, 1 H). 13C NMR (CDCl3, 125 MHz) δ 20.9 (p), 22.6
(s), 28.5 (p), 32.1 (s), 33.5 (s), 35.8 (s), 39.5 (s), 46.2 (t), 50.7 (t),
62.3 (s), 63.79 (s), 63.82 (s), 79.3 (q), 106.7 (q), 155.0 (q). IR (neat)
ν = 1137, 1661, 2922, 3449 cm−1. HRMS (ESI+): calcd for
C17H31NO5Na) [M + Na]+ 352.20999, found 352.2102. Anal. Calcd
for C17H31NO5 (329.43): C 61.98, H 9.48, N 4.25. Found: C 62.12, H
9.59, N 4.23.
(7S,9S)-(−)-7-(4-Hydroxy-butyl)-9-methyl-1,4-dioxa-8-aza-
spiro[4.5]decane-8-carboxylic Acid tert-Butyl Ester [(−)-18],
New Derivative. The synthesis was as reported for (+)-18 but with
4-piperidone (−)-17 to afford derivative (−)-18 as a white solid. Mp =
95 °C. [α]22 −10.2 (c 1.0, CHCl3).
(7R,9R)-(D+)7-(4-Bromo-butyl)-9-methyl-1,4-dioxa-8-aza-
spiro[4.5]decane-8-carboxylic Acid tert-Butyl Ester [(+)-19],
New Derivative. 4-Piperidone (+)-18 (1.06 g, 3.21 mmol) was
dissolved in 20 mL of dichloromethane. Then, 1.44 g (4.34 mmol) of
CBr4 and 1.05 g (4.00 mmol) of triphenylphosphine were successively
added, and the resulting solution was stirred at ambient temperature
for 24 h. The excess of CBr4 was destroyed by the addition of 2 mL of
EtOH, and stirring was continued for 2 h. The solvents were
evaporated, and the crude oil was poured into a chromatographic
column (diameter = 5.0 cm) prepared with 20 g of silica and 50:50
pentane/diethyl ether. The combined fractions were evaporated to
1
petroleum ether/diethyl ether). H NMR (C6D6, 400 MHz) δ 1.35−
1.45 (m, 2 H), 1.54−1.62 (m, 2 H), 2.71 (t, J = 7.0 Hz, 2 H), 3.08 (t, J
= 7.0 Hz, 2 H), 4.20 (s, 2 H), 7.08 (tt, J = 7.2, 1.5 Hz, 1 H), 7.16 (tt, J
= 7.2, 1.5 Hz, 2 H), 7.23 (dm, J = 7.2 Hz, 2 H). 13C NMR (CDCl3,
100 MHz) δ 6.3 (s), 30.3 (s), 30.5 (s), 68.8 (s), 72.6 (s), 127.31 (t),
127.34 (t), 128.2 (t), 138.9 (q). HRMS (ESI+): calcd for
C11H15OINa) [M + Na]+ 313.00654, found 313.0066.
yield 1.12 g (89%) of 4-piperidone (+)-19 as a colorless oil. [α]22
+9.0 (c 1.4, CHCl3). Rf = 0.38 (diethyl ether/pentane 50:50). H
D
1
NMR (CDCl3, 400 MHz) δ 1.28 (d, J = 7.0 Hz, 3 H), 1.35−1.50 (m, 2
H), 1.46 (s, 9 H), 1.55−1.75 (m, 2 H), 1.80 (dd, J = 14.7, 3.6 Hz, 1
H), 1.88 (quint. J = 7.2 Hz, 2 H), 1.95 (dd, J = 14.8, 3.4 Hz, 1 H), 2.05
(dd, J = 14.7, 5.3 Hz, 1 H), 2.12 (dd, J = 14.6, 5.3 Hz, 1 H), 3.42 (t, J =
6.8 Hz, 2 H), 3.82−3.93 (m, 3 H), 3.95−3.99 (m, 2 H), 4.00−4.06 (m,
1 H). 13C NMR (CDCl3, 100 MHz) δ 20.8 (p), 25.3 (s), 28.6 (p),
32.5 (s), 33.2 (s), 33.9 (s), 35.8 (s), 39.6 (s), 46.2 (t), 50.6 (t), 63.8
(s), 63.9 (s), 79.3 (q), 106.6 (q), 155.0 (q). IR (neat) ν = 1123, 1682,
2970 cm−1. HRMS (ESI+): calcd for C17H30BrNO4Na) [M + Na]+
414.12559, found 414.1253. Anal. Calcd for C17H30BrNO4 (392.33):
C 52.04, H 7.71, N 3.57. Found: C 52.20, H 7.70, N 3.60.
(7R,9R)-(+)-7-(4-Benzyloxy-butyl)-9-methyl-1,4-dioxa-8-aza-
spiro[4.5]decane-8-carboxylic Acid tert-Butyl Ester [(+)-17],
New Derivative. The synthesis of 4-piperidone (+)-17 (82%) was
carried out according to procedure B, but with 1.00 g (3.88 mmol) of
4-piperidone (−)-11 and 1.57 g (5.41 mmol) of iodide 16 as the
alkylating agent. Colorless oil. Rf = 0.64 (diethyl ether/pentane 60:40).
[α]22D +10.6 (c 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz) δ 1.28 (d, J
= 7.0 Hz, 3 H), 1.25−1.35 (m, 1 H), 1.45 (s, 9 H), 1.38−1.50 (m, 1
H), 1.60−1.75 (m, 4 H), 1.80 (dd, J = 14.6, 3.7 Hz, 1 H), 1.95 (dd, J =
14.7, 3.3 Hz, 1 H), 2.03 (dd, J = 14.7, 5.2 Hz, 1 H), 2.12 (dd, J = 14.6,
5.3 Hz, 1 H), 3.47 (t, J = 6.8 Hz, 2 H), 3.82−3.90 (m, 3 H), 3.91−3.99
(m, 2 H), 4.00−4.06 (m, 1 H), 4.50 (s, 2 H), 7.25−7.30 (m, 2 H),
7.32−7.35 (m, 3 H). 13C NMR (CDCl3, 125 MHz) δ 20.8 (p), 23.4
(s), 28.6 (p), 29.6 (s), 34.0 (s), 36.0 (s), 39.5 (s), 46.2 (t), 50.8 (t),
63.77 (s), 63.84 (s), 70.4 (s), 72.8 (s), 79.2 (q), 106.6 (q), 127.4 (t),
127.6 (t), 128.3 (t), 138.7 (q), 155.0 (q). IR (neat) ν = 1116, 1683,
2956 cm−1. HRMS (ESI+): calcd for C24H37NO5) [M + Na]+
442.25639, found 442.2563. Anal. Calcd for C24H37NO5 (419.55): C
68.71, H 8.89, N 3.34. Found: C 68.51, H 8.91, N 3.38.
(7S,9S)-(−)-7-(4-Bromo-butyl)-9-methyl-1,4-dioxa-8-aza-
spiro[4.5]decane-8-carboxylic Acid tert-Butyl Ester (−)-19,
New Derivative. The synthesis was as reported for (+)-19 but
with 4-piperidone (−)-18 to afford derivative (−)-19 as a colorless oil.
[α]22 −9.5 (c 1.0, CHCl3).
D
(4′R,9a′R)-(+)-4′-Methyloctahydrospiro[[1,3]-dioxolane-2,2′-
quinolizine] [(+)-20], New Derivative. Quinolizidine (+)-20 (0.73
g, 97%) was synthesized according to procedure B, but starting from
1.40 g (3.56 mmol) of 4-piperidone (+)-19. The crude oil was poured
into a chromatographic column (diameter = 2.5 cm) prepared with 10
g of silica and eluted with 70:30 dichloromethane/methanol. Colorless
oil. [α]22 +11.1 (c 1.0, CHCl3). Rf = 0.40 (dichloromethane/
(7S,9S)-(−)-7-(4-Benzyloxy-butyl)-9-methyl-1,4-dioxa-8-aza-
spiro[4.5]decane-8-carboxylic Acid tert-Butyl Ester [(−)-17],
New Derivative. The synthesis was as reported for (+)-17 but with
4-piperidone (+)-11 to afford derivative (−)-17 as a colorless oil.
D
methanol 70:30). 1H NMR (CDCl3, 400 MHz) δ 1.13 (d, J = 7.0 Hz,
3 H), 1.15−1.37 (m, 2 H), 1.50−1.75 (m, 7 H), 2.08 (dd, J = 13.4, 5.7
Hz, 1 H), 2.45−2.52 (m, 1 H), 2.61 (tt, J = 10.6, 3.0 Hz, 1 H), 2.74
(dm, J = 10.6 Hz, 1 H), 3.19−3.27 (m, 1 H), 3.86−3.91 (m, 2 H),
3.92−3.89 (m, 2 H). 13C NMR (CDCl3, 100 MHz) δ 12.1 (p), 24.0
(s), 25.5 (s), 33.2 (s), 40.0 (s), 42.1 (s), 51.39 (s), 51.43 (t), 54.5 (t),
63.6 (s), 64.5 (s), 107.5 (q). IR (neat) ν = 1066, 2807, 2930 cm−1.
HRMS (ESI+): calcd for C12H22NO2) [M + H]+ 212.16505, found
212.1649. Anal. Calcd for C12H21NO2 (211.30): C 68.21, H 10.02, N
6.63. Found: C 67.83, H 10.04, N 6.50.
[α]22 −8.3 (c 1.1, CHCl3).
D
(7R,9R)-(+)-7-(4-Hydroxy-butyl)-9-methyl-1,4-dioxa-8-aza-
spiro[4.5]decane-8-carboxylic Acid tert-Butyl Ester [(+)-18],
New Derivative. A 50-mL low-pressure hydrogenator was charged
with 40 mL of methanol, 2.00 g (4.77 mmol) of 4-piperidone (+)-17,
and 0.20 g (10% in mass) of 10% Pd/C. The hydrogen pressure (3.75
× 103 Torr, 5 bar) was applied, and the homogeneous solution was
stirred for 24 h at room temperature. The suspension was filtered over
a small pad of Celite, and the methanolic solution was concentrated to
afford a crude residue (1.65 g), which was poured on a into a
chromatographic column (diameter = 2.0 cm) prepared with 10 g of
silica and diethyl ether. The combined fractions were evaporated to
yield 1.51 g (96%) of 4-piperidone (+)-18 as a white solid. A slow
crystallization of this solid in diethyl ether afforded single crystals,
which were analyzed by X-ray diffraction. Mp = 95 °C. [α]22D +9.4 (c
1.0, CHCl3). Rf = 0.36 (diethyl ether). 1H NMR (CDCl3, 500 MHz) δ
1.28 (d, J = 7.0 Hz, 3 H), 1.30−1.45 (m, 2 H), 1.45 (s, 9 H), 1.50−
(4′S,9a′S)-(−)-4′-Methyloctahydrospiro[[1,3]-dioxolane-2,2′-
quinolizine] [(−)-20], New Derivative. The synthesis was as
reported for (+)-20 but with 4-piperidone (−)-19 to afford derivative
(−)-20 as a colorless oil. [α]22 −10.8 (c 1.0, CHCl3).
D
(+)-Myrtine [(+)-1]. A 50-mL round-bottom flask was charged with
15 mL of acetone, 4 mL of a 5 N HCl solution, and 0.24 g (1.13
mmol) of 4-piperidone (+)-20. The solution was refluxed for 4 h, and
stirring was continued for 12 h at ambient temperature. Then, 20 mL
of a 2 N NaOH solution was added to the reaction mixture, which was
extracted with 3 × 30 mL of diethyl ether. The organic phases were
3368
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
dried over MgSO4 and concentrated to afford 0.220 g of a crude oily
residue, which was poured into a chromatographic column (diameter
= 2.5 cm) prepared with 10 g of silica and 80:20 dichloromethane/
methanol. The combined fractions were evaporated to yield 0.18 g
(95%) of (+)-myrtine (1) as a white solid. Mp = 50 °C. [α]22D +10.5
as a 80:20 cis/trans mixture. The sample contained trace amount (ca.
2−3%) of unreacted 4-piperidone (−)-11. 1H NMR (major
diastereoisomer, CDCl3, 400 MHz) δ 1.29 (d, J = 7.1 Hz, 3 H),
1.47 (s, 9 H), 1.60 (dt, J = 13.6, 2.0 Hz, 1 H), 1.80 (dd, J = 13.8, 7.2
Hz, 1 H), 1.97 (dd, J = 13.6, 7.2 Hz, 1 H), 3.00 (dt, J = 13.7, 2.5 Hz, 1
H), 3.80−4.00 (m, 4 H), 4.50 (quint.d, J = 7.1, 1.9 Hz, 1 H), 4.65 (dd,
J = 7.5, 2.2 Hz, 1 H), 9.63 (d, J = 1.0 Hz, 1 H). 13C NMR (CDCl3, 100
MHz) δ 20.7 (p), 28.3 (p), 32.4 (s), 37.2 (s), 47.4 (t), 59.9 (t), 64.0
(s), 64.4 (s), 80.7 (q), 106.2 (q), 155.2 (q), 200.3 (t). IR (neat) ν =
1143, 1678, 1741, 2801 cm−1. HRMS (ESI+): calcd for
C14H23NO5Na) [M + Na]+ 308.14739, found 308.1472. Anal. Calcd
for C14H23NO5 (285.33): C 58.93, H 8.12, N 4.91. Found: C 59.00, H
8.15, N 4.89.
(c 0.9, CHCl3), lit.6b [α]22 +10.1 (c 1.5, CHCl3). Rf = 0.70
D
1
(dichloromethane/methanol 80:20). H NMR (CDCl3, 400 MHz) δ
0.97 (d, J = 6.8 Hz, 3 H), 1.17−1.35 (m, 2 H), 1.55−1.65 (m, 1 H),
1.66−1.75 (m, 3 H), 2.16−2.30 (m, 3 H), 2.48 (td, J = 11.5, 3.0 Hz, 1
H), 2.61−2.70 (m, 1 H), 2.79 (dm, J = 11.5 Hz, 1 H), 2.85 (dd, J =
13.4, 6.0 Hz, 1 H), 3.38 (quint.d, J = 6.7, 2.3 Hz, 1 H). 13C NMR
(CDCl3, 100 MHz) δ 11.1 (p), 23.4 (s), 25.9 (s), 34.3 (s), 48.0 (s),
48.7 (s), 51.4 (s), 53.5 (t), 57.1 (t), 209.6 (q). IR (neat) ν = 1702,
2856, 2930 cm−1. HRMS (ESI+): calcd for C10H18NO) [M + H]+
168.13884, found 168.1387. Anal. Calcd for C10H17NO (167.25): C
71.81, H 10.25, N 8.37. Found: C 71.50, H 10.17, N 8.23.
(7R,9R)-7-Methyl-9-non-1-enyl-1,4-dioxa-8-aza-spiro[4.5]-
decane-8-carboxylic Acid tert-Butyl Ester (22), New Derivative.
An oven-dried, 200-mL, one-necked Schlenk tube, fitted with a
magnetic stirring bar, containing 20 mL of dry THF and 0.75 g (1.65
mmol) of n-octyl-triphenyl-phosphonium bromide, was flushed with
argon and the suspension was cooled to −40 °C. A solution of nBuLi
(0.67 mL, 1.67 mmol, 2.5 M in cyclohexane) was added dropwise and
the resulting clear orange phosphonium ylide solution was warmed to
0 °C over a 2 h period and cooled to −70 °C. Then, 5 mL of a THF
solution of 4-piperidone 21 (0.39 g, 1.36 mmol as a 80:20 cis/trans
mixture) was added dropwise, and the reaction mixture was warmed to
ambient temperature over a 3 h period and stirring was continued
overnight. The solution was poured in 50 mL of water, the crude
material was extracted with diethyl ether (2 × 50 mL), and the organic
phase was dried over MgSO4, concentrated, and poured into a
chromatographic column (diameter = 2.0 cm) prepared with 10 g of
silica and 50:50 diethyl ether/petroleum ether. The combined
fractions were evaporated to yield 0.45 g (86%) of 4-piperidone 22
as a 75:25 cis/trans ratio. Colorless oil. Rf = 0.47 (diethyl ether/
(−)-Myrtine [(−)-1]. The synthesis was as reported for (+)-myrtine
but with 4-piperidone (−)-20 to afford (−)-myrtine as a white solid.
Mp = 55 °C. [α]22 −10.7 (c 1.0, CHCl3). lit.9a [α]22 −12.5 (c 0.4,
D
D
CHCl3).
2[(+)-Myrtine (99:1 er)]·(+)-DBTA, New Derivative. Mp = 72
°C. [α]22D +22.2 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 1.13
(d, J = 6.8 Hz, 6 H), 1.16−1.26 (m, 2 H), 1.50−1.65 (m, 4 H), 1.70
(d, J = 12.0 Hz, 2 H), 1.77−1.92 (m, 4 H), 2.20 (d, J = 14.0 Hz, 2 H),
2.40 (d, J = 12.0 Hz, 2 H), 2.65 (t, J = 12.0 Hz, 2 H), 2.65 (t, J = 12.0
Hz, 2 H), 2.80 (t, J = 14.0 Hz, 2 H), 3.05−3.18 (s, 2 H), 3.24−3.35
(m, 2 H), 3.82−3.90 (m, 2 H), 5.97 (s, 2 H), 7.33 (t, J = 7.9 Hz, 4 H),
7.51 (tt, J = 7.9, 1.3 Hz, 2 H), 8.12 (dd, J = 8.4, 1.3 Hz, 4 H). 13C
NMR (CDCl3, 100 MHz) δ 12.6 (p), 21.9 (s), 22.5 (s), 30.4 (s), 45.2
(s), 45.8 (s), 51.0 (s), 55.8 (t), 56.9 (t), 73.7 (t), 128.3 (t), 129.9 (q),
130.0 (t), 165.8 (q), 171.0 (q), 203.4 (q). Anal. Calcd for
C38H48N2O10 (692.79): C 65.88, H 6.98, N 4.04. Found: C 66.00,
H 7.05, N 4.02.
1
petroleum ether, 50:50). H NMR (major diastereoisomer, CDCl3,
2[(+)-Myrtine (65:35 er)]·(+)-DBTA. (+)-Myrtine (12.00 mg,
71.74 μmol, 99:1 er), (−)-myrtine (8.00 mg, 47.83 μmol, 99:1 er) and
21.40 mg (59 μmol) of (+)-2,3-dibenzoyl-D-tartaric acid [(+)-DBTA]
were mixed in CDCl3 in a 5-mm NMR tube. Splitting signals are
indicated with a hash (#). 1H NMR (CDCl3, 400 MHz) δ 1.07 (d, J =
6.8 Hz, 3.9 H), 1.13 (d, J = 6.8 Hz, 2.1 H)#, 1.12−1.28 (m, 2 H),
1.50−1.95 (m, 10 H), 2.04 (d, J = 12 Hz, 1.30 H)#, 2.17 (d, J = 12 Hz,
0.70 H)#, 2.28 (d, J = 12 Hz, 1.30 H)#, 2.35 (d, J = 12 Hz, 0.70 H)#,
2.57−2.80 (m, 4 H), 2.95−3.30 (6 H), 3.72−3.84 (m, 2 H), 5.97 (s, 2
H), 7.38 (t, J = 7.9 Hz, 4 H), 7.51 (tt, J = 7.9, 1.3 Hz, 2 H), 8.14 (dd, J
= 8.4, 1.3 Hz, 4 H). 13C NMR (CDCl3, 100 MHz) δ 12.4 (p), 22.03
(s)#, 22.1 (s), 22.6 (s), 30.6 (s), 45.3 (s)#, 45.4 (s)#, 45.9 (s), 46.0 (s)#,
50.8 (s), 55.4 (s)#, 55.6 (t), 56.6 (t), 74.2 (t), 128.3 (t), 130.0 (2 C),
133.0 (t), 165.9 (q), 171.3 (q), 204.0 (q), 204.1 (q)#.
(7R,9R)-7-Formyl-9-methyl-1,4-dioxa-8-aza-spiro[4.5]-
decane-8-carboxylic Acid tert-Butyl Ester (21).6c An oven-dried,
200-mL, one-necked Schlenk tube, fitted with a magnetic stirring bar,
containing 40 mL of dry diethyl ether, and connected to an argon inlet
tube, was flushed with argon and was cooled to −80 °C. Then, 1.00 g
(3.88 mmol) of 4-piperidone (−)-11 and 0.87 mL of TMEDA (0.67 g,
5.76 mmol, 1.50 equiv) were successively added. A solution of sBuLi
(3.60 mL, 5.04 mmol, 1.30 equiv, 1.4 M in cyclohexane) was added
dropwise. The resulting solution was stirred between −80 and −65 °C
for 3 h and was cooled to −80 °C. Then, 0.75 mL (0.71 g, 9.70 mmol,
2.50 equiv) of DMF was added dropwise, and the reaction mixture was
warmed to room temperature over a 12 h period and then poured in
50 mL of water. The resulting reaction mixture was extracted with
diethyl ether (2 × 50 mL), and the organic phase was dried over
MgSO4, concentrated, and poured into a chromatographic column
(diameter = 2.0 cm) prepared with 10 g of silica and 20:80 ethyl
acetate/petroleum ether. The combined fractions were evaporated to
yield 0.92 g (83%) of 4-piperidone 21 as a 75:25 trans/cis ratio. Rf =
0.35 (petroleum ether/ethyl acetate, 80:20). Epimerization proce-
dure: This mixture was stirred at ambient temperature for 60 h in a
suspension of silica (0.35 g) in 25 mL of diethyl ether containing 0.1
mL of triethylamine. This mixture was filtered on a small pad of Celite,
and the solvents were evaporated to dryness to afford 4-piperidone 21
400 MHz) δ 0.87 (t, J = 6.7 Hz, 3 H), 1.26−1.38 (m, 10 H), 1.34 (d, J
= 7.1 Hz, 3 H), 1.45 (s, 9 H), 1.68−1.78 (m, 2 H), 1.88−1.98 (m, 2
H), 2.05−2.15 (m, 2 H), 3.83−4.03 (m, 4 H), 4.45 (quint.d, J = 7.2,
3.0 Hz, 1 H), 5.14 (tm, J = 7.5 Hz, 1 H), 5.30−5.37 (m, 1 H), 5.82
(ddt, J = 9.5, 8.0, 1.6 Hz, 1 H). 13C NMR (CDCl3, 100 MHz) δ 14.1
(p), 21.7 (p), 22.6 (s), 27.15 (s), 28.5 (p), 29.2 (s), 29.3 (s), 29.8 (s),
31.9 (s), 37.9 (s), 38.3 (s), 46.8 (t), 48.0 (t), 63.5 (s), 64.6 (s), 79.5
(q), 107.2 (q), 130.2 (t), 131.7 (t), 154.8 (q). IR (neat) ν = 1090,
1687, 2925 cm−1. HRMS (ESI+): calcd for C22H39NO4Na) [M + Na]+
404.27768, found 404.2777. Anal. Calcd for C22H39NO4 (381.55): C
69.25, H 10.30, N 3.67. Found: C 69.10, H 10.10, N 3.60.
(7R,9S)-(−)-7-Methyl-9-nonyl-1,4-dioxa-8-aza-spiro[4.5]-
decane-8-carboxylic Acid tert-Butyl Ester [(−)-23-A], New
Derivative. A 50-mL low-pressure hydrogenator was charged with
30 mL of ethanol, 1.13 g (2.96 mmol) of 4-piperidone 22 (as a 80:20
cis/trans mixture), and 0.11 g (10% in mass) of 20% Pd(OH)2/C. The
hydrogen pressure (2.25 × 103 Torr, 3 bar) was applied, and the
homogeneous solution was stirred for 18 h at room temperature. The
suspension was filtered over a small pad of Celite, and the ethanolic
solution was concentrated to afford 1.10 g of an oily residue, which
was poured into a chromatographic column (diameter = 2.5 cm)
prepared with 30 g of silica and 20:80 diethyl ether/petroleum ether to
afford 0.25 g (22%) of the less polar minor trans diastereoisomer
(+)-23-B and 0.80 g (71%) of the more polar major cis
diastereoisomer (−)-23-A, respectively. 4-Piperidone (−)-23-A.
Colorless oil. [α]22 −8.5 (c 0.8, CHCl3). Rf = 0.25 (diethyl ether/
D
1
petroleum ether, 20:80). H NMR (CDCl3, 400 MHz) δ 0.88 (t, J =
6.7 Hz, 3 H), 1.23−1.33 (m, 16 H), 1.29 (d, J = 7.2 Hz, 3 H), 1.46 (s,
9 H), 1.65−1.80 (m, 3 H), 2.71 (dd, J = 13.7, 7.3 Hz, 1 H), 3.87−4.02
(m, 4 H), 4.20−4.28 (m, 1 H), 4.45 (quint.d, J = 7.1, 1.5 Hz, 1 H). 13C
NMR (CDCl3, 100 MHz) δ 14.1 (p), 21.2 (p), 22.7 (s), 27.4 (s), 28.5
(p), 29.5 (s), 29.56 (s), 29.61 (s), 29.7 (s), 32.0 (s), 35.2 (s), 35.7 (s),
37.9 (s), 46.4 (t), 51.1 (t), 63.3 (s), 64.7 (s), 79.3 (q), 107.4 (q), 155.0
(q). IR (neat) ν = 1117, 1685, 2924 cm−1. HRMS (ESI+): calcd for
C22H41NO4Na) [M + Na]+ 406.29333, found 406.2934. Anal. Calcd
for C22H41NO4 (383.57): C 68.89, H 10.77, N 3.65. Found: C 69.23,
H 10.71, N 3.63.
3369
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
(7R,9R)-(+)-7-Methyl-9-nonyl-1,4-dioxa-8-aza-spiro[4.5]-
decane-8-carboxylic Acid tert-Butyl Ester [(+)-23-B], New
organic layers were dried over MgSO4 and concentrated under
reduced pressure to afford 0.10 g of a crude residue, which was poured
into a chromatographic column (diameter = 1.5 cm) prepared with 5.0
g of silica and 65:35 ethyl acetate/methanol to afford 0.08 g (80%) of
alkaloid (+)-241D (2) as a white solid and 0.01 g (10%) of its C-4
epimer. Alkaloid (+)-241D. Mp = 109−110 °C (lit. 108−109 °C). Rf =
0.18 (ethyl acetate/methanol 65:35). [α]22D +6.8 (c 0.5, EtOH), lit.10a
[α]22D +5.66 (c 0.60, MeOH). 1H NMR (CDCl3, 400 MHz) δ 0.88 (t,
J = 6.7 Hz, 3 H), 0.98 (q, J = 11.3 Hz, 1 H), 1.40 (q, J = 11.0 Hz, 1 H),
1.12 (d, J = 6.3 Hz, 3 H), 1.23−1.48 (m, 16 H), 1.86−1.91 (s, br, 2 H),
1.93−2.02 (m, 2 H), 2.51−2.60 (m, 1 H), 2.65−2.74 (m, 1 H), 3.65−
2.60 (tt, J = 10.4, 4.6 Hz 1 H). 13C NMR (CDCl3, 100 MHz) δ 14.1
(p), 22.4 (p), 23.7 (s), 26.0 (s), 29.3 (s), 29.56 (s), 29.57 (s), 29.75
(s), 31.9 (s), 36.7 (s), 41.6 (s), 43.8 (s), 50.2 (t), 54.9 (t), 69.3 (t). IR
(neat) ν = 2916, 3177, 3270 cm−1 HRMS (ESI+): calcd for C15H32NO
[M + H]+ 242.24839, found 242.248. C15H31NO (241.41): C 74.63, H
12.94, N 5.80. Found: C 74.58, H 12.68, N 5.70.
Derivative. Colorless oil; [α]22 +13.2 (c 1.59, CHCl3); Rf = 0.25
D
(diethyl ether/petroleum ether, 20:80); 1H NMR (CDCl3, 500 MHz)
δ 0.88 (t, J = 6.7 Hz, 3 H), 1.23−1.33 (m, 14 H), 1.29 (d, J = 7.2 Hz, 3
H), 1.46 (s, 9 H), 1.54−1.70 (m, 2 H), 1.80 (dd, J = 14.6, 3.7 Hz, 1
H), 1.95 (dd, J = 14.7, 3.3 Hz, 1 H), 2.03 (dd, J = 14.7, 5.1 Hz, 1 H),
2.12 (dd, J = 14.6, 6.2 Hz, 1 H), 3.85−3.89 (m, 3 H), 3.92−3.98 (m, 2
H), 4.00−4.06 (m, 1 H). 13C NMR (CDCl3, 125 MHz) δ 14.1 (p),
20.8 (p), 22.7 (s), 26.8 (s), 28.6 (p), 29.3 (s), 29.5 (s), 29.6 (s), 29.7
(s), 31.9 (s), 34.2 (s), 35.9 (s), 39.5 (s), 42.2 (t), 51.1 (t), 63.76 (s),
63.82 (s), 79.2 (q), 106.8 (q), 155.0 (q). Anal. Calcd for C22H41NO4
(383.57): C 68.89, H 10.77, N 3.65. Found: C 69.20, H 10.65, N 3.60.
(7S,9R)-(+)-7-Methyl-9-nonyl-1,4-dioxa-8-aza-spiro[4.5]-
decane-8-carboxylic Acid tert-Butyl Ester [(+)-23-A], New
Derivative. The synthesis was as reported for (−)-23-A, but from
4-piperidone (+)-11 to afford derivative (+)-23-A as a colorless oil.
[α]22 +9.5 (c 1.0, CHCl3).
D
Alkaloid (−)-241D [(−)-2]. The synthesis was as reported for
alkaloid (+)-241D but from 4-piperidone (+)-25 to afford alkaloid
(−)-241D as a white solid. [α]22 −6.4 (c 0.6, EtOH); lit.14 [α]22
(7R,9S)-(+)-7-Methyl-9-nonyl-1,4-dioxa-8-aza-spiro[4.5]-
decane [(+)-24], New Derivative. The synthesis of 0.36 g (98%) of
4-piperidone (+)-24 was carried out according to procedure B.
Colorless oil. [α]22D +3.0 (c 1.1, EtOH). 1H NMR (CDCl3, 400 MHz)
δ 0.88 (t, J = 6.7 Hz, 3 H), 1.10 (d, J = 6.3 Hz, 3 H), 1.25−1.45 (m, 18
H), 1.50−1.60 (s, br. One H), 1.66−1.74 (m, 2 H), 2.72−2.80 (m, 1
H), 2.84−2.94 (m, 1 H), 3.94−3.96 (m, 4 H). 13C NMR (CDCl3, 100
MHz) δ 14.1 (p), 22.4 (p), 22.7 (s), 25.9 (s), 29.3 (s), 29.5 (s), 29.6
(s), 29.7 (s), 32.0 (s), 36.8 (s), 41.4 (s), 43.4 (s), 49.5 (t), 54.1 (t),
64.1 (s), 64.4 (s), 108.4 (q). IR (neat) ν = 1070, 2921 cm−1. HRMS
(ESI+): calcd for C17H34NO2) [M + H]+ 284.25895, found 284.259.
Anal. Calcd for C17H33NO2 (283.45): C 72.03, H 11.73, N 4.94.
Found: C 72.01, H 11.57, N 4.81.
D
D
−5.9 (c 0.75, MeOH).
Alkaloid (+)-241D (>99:1 er)·(+)-10. Alkaloid (+)-241D (12.0
mg, 49.7 μmol, 99:1 er) and CDCl3 (0.7 mL) were mixed in a 5-mm
NMR tube, and 17.0 mg (79.3 μmol, γ = 1.60) of (R)-tert-butyl-
phenyl-phosphinothioic acid [(+)-10] was added to it. 1H NMR
(CDCl3, 400 MHz, 300 K, transients = 64) δ 0.89 (t, J = 7.2 Hz, 3 H),
0.91−1.00 (m, 1 H), 1.13 (d, 3JPH = 16.5 Hz, 15 H), 1.05−1.35 (m, 14
H), 1.27 (d, J = 6.5 Hz, 3 H), 1.43 (q, J = 12.6 Hz,1 H), 1.52 (q, J =
12.6 Hz, 1 H), 1.82−1.92 (m, 1 H), 2.01 (dm, J = 13.4 Hz, 1 H), 2.11
(dm, J = 13.4 Hz, 1 H), 2.94−3.03 (m, 1 H), 3.07−3.18 (m, 1 H),
3.68−3.78 (m, 1 H), 7.35−7.45 (m, 4.8 H), 7.92−7.99 (m, 3.2 H). 13C
NMR (CDCl3, 100 MHz, transients = 480) δ 14.1 (p), 18.9 (p), 22.7
(s), 24.9 [(p), d, 2JPH = 2.0 Hz)], 25.5 (s), 29.1 (s), 29.3 (s), 29.3 (s),
29.5 (s), 31.9 (s), 32.6 (s), 36.3 [(q), d, 1JPH = 75.0 Hz], 37.2 (s), 40.2
(s), 51.8 (t), 56.0 (t), 66.6 (t), 127.2 [(t), (d, 2JPH = 11.0 Hz)], 130.1
[(t), (d, 4JPH = 2.4 Hz)], 132.6 [(t), (d, 3JPH = 9.2 Hz)], 136.6 [(q), (d,
1JPH = 90.0 Hz)]. 31P NMR (CDCl3, 161 MHz) δ 84.03.
(7S,9R)-(−)-7-Methyl-9-nonyl-1,4-dioxa-8-aza-spiro[4.5]-
decane [(−)-24], New Derivative. The synthesis was as reported for
(+)-24 but from 4-piperidone (+)-23-A to afford derivative (−)-24 as
a colorless oil. [α]22 −3.0 (c 1.0, EtOH).
D
(2R,6S)-(−)-2-Methyl-6-nonyl-piperidin-4-one [(−)-25].10b
A
50-mL round-bottom flask was charged with 15 mL of acetone, 4 mL
of a 5 N HCl solution, and 0.28 g (0.98 mmol) of 4-piperidone
(+)-24. The solution was refluxed for 4 h and stirred at ambient
temperature for 12 h. Then, 20 mL of a 2 N NaOH solution was
added to the reaction mixture, which was extracted with 3 × 30 mL of
diethyl ether. The organic phases were dried over MgSO4 and
concentrated to afford 0.25 g of a crude oily residue, which was poured
into a chromatographic column (diameter = 2.5 cm) prepared with 5 g
of silica and 85:15 diethyl ether/methanol. The combined fractions
were evaporated to yield 0.23 g (97%) of 4-piperidone (−)-25 as a
viscous colorless oil, [α]22 −1.5 [c 1.0, CHCl3], [α]22 +2.0 (c 0.93,
Alkaloid (+)-241D (90:10 er)·(+)-10. Alkaloid (+)-241D (12.0
mg, 49.7 μmol, >99:1 er), alkaloid (−)-241D (1.2 mg, 4.90 μmol,
>99:1 er), and CDCl3 (0.7 mL) were mixed in a 5-mm NMR tube, and
17.0 mg (79.3 μmol, γ = 1.65) of (R)-tert-butyl-phenyl-phosphino-
thioic acid [(+)-10] was added to it. Signals attributed to the salt
1
(−)-241D·(+)-10 are indicated with a hash (#). H NMR (CDCl3,
400 MHz, 300 K, transients = 64) δ 0.89 (t, J = 7.2 Hz, 3 H), 0.91−
3
1.00 (m, 1 H), 1.13 (d, JPH = 16.5 Hz, 15 H), 1.05−1.35 (m, 16 H),
1.27 (d, J = 6.5 Hz,1 H), 1.43 (q, J = 12.6 Hz,1 H), 1.52 (q, J = 12.6
Hz,1 H), 1.82−1.92 (m, 1 H), 2.01 (dm, J = 13.4 Hz, 1 H), 2.11 (dm, J
= 13.4 Hz, 1 H), 2.94−3.03 (m, 1 H), 3.07−3.16 (m, 1 H), 3.17−3.18
(m, 0.1 H)#, 3.68−3.78 (m, 1 H),3.90−4.00 (m, 0.1 H)#, 7.35−7.45
(m, 5 H), 7.92−7.99 (m, 3.3 H). 13C NMR (CDCl3, 100 MHz,
transients = 1200) δ 14.1 (p), 18.96 (p)#, 19.0 (p), 22.7 (s), 24.9 [(p),
d, 2JPH = 2.0 Hz)], 25.4 (s)#, 25.5 (s), 29.1 (s), 29.3 (s), 29.3 (s), 29.5
(s), 31.9 (s), 32.7 (s), 32.8 (s)#, 36.3 [(q), d, 1JPH = 75.0 Hz], 37.1 (s),
37.2 (s)#, 40.0 (s)#, 40.2 (s), 51.7 (t)#, 51.8 (t), 56.0 (t), 66.6 (t),
127.2 [(t), (d, 2JPH = 11.0 Hz)], 130.1 [(t), (d, 4JPH = 2.4 Hz)], 132.6
D
D
EtOH), [lit.10b [α]22D −1.1 [c 1.56, CHCl3]. Rf = 0.50 (diethyl ether/
methanol 85:15). 1H NMR (CDCl3, 400 MHz) δ 0.88 (d, J = 6.7 Hz,
3 H), 1.21 (d, J = 6.2 Hz, 3 H), 1.23−1.40 (m, 14 H), 1.40−1.55 (m, 2
H), 1.60−1.75 (s, br., 1 H), 2.00−2.11 (m, 2 H), 2.30−2.39 (m, 2 H),
2.80−2.87 (m, 1 H), 2.91−3.01 (m, 1 H). 13C NMR (CDCl3, 100
MHz) δ 14.1 (p), 22.66 (p), 22.67 (s), 25.7 (s), 29.3 (s), 29.5 (s, 2 C),
29.6 (s), 31.9 (s), 37.1 (s), 48.1 (s), 50.2 (s), 52.1 (t), 56.6 (t), 209.6
(q). IR (neat) ν = 1703, 2916, 3325 cm−1. HRMS (ESI+): calcd for
C15H30NO) [M + H]+ 240.23274, found 240.2325. Anal. Calcd for
C15H29NO (239.39): C 75.26, H 12.21, N 5.85. Found: C 75.23, H
12.09, N 5.68.
3
1
[(t), (d, JPH = 9.2 Hz)], 136.6 [(q), (d, JPH = 90.0 Hz)]. 31P NMR
(CDCl3, 161 MHz) δ 82.50.
Single-Crystal X-ray Analysis of Collection and Refinement
Results of Derivatives (−)-6-A, (+)-6-B, (−)-7, (−)-9·rac-10, and
(+)-18. The structures were solved by direct methods with SIR-97,43
which revealed the non-hydrogen atoms of the molecules. Refinement
was performed by full-matrix least-squares techniques based on F2 with
SHELXL-9744 with the aid of the WINGX45 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. The absolute configuration of
derivative (−)-9·rac-10 was estimated by the determination of Flack
parameters [−0.01 (4)] values calculated from Friedel pair reflections
for each structure. CCDC-972124 [(−)-6-A], CCDC-972128 [(+)-6-
B], CCDC-972127 [(−)-7], CCDC-972125 [(−)-9·rac-10], and
(2S,6R)-(+)-2-Methyl-6-nonyl-piperidin-4-one [(+)-25]. The
synthesis was as reported for (−)-25 but from 4-piperidone (−)-24
to afford derivative (+)-25 as a colorless oil, [α]22 +1.4 [c 1.0,
D
CHCl3], [α]22 −3.0 (c 1.0, EtOH).
D
Alkaloid (+)-241D [(+)-2]. A 50-mL, one-necked Schlenk tube
fitted with a magnetic stirring bar was successively charged with 0.10 g
(0.42 mmol) of 4-piperidone (−)-25 and 5 mL of ethanol. The
resulting solution was cooled to 0 °C, 31 mg (0.82 mmol, 2.0 equiv) of
NaBH4 was added in portions, and stirring was continued for 1 h at
that temperature. The solvent was removed under reduced pressure,
and the crude material was taken up with a 15% ammonia solution (30
mL) and extracted with diethyl ether (3 × 50 mL). The combined
3370
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
CCDC-972126 [(+)-18] contain the supplementary crystallographic
data for this paper. These data can be obtained from the Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/
cif
Crystal Data, X-ray Data Collection, and Refinement Results
of Derivative (−)-6-A. C16H20N2O2, M = 272.34, monoclinic, P 21, a
= 8.5091(19), b = 5.3731(11), c = 16.347(4) Å, α = 90°, β =
92.714(7)°, γ = 90°, V = 746.6(3) Å−3, Z = 2, Dx = 1.212 Mg m−3, μ =
0.81 cm−1, λMo Kα = 0.71073 Å, F(000) = 292, T = 150(2) K. The
sample (0.52 × 0.14 × 0.1 mm) was studied on a diffractometer with
graphite monochromatized Mo Kα radiation. The data collection
(Θmax = 27.48°, range of HKL: H −11 → 10, K −6 → 6, L −21 → 21)
gave 9358 reflections with 1879 unique reflections from which 1686
with I > 2.0σ(I).
Crystal Data, X-ray Data Collection, and Refinement Results
of Derivative (+)-6-B. C16H20N2O2, M = 272.34, monoclinic, P 21, a
= 8.9941(7), b = 7.7180(5), c = 10.8751(9) Å, α = 90°, β =
101.498(3)°, γ = 90°, V = 739.76(10) Å−3, Z = 2, Dx = 1.223 Mg m−3,
μ = 0.81 cm−1, λMo Kα = 0.71073 Å, F(000) = 292, T = 150(2) K. The
sample (0.58 × 0.53 × 0.27 mm) was studied on a diffractometer with
graphite monochromatized Mo Kα radiation. The data collection
(Θmax = 27.46°, range of HKL: H −11 → 11, K −9 → 6, L −14 → 14)
gave 6394 reflections with 1879 unique reflections from which 1645
with I > 2.0σ(I).
Crystal Data, X-ray Data Collection, and Refinement Results
of Derivative (−)-7. C17H22N2O2, M = 286.37, orthorhombic, P 21
21 21, a = 6.8561(2), b = 12.1178(5), c = 18.7361(8) Å, α = 90°, β =
90°, γ = 90°, V = 1556.61(10) Å−3, Z = 4, Dx = 1.222 Mg m−3, μ =
0.81 cm−1, λMo Kα = 0.71073 Å, F(000) = 616, T = 150(2) K. The
sample (0.58 × 0.51 × 0.22 mm) was studied on a diffractometer with
graphite monochromatized Mo Kα radiation. The data collection
(Θmax = 27.48°, range of HKL: H −7 → 8, K −14 → 15, L −16 → 24)
gave 7631 reflections with 2041 unique reflections from which 1833
with I > 2.0σ(I).
Crystal Data, X-ray Data Collection, and Refinement Results
of Derivative (−)-9·rac-10. 2(C10H14OPS)·2(C8H16NO2), M =
742.92, triclinic, P 1, a = 9.6316(4), b = 10.2372(4), c = 10.7405(5) Å,
α = 97.580(2)°, β = 94.223(2)°, γ = 108.013(2)°, V = 990.93(7) Å−3,
Z = 1, Dx = 1.245 Mg m−3, μ = 2.59 cm−1, λMo Kα = 0.71073 Å, F(000)
= 400, T = 150(2) K. The sample (0.55 × 0.50 × 0.43 mm) was
studied on a diffractometer with graphite monochromatized Mo Kα
radiation. The data collection (Θmax = 27.48°, range of HKL: H −12
→ 12, K −13 → 9, L −13 → 13) gave 16421 reflections with 7236
unique reflections from which 6898 with I > 2.0σ(I).
Crystal Data, X-ray Data Collection, and Refinement Results
of Derivative (+)-18. C17H31NO5, M = 329.43, monoclinic, P 21, a =
5.7765(2), b = 10.9416(4), c = 14.4434(6) Å, α = 90°, β = 93.134(2)°,
γ = 90°, V = 991.52(6) Å−3, Z = 2, Dx = 1.200 Mg m−3, μ = 0.87 cm−1,
λMo Kα = 0.71073 Å, F(000) = 360, T = 150(2) K. The sample (0.60 ×
0.59 × 0.45 mm) was studied on a diffractometer with graphite
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
V.H.V. is grateful to the Ministry of Education and Training of
the Socialist Republic of Vietnam for Ph.D. funding. This work
■
was supported in part by the Programme Franco-Alger
Formation Superieure en France (PROFAS). We also thank Dr.
Saurabh Shahane for technical assistance.
́
ien de
́
REFERENCES
■
(1) (a) Toyooka, N. In Asymmetric Synthesis of Nitrogen Heterocycles;
Royer, J., Ed.; Wiley-VCH: Weinheim, 2009. (b) Fodor, G. B.;
Colasanti, B. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; John Wiley: New York, 1985; Vol. 3, p 1.
(c) Schneider, M. J. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; John Wiley: New York, 1996; Vol. 10, p 155.
(2) For reviews on the synthesis of piperidine derivatives, see:
(a) Amara, Z.; Caron, J.; Joseph, D. Nat. Prod. Rep. 2013, 30, 1211.
(b) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (c) Laschat, S.;
Dickner, T. Synthesis 2000, 1781. (d) Bailey, P. D.; Millwood, P. A.;
Smith, P. D. Chem. Commun. 1998, 633. (e) Sardina, F. J.; Rapoport,
H. Chem. Rev. 1996, 96, 1825.
(3) Vu, V. H.; Jouanno, L. A.; Cheignon, A.; Roisnel, T.; Dorcet, V.;
Sinbandhit, S.; Hurvois, J. P. Eur. J. Org. Chem. 2013, 5464.
(4) (a) Slosse, P.; Hootele,
P.; Hootele, C. Tetrahedron 1981, 24, 4287. For a review on the
synthesis of quinolizidine alkaloids, see: (c) Michael, J. P. Nat. Prod.
Rep. 2004, 21, 625.
(5) Edwards, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188.
(6) For the stereoselective synthesis of myrtine, see: (a) Ying, Y.;
Kim, H.; Hong, J. Org. Lett. 2011, 13, 796. (b) Fustero, S.; Moscardo,
́
C. Tetrahedron Lett. 1978, 397. (b) Slosse,
́
́
́ ́
J.; Sanchez-Rosello, M.; Flores, S.; Guerola, M. Tetrahedron 2011, 67,
7412. (c) Pizzuti, M. G.; Minnard, A. J.; Feringa, B. L. Org. Biomol.
Chem. 2008, 6, 3464. For the stereoselective synthesis of alkaloid
214D, see: (d) Kumar, R. S. C.; Reddy, G. V.; Shankaraiah, G.; Babu,
K. S.; Rao, J. M. Tetrahedron Lett. 2010, 51, 1114. (e) Gnamm, C.;
Krauter, C. M.; Brodner, K.; Helmchen, G. Chem.Eur. J. 2009, 15,
̈
2050. (f) Gnamm, C.; Krauter, C. M.; Brodner, K.; Helmchen, G.
̈
Chem.Eur. J. 2009, 15, 10514.
(7) Comins, D. L.; LaMunyon, D. H. J. Org. Chem. 1992, 57, 5807.
(8) Gardette, D.; Gelas-Mialhe, Y.; Gramain, J.-C.; Perrin, B.;
Remuson, R. Tetrahedron: Asymmetry 1998, 9, 1823.
(9) For the stereoselective synthesis of myrtine, see: (a) Davis, F. A.;
Xu, H.; Zhang, J. J. Org. Chem. 2007, 72, 2046. For the stereoselective
synthesis of alkaloid 241D, see: (b) Damodar, K.; Das, B. Synthesis
2012, 44, 83. (c) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 20,
3169.
(10) For the stereoselective synthesis of alkaloid 241D, see:
(a) Abrunhosa-Thomas, I.; Plas, A.; Vogrig, A.; Kandepedu, N.;
Chalard, P.; Troin, Y. J. Org. Chem. 2013, 78, 2511. (b) Ciblat, S.;
Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem. Soc. Perkin Trans. 1 2000,
353.
monochromatized Mo Kα radiation. The data collection (Θmax
=
27.46°, range of HKL: H −7 → 6, K −14 → 13, L −18 → 16) gave
7689 reflections with 3900 unique reflections from which 3451 with I
> 2.0σ(I).
(11) For the stereoselective synthesis of alkaloid 241D, see:
(a) Murali, R. V. N. S.; Chandrasekhar, S. Tetrahedron Lett. 2012,
53, 3467. (b) Gouault, N.; Le Roch, M.; de Campos Pinto, G.; David,
M. Org. Biomol. Chem. 2012, 10, 5541. (c) Ma, D.; Sun, H. Org. Lett.
2000, 2, 2503.
ASSOCIATED CONTENT
■
S
* Supporting Information
Proton and carbon NMR spectra of derivatives 1−25 and
ORTEP views of derivatives (−)-6-A, (+)-6-B, (−)-7, (−)-9·
rac-10. and (+)-18; determination of enantiomeric ratios of 4-
piperidones (+)-9, (+)-myrtine, and alkaloid (+)-241D by
proton and carbon NMR. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) For the stereoselective synthesis of alkaloid 241D, see: Saha, N.;
Chattopadhyay, S. K. J. Org. Chem. 2012, 77, 11056.
(13) For the electrochemical synthesis of α-amino nitrile systems,
see: (a) Louafi, F.; Moreau, J.; Shahane, S.; Golhen, S.; Roisnel, T.;
Sinbandhit, S.; Hurvois, J. P. J. Org. Chem. 2011, 76, 9720. (b) Louafi,
F.; Hurvois, J.-P.; Chibani, A.; Roisnel, T. J. Org. Chem. 2010, 75, 5721.
(c) Libendi, S. S.; Demizu, Y.; Onomura, O. Org. Biomol. Chem. 2009,
7, 351. (d) Tajima, T.; Nakajima, A. J. Am. Chem. Soc. 2008, 130,
10496. (e) Liu, W.; Ma, Y.; Yin, Y.; Zhao, Y. Bull. Chem. Soc. Jpn. 2006,
79, 577. (f) Girard, N.; Hurvois, J.-P.; Moinet, C.; Toupet, L. Eur. J.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jean-pierre.hurvois@univ-rennes1.fr.
3371
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
Org. Chem. 2005, 2269. (g) Malassene, R.; Vanquelef, E.; Toupet, L.;
Hurvois, J.-P.; Moinet, C. Org. Biomol. Chem. 2003, 1, 547. (h) Renaud,
T.; Hurvois, J.-P.; Uriac, P. Eur. J. Org. Chem. 2001, 987. (i) Le Gall,
E.; Hurvois, J.-P.; Sinbandhit, S. Eur. J. Org. Chem. 1999, 2645.
(j) Yoshida, J.-I.; Itoh, M.; Morita, Y.; Isoe, S. J. Chem. Soc., Chem.
Commun. 1994, 549. (k) Chiba, T.; Takata, Y. J. Org. Chem. 1977, 42,
2973. (l) Andreades, S.; Zahnow, E. W. J. Am. Chem. Soc. 1969, 91,
4181.
(14) For the synthesis of α-amino nitriles with SET oxidants, see:
(a) Allen, J. M.; Lambert, T. H. J. Am. Chem. Soc. 2011, 133, 1260.
(b) Allen, J. M.; Lambert, T. H. J. Am. Chem. Soc. 2011, 133, 1260.
(c) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M.
J. Org. Chem. 2009, 74, 7464. (d) Hametner, C.; Hemetsberger, M.;
−1.45 V vs ENH; see: (a) Fu, Y.; Liu, L.; Yu, H.-Z.; Wang, Y.-M.; Guo,
Q.-X. J. Am. Chem. Soc. 2005, 127, 7227. See also: (b) Schmittel, M.;
Lal, M.; Rock, M.; Langels, A.; Rappoport, Z.; Basheer, A.; Schlirf, J.;
̈
Deiseroth, H.-J.; Florke, U.; Gescheidt, G. Tetrahedron 2009, 65,
10842.
̈
(23) For the chemistry of deprotonated α-amino nitriles, see:
(a) Opatz, T. Synthesis 2009, 12, 1941. (b) Enders, D.; Gerdes, P.;
Kippart, H. Angew. Chem. Int. Eng. 1990, 29, 179. (c) Roulland, E.;
Cecchin, F.; Husson, H.-P. J. Org. Chem. 2005, 70, 4474.
(d) Wolchenhauer, S. A.; Rychnovsky, S. D. Tetrahedron 2005, 61,
3371. (e) Hauser, C. R.; Morris, G. F. J. Org. Chem. 1961, 26, 4740.
(f) Stork, G.; Jacobson, R. M. Tetrahedron Lett. 1979, 9, 771.
(24) For a review on α-PEA as a chiral auxiliary, see: (a) Juaristi, E.;
Treu, M.; Mereiter, K.; Jordis, U.; Frolich, J. Eur. J. Org. Chem. 2005,
404. (e) Zhdankin, V. V.; Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.;
́
Leon-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry
1999, 10, 2441.
̈
Mismash, B.; Woodward, J. K.; Simonsen, A. J. Tetrahedron Lett. 1995,
36, 7975. (f) Sundberg, R. J.; Theret, M.-H.; Wright, L. Org. Prep.
́
Proced. Int. 1994, 26, 386. (g) Sundberg, R. J.; Hunt, P. J.; Desos, P.;
Gadamasetti, K. G. J. Org. Chem. 1991, 56, 1689. (h) Chen, C.-K.;
Hortmann, A. G.; Marzabadi, M.-R. J. Am. Chem. Soc. 1988, 110, 4829.
(i) Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.; Ochiai, M.; Inegana,
M.; Nagao, Y. Tetrahedron Lett. 1988, 29, 6913.
(25) For selected examples of diastereoselective hydride reduction of
iminium systems containing an α-PEA group, see: (a) Zein, A. L.;
Dakhil, O. O.; Dawe, L. N.; Georghiou, P. E. Tetrahedron Lett. 2010,
51, 177. (b) Girard, N.; Pouchain, L.; Hurvois, J.-P.; Moinet, C. Synlett
2006, 11, 1679. (c) Adriaenssens, L. V.; Austin, C. A.; Gibson, M.;
Smith, D.; Hartley, R. C. Eur. J. Org. Chem. 2006, 4998. (d) Hayes, J.
F.; Shipman, M.; Twin, H. Chem. Commun. 2001, 1784. (e) Cola, N.;
Mokhtari, N.; Vasse, J.-L.; Szymoniak, J. Org. Lett. 2011, 13, 6292.
(f) Polniaszek, R. P.; Kaufman, C. R. J. Am. Chem. Soc. 1989, 111,
4859. (g) Kawagushi, M.; Hayashi, O.; Sakai, N.; Hamada, M.;
Yamamoto, Y.; Oda, J. Agric. Biol. Chem. 1986, 50, 3107. (h) Kametani,
T.; Okawara, T. J. Chem. Soc., Perkin Trans. 1 1977, 579.
(26) For the synthesis of rac-tert-butylphenylphosphinothioic acid
(rac-10), see: (a) Hoffman, H.; Schellenbeck, P. Chem. Ber. 1966,
1134. For optical resolution of rac-10, see: (b) Haynes, R. K.; Au-
Yeung, T.-L.; Chan, W.-K.; Lam, W.-L.; Li, Z.-Y.; Yeung, L.-L.; Chan,
A. S. C.; Li, P.; Koen, M.; Mitchell, C. R.; Vonwiller, S. C. Eur. J. Org.
Chem. 2000, 3205. For the determination of enantiomeric ratios of
THIQ alkaloids, see: (c) Szawkało, J.; Zawadzka, A.; Wojtasiewicz, K.;
Leniewski, A.; Drabowicz, J.; Czarnocki, Z. Tetrahedron: Asymmetry
2005, 16, 3619.
(15) For a review on metal-catalyzed synthesis of α-amino nitriles,
see: (a) North, M. Angew. Chem., Int. Ed. 2004, 43, 4126. See also:
(b) Wagner, A.; Han, W.; Mayer, P.; Ofial, A. R. Adv. Synth. Catal.
2013, 355, 3058. (c) Dhineshkumar, J.; Lamani, M.; Alagiri, K.;
Prabhu, K. R. Org. Lett. 2013, 15, 1092. (d) Boess, E.; Schmitz, C.;
Klussmann, M. J. Am. Chem. Soc. 2012, 134, 5317. (e) Alagiri, K.;
Prabhu, R. Org. Biomol. Chem. 2012, 10, 835. (f) Zhang, Y.; Peng, H.;
Zhang, M.; Cheng, Y.; Zhu, C. Chem. Commun. 2011, 47, 2354.
(g) Singhal, S.; Jain, S. L.; Sain, B. Chem. Commun. 2009, 2371.
(h) Murahashi, S.-I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem.
Soc. 2008, 130, 11005. (i) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005,
3173.
(16) For photoinduced synthesis of α-amino nitriles, see:
(a) Rueping, M.; Zoller, J.; Fabry, D. C.; Poscharny, K.; Koenigs, R.
M.; Weirich, T. E.; Mayer, J. Chem.Eur. J. 2012, 18, 3478.
(b) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J. Org.
Lett. 2012, 14, 94. (c) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem.
Commun. 2011, 47, 12709. (d) Kamijo, S.; Hoshikawa, T.; Inoue, M.
Org. Lett. 2011, 13, 5928. (e) Gomez, J.-M.; Gil, L.; Ferroud, C.;
Gateau-Olesker, A.; Martin, M.-T.; Marazano, C. J. Org. Chem. 2001,
66, 4898. (f) Cocquet, G.; Rool, P.; Ferroud, C. J. Chem. Soc., Perkin
Trans. 1 2000, 2277. (g) Ferroud, C.; Cocquet, G.; Guy, A.
Tetrahedron Lett. 1999, 40, 5005. (h) Santamaria, J.; Kaddachi, M.
T.; Ferroud, C. Tetrahedron Lett. 1992, 33, 781.
(27) Flack, H. D. Acta Crystallogr. 1983, A39, 876.
(28) For selected reviews on the lithiation of N-Boc derivatives, see:
(a) Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S.
Acc. Chem. Res. 1996, 29, 552. (b) Beak, P.; Meyers, A. I. Acc. Chem.
Res. 1986, 19, 356.
(29) (a) Dieter, R. K.; Oba, G.; Chandupatla, K. R.; Topping, C. M.;
Lu, K.; Watson, R. T. J. Org. Chem. 2004, 69, 3076. (b) Dieter, R. K.;
Li, S.; Chen, N. J. Org. Chem. 2004, 69, 2867.
(30) For the structural study of the SnCl4·(Et2O)2 complex, see:
Farcasiu, D.; Leu, R.; Ream, P. J. Chem. Soc. Perkin Trans. 2 2001, 427.
̆
(17) For selected reviews on the synthesis and chemistry of α-amino
nitrile systems, see: (a) Enders, D.; Shilvock, J. P. Chem. Soc. Rev.
2000, 29, 359. (b) Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28,
383. (c) Husson, H.-P. J. Nat. Prod. 1985, 6, 894. See also: (d) Ma, J.;
Chen, W.; Seidel, D. J. Am. Chem. Soc. 2012, 134, 15305. (e) Agami,
C.; Couty, F.; Evano, G.; Darro, F.; Kiss, R. Eur. J. Org. Chem. 2003,
2062. (f) Heathcock, C. H.; Norman, M. H.; Dickman, D. A. J. Org.
Chem. 1990, 55, 798.
(18) (a) Amato, J. S.; Chung, J. Y. L.; Cvetovich, R. L.; Reamer, R. A.;
Zhao, D.; Zhou, G.; Gong, X. Org. Prep. Res. Dev. 2004, 8, 939.
(b) Kuehne, M. E.; Muth, R. S. J. Org. Chem. 1991, 56, 2701.
(c) Mistryukov, E. A.; Aronova, N. I.; Kucherov, V. F. Izv. Akad. Nauk
SSSR, Ser. Khim. 1961, 932.
(31) No detectable amount of the alternate diastereoisomer could be
detected in the proton and in the carbon NMR spectra.
(32) For the trans alkylation of N-Boc piperidine systems, see:
(a) Herath, H. M. T. B.; Nanayakkara, N. P. D. J. Heterocycl. Chem.
2008, 45, 129. (b) Kumareswaran, R.; Hassner, A. Tetrahedron:
Asymmetry 2001, 12, 2269. (c) Adamo, M. F. A.; Aggarwal, V. K.; Sage,
M. A. Synth. Commun. 1999, 29, 1747. (d) Beak, P.; Lee, W.-K. J. Org.
Chem. 1990, 55, 2578. (e) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58,
1109. (f) Reding, M. T.; Buchwald, S. L. J. Org. Chem. 1998, 63, 6344.
(g) Comins, D. L.; Benjelloun, N. R. Tetrahedron Lett. 1994, 35, 829.
(33) Appel, R. Angew. Chem., Int. Ed. 1975, 12, 801.
(34) In contrast, the (+)-myrtine·(+)-DBTA salt proved to be
sparingly soluble in CDCl3.
(19) Pawłowska, J.; Krawczyk, K. K.; Wojtasiewicz, K.; Maurin, J. K.;
Czarnocki, Z. Monatsh. Chem. 2009, 140, 83.
(35) (a) Liu, L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org.
Chem. 2004, 69, 6001. (b) Chackalamannil, S.; Davies, R. Org. Lett.
2001, 10, 1427.
(36) In the trans isomer, the aldehyde proton resonated as a doublet
(J = 2.1 Hz) at d = 9.46 ppm, whilst that of the cis isomer resonated as
a doublet (J = 1.0 Hz) at d = 9.63 ppm.
(20) For homogeneous redox exchange between stable triarylamine
nitrogen centered radical cation and cyanide anion, see: Papouchado,
L.; Adams, R. N.; Feldberg, S. W. J. Electroanal. Chem. 1969, 21, 408.
(21) In practice, the excess of electrogenerated base (EGB) produced
at the cathode deprotonates the radical cation A during the macroscale
electrolysis of (+)-5.
(37) 4-Piperidone 25 proved to be dextrorotatory in ethanol and
levorotatory in chloroform.
(22) Quantum-chemical calculations have shown that α-amino
(38) Stoll, R. S.; Peters, M. V.; Kuhn, A.; Heiles, S.; Goddard, R.;
radicals displayed standard redox potentials ranging from −0.65 to
Buhl, M.; Thiele, C. M.; Hecht, S. J. Am. Chem. Soc. 2009, 131, 357.
̈
3372
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373

The Journal of Organic Chemistry
Article
(39) Wang, Y.; Wang, J.; Lin, Y.; Si-Ma, L.-F.; Wang, D.-H.; Chen, L.-
G.; Liu, D.-K. Bioorg. Med. Chem. 2011, 21, 4454.
(40) Barker, G.; O’Brien, P.; Campos, K. R. Org. Lett. 2010, 12, 4176.
(41) Trost, B. M.; Maulide, N.; Livingstone, R. C. J. Am. Chem. Soc.
2008, 130, 16502.
(42) Bull, J. A.; Charette, A. B. J. Org. Chem. 2008, 73, 8097.
(43) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, C.;
Giacovazzo, C.; Militerni, A. G. G.; Polidori, G.; Spagna, R. J. Appl.
Crystallogr. 1999, 32, 115.
(44) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.
(45) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.
3373
dx.doi.org/10.1021/jo500104c | J. Org. Chem. 2014, 79, 3358−3373