Enantiodivergent Approach to the Synthesis of Cis-2,6-Disubstituted Piperidin-4-ones

Article abstract of DOI:10.1021/acs.joc.9b01008

Enantiopure β-amino ketone derivatives were synthesized by decarboxylative Mannich reaction of chiral N-tert-butanesulfinyl imines with β-keto acids and were subsequently transformed into cis-2,6-disubstituted piperidin-4-ones through an organocatalyzed condensation with aldehydes. Both enantiomers were accessible from the same precursors by inverting the order in the reaction sequence of the aldehydes involved in the imine formation and the intramolecular Mannich condensation. The synthesis of the piperidine alkaloids (+)-241D, (-)-epimyrtine, and (-)-lasubine II demonstrated the utility of this methodology.

Full text of DOI:10.1021/acs.joc.9b01008

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Article
Enantiodivergent Approach to the Synthesis
of cis-2,6-Disubstituted Piperidin-4-ones
Alejandro Lahosa, Miguel Yus, and Francisco Foubelo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01008 • Publication Date (Web): 07 May 2019
Downloaded from http://pubs.acs.org on May 8, 2019
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Enantiodivergent Approach to the Synthesis of cis-2,6-Disubstituted
Piperidin-4-ones
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Alejandro Lahosa,a,b,c Miguel Yus and Francisco Foubeloa,b,c*
c
a
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99,
3080 Alicante (Spain)
0
b
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante (Spain)
c
Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo.
9, 03080 Alicante (Spain)
9
E-mail: foubelo@ua.es
O
S
A
B
C
D
O
O
O
O
Me
Me
H N
2
R1
R2
H
HO
Me
H
Me
Decarboxylative Mannich reaction
O
O
A
A
C
D
B
C
+
+
R1
N
H
R2
R2
N
H
R1
B
D
Organocatalyzed Mannich reaction
ABSTRACT. Enantiopure β-amino ketone derivatives were synthesized by decarboxylative
Mannich reaction of chiral N-tert-butanesulfinyl imines with β-keto acids, and were subsequently
transformed into cis-2,6-disubstituted piperidin-4-ones through an organocatalyzed condensation
with aldehydes. Both enantiomers were accessible from the same precursors by inverting the order
in the reaction sequence of the aldehydes involved in the imine formation and the intramolecular
Mannich condensation. The synthesis of the piperidine alkaloids (+)-241D, (−)-epimyrtine and (−)-
lasubine II demonstrated the utility of this methodology.
KEYWORDS. Chiral sulfinyl imines, β-amino ketones, diastereoselective Mannich reactions,
enantioselective synthesis, piperidine alkaloids.
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INTRODUCTION
Piperidine moiety is commonly found in natural alkaloids, pharmaceuticals and other compounds
1
which exhibit a broad range of biological activities. Particularly, systems with the piperidin
skeleton having substituents at 2- and 6-positions with a relative cis-configuration, and a carbonyl
or a hydroxyl group at 4-position are of special interest. Consequently, the asymmetric synthesis of
these polysubstituted piperidine derivatives has attracted much attention that is reflected in the
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development of numerous strategies on that purpose. The most general methods involve as key
steps of the synthesis of these compounds either an intramolecular condensation follow by
reduction from the corresponding amino ketone derivative3 or an intramolecular allylic
4
substitution, as depicted in Scheme 1A. Access to piperidin-4-one derivatives was also possible by
5
intramolecular conjugate addition in α,β-unsaturated amino ketones, or by double conjugate
6
addition to N-protected pyridine-4(1H)-ones (Scheme 1B). Although some of these methods work
efficiently, long reaction sequences and the use of expensive reagents and ligands to control the
stereochemistry are important drawbacks that should be mentioned. Due to that, new general,
simple and efficient methods to prepare cis-2,6-disubstituted piperidin-4-ones in an enantioselective
fashion are highly desirable. For that reason, we envisaged a new strategy in which a sequential
decarboxylative Mannich reaction of a chiral N-tert-butanesulfinyl imine and a β-keto acid,7
8
followed by an organocatalyzed intramolecular Mannich reaction involving an aldehyde would
produce the substituted piperidines in a straightforward manner, comprising this methodology three
synthetic operations (imine formation and two consecutive Mannich reactions) from readily
available starting materials (Scheme 1C).
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Scheme 1. Previous work and our methodology for the synthesis of substituted piperidines
Previous work
OH
PG
PG
R1
NH OH
*
O
NH OH
*
*
A
R1
R2
LG
R1
R2
N
PG
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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2
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0
O
O
O
B
R1
NH R2
PG
R1
N
R2
N
PG
PG
This work
O
O
O
S
N
t-Bu
2
R CHO
Me
R1
H
C
R1
NH
S
R1
N
R2
+
O
O
H
O
t-Bu
HO
Me
RESULTS AND DISCUSSION
We commenced our study with chiral β-amino ketone derivatives 5. We had already described the
stereoselective synthesis of these compounds in a previous communication, by coupling of 3-
7
oxobutanoic acid (4a) and N-tert-butanesulfinyl imines 3 under basic conditions, except 5b which
is a new compound. The decarboxylative Mannich reaction proceeded with high yields and
9
excellent diastereoselectivities (Table 1). In addition, the starting chiral imines 3, which have been
extensively used as electrophiles in synthesis over the past decade, were easily accessible by
condensation of aldehydes 2 and (R)-tert-butanesulfinamide [(R)-1] in the presence of titanium
1
0
tetraethoxide. Regarding the configuration of the newly created stereogenic center, we observed
7
that the nucleophilic attack took always place to the Si-face of imines 3 with R configuration.
S
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Table 1. Decarboxylative Mannich-type coupling of imines 3 and 3-oxobutanoic acid (4a)a
O
O
S
O
S
H N
t-Bu
2
Me
O
O
(R)-1
N
t-Bu
LiOH/MeOH (2M, 0.5 mmol)
Me
THF, 0 to 23 ºC
R1
NH
+
R1
HO
O
H
0
1
2
3
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5
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9
0
1
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5
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
S
(0.2 mmol)
(0.4 mmol)
O
t-Bu
R1
H
3
4a
5
2
O
O
O
O
Me
NH
Me
Me
Me
Me
Me
Me
NH
S
NH
S
( )8 NH
S
Me
S
O
t-Bu
O
t-Bu
O
t-Bu
O
t-Bu
5a (98%, >95:5 dr)
5b (90%, >95:5 dr)
5c (62%, >95:5 dr)
5d (82%, >95:5 dr)
O
O
O
Me
Me
Me
NH
Br
NH
S
NH
S
( )4
S
O
t-Bu
Br
O
t-Bu
O
t-Bu
5e (92%, >95:5 dr)
5f (99%, >95:5 dr)
5g (99%, >95:5 dr)
a
Isolated yields after column chromatography purification are given in parentheses. Diastereomeric ratios were
1
determined by H NMR analysis of crude reaction mixture.
With enantiopure β-amino ketone derivatives 5 in hand, we focused then on the development of
reaction conditions to perform an intramolecular Mannich condensation involving a second
aldehyde. We took compound 5a derived from 3-phenylpropanal (2a) as a model compound, and
8
inspired by the work of Rutjes and co-workers, the amine hydrochloride 6a, resulting from the
removal of the tert-butanesulfinyl group under acidic reaction conditions, was treated with 1
equivalent of triethylamine, magnesium sulfate and benzaldehyde (2e) in ethanol, in the presence of
20 mol% of racemic proline, at room temperature for 5 hours. The expected 2,6-disubstituted
piperidin-4-one 7a was obtained in 60% isolated yield (Table 2, entry 1). The intramolecular
condensation did not work in the absence of proline or triethyl amine (Table 2, entries 2 and 3). On
the other hand, the condensation proceeded only in 39% if pyrrolidine was used instead of proline
as organocatalyst (Table 2, entry 4). It seems that the amino acid functionality was beneficial for
this transformation. However, yield was even lower when the reaction was performed in the
presence of sarcosine, the simplest acyclic secondary β-amino acid (22%, Table 2, entry 5).
Remarkably, working with enantiopure proline, the desired compound 7a was formed in more than
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5% yield (Table 2, entries 6 and 7). Concerning the configuration of the new stereocenter,
compound 7a was always isolated with relative cis configuration, independently of the
configuration of the organocatalyst (Table 2, entries 1, 6 and 7). That means that the stereochemical
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outcome is governed exclusively by the stereocenter already present in compound 6 and not by the
organocatalyst.
Table 2. Optimization of the reaction conditions for 2,6-disubstituted piperidin-4-ones 7 formation
O
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
S
O
O
Ph
H
t-Bu
Ph
NH
O
Ph
Me
NH ·HCl
Ph
HCl/Et O (10 equiv)
2e (1 equiv)
2
MeOH, 0 ºC
Reaction conditions
Me
N
H
7a
Ph
2
(
0.2 mmol)
5
a
6a
Entry
Reaction conditions
N (1 equiv), MgSO
(1 equiv), EtOH, rt, 5 h
D/L-Proline (20 mol%), MgSO (1 equiv), EtOH, rt, 5 h
Pyrrolidine (20 mol%), Et N (1 equiv), MgSO (1 equiv), EtOH, rt, 5 h
Sarcosine (20 mol%), Et N (1 equiv), MgSO
D-Proline (20 mol%), Et N (1 equiv), MgSO
L-Proline (20 mol%), Et N (1 equiv), MgSO
Yield (%)a
60
1
2
3
4
5
6
7
D/L-Proline (20 mol%), Et
Et N (1 equiv), MgSO
3
(1 equiv), EtOH, rt, 5 h
4
--
3
4
--
4
39
22
75
77
3
4
(1 equiv), EtOH, rt, 5 h
(1 equiv), EtOH, rt, 5 h
(1 equiv), EtOH, rt, 5 h
4
3
4
3
4
3
a
Isolated yields after column chromatography purification based on the starting β-amino ketone derivative 5a.
_
_
Me +
N
+
CO2
CO2
N
H
H
H
H
Sarcosine
Proline
We studied next the scope of the intramolecular Mannich reaction involving β-amino ketone
derivatives 5 and different aldehydes 2, by applying the optimized conditions shown in Table 2,
entry 7, and using L-proline, which is by far the most economical stereoisomer of proline, as
organocatalyst. The relative configuration was determined to be cis by NOESY experiments in 2,6-
disubstituted piperidin-4-ones 7, which were obtained in relatively good to moderate yields (Table
3
). As a general rule, enolizable aldehydes 2 provided lower yields than aromatic aldehydes. It
merits mention that this methodology allows access to the quinolizidine moiety when starting from
the appropriate precursors. For instance, the reaction of compound 5g derived from the imine of 5-
bromopentanal (2g) with veratraldehyde (3,4-dimethoxybenzaldehyde, 2k) led to quinolizidinone
derivative 7j in only 31% yield, meanwhile, the reaction of 5b with 5-chloropentanal (2l) gave rise
1
1
12
to natural product (−)-epimyrtine (7k), isolated from bilberry (Vaccinium Myrtillus) (Table 3).
In both cases, after formation of the piperidine ring through the expected Mannich condensation, a
13
subsequent intramolecular N-alkylation involving the carbon-halogen bond occurred to produce
the quinolizidinic systems. The relatively low yield for quinolizidine 7j could be explained
considering the competition between intramolecular N-alkylation and imine formation previous to
the intramolecular Mannich condensation. Thus, if intramolecular N-alkylation involving highly
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reactive carbon-bromine bond takes place first, subsequent intramolecular Mannich condensation
does not occur. Importantly, it is possible through this methodology to synthesize two enantiomeric
piperidines 7 starting from the same precursors. For instance, (R)-tert-butanesulfinamide [(R)-1], 3-
phenylpropanal (2a), benzaldehyde (2e) and 3-oxobutanoic acid (4a) were the common starting
materials in the synthesis of 7a and ent-7a. This could be considered a kind of enantiodivergent14
approach to 2,6-disubstituted piperidines 7. Moreover, the order in the reaction sequence involving
aldehydes 2 determines the configuration of the two possible enantiomers. In the same way, 7d and
ent-7d were prepared from 3-phenylpropanal (2a) and decanal (2d), 7h and ent-7h from
isobutyraldehyde (2c) and benzaldehyde (2e), and piperidines 7i and ent-7i from benzaldehyde (2e)
and p-bromobenzaldehyde (2f) (Table 3). Regarding the absolute configuration of cis 2,6-
disubstituted piperidin-4-ones 7, the stereochemical integrity of these compounds was determined
by chiral HPLC and GC analysis. Relatively high enantiomeric ratios were observed for compounds
wearing alkyl substituents at 2 and 6 positions, meanwhile almost racemic mixtures were formed in
the case of diaryl substituted piperidinones (7i and ent-7i) in the organocatalyzed cyclization step
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1
2
3
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5
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8
9
0
1
2
3
4
5
6
7
8
9
0
(Table 3).
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Table 3. Synthesis of 2,6-disubstituted piperidin-4-ones 7 from β-amino ketone derivatives 5a
O
O
2
O
R
H
O
Me
2 (1 equiv)
R1
NH
HCl/Et O (10 equiv)
Me
2
L-Proline (20 mol%), Et N (1 equiv)
3
S
MeOH, 0 ºC
R1
MgSO (1 equiv), EtOH, rt, 5 h
R1
R2
NH ·HCl
4
N
H
O
t-Bu
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(0.2 mmol)
5
6
7
O
O
O
Me
N
H
N
H
N
H
7a (77%, 90:10 er)
ent-7a (31%, 88:12 er)
7b (69%, 94:6 er)
O
O
O
Me
Me
N
H
N
( )8
( )8
N
H
H
OMe
7d
7c (64%, 88:12 er)
7d (41%, 89:11 er)
ent- (62%, 93:7 er)
O
O
O
Me
Me
Me
N
H
( )3
Me
Me
N
Me
N
( )8
H
H
7
e (56%, 93:7 er)
7f (59%, 90:10 er)
7g (72%, 92:8 er)
O
O
O
O
Me
Me
Me
N
H
N
H
N
H
N
H
Me
Br
Br
7h (76%, 72:28 er)
ent-7h (76%, 78:22 er)
7i (76%, 56:44 er)
ent-7i (73%, 53:47 er)
O
N
O
N
OMe
OMe
Me
1
2
b
7
j [R = (CH ) Br, 31%, 93:7 er]
()-Epimyrtine [7k, R = (CH ) Cl, 64%, 93:7 er]
2 4
2 4
a
Isolated yields after column chromatography purification are given in parentheses and are based on the starting β-
b
amino ketone derivative 5. Isolated as the corresponding hydrochloride derivative.
Enantiomeric piperidines ent-7 were also obtained working with sulfonamide (S)-1 (through the
looking glass) under the optimized reaction conditions, as depicted on Scheme 2. Thus, compounds
ent-7a and ent-7j were prepared starting from chiral imines ent-3a and ent-3h, respectively. The
organocatalyzed intramolecular Mannich condensation is the key step to be considered in the
election of the best strategy for the synthesis of both enantiomers. For instance, ent-7a was obtained
from ent-5a by condensation with benzaldehyde (2e) in 83% (Scheme 2). However, condensation of
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5e with enolizable 3-phenylpropanal (2a) proceeded in a poor 31% yield to give the same
stereoisomer ent-7a (Table 3).
Scheme 2. Synthesis of 2,6-disubstituted piperidin-4-ones 7 starting from sulfonamide (S)-1
O
O
S
O
S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
1
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
LiOH/MeOH
(2M, 0.5 mmol)
O
O
Me
NH
H N
t-Bu
N
t-Bu
2
+
R1
(
S)-1
R1
HO
Me
H
THF, 0 to 23 ºC
S
(0.2 mmol)
(0.4 mmol)
O
O
t-Bu
1
ent-3a [R = (CH ) Ph]
4a
ent-5a (85%, >95:5 dr)
ent-5h (98%, >95:5 dr)
2
2
R1
H
1
ent-3h [R = (CH ) Cl]
2
5
2
HCl/Et O
2
O
(10 equiv)
O
N
R2
MeOH, 0 ºC
O
H
2
(1 equiv)
O
L-Proline (20 mol%)
OMe
OMe
Et N (1 equiv)
3
Me
N
H
MgSO (1 equiv)
EtOH, rt, 5 h
4
R1
NH ·HCl
2
ent-7j (65%, 95:5 er)
ent-6
ent-7a (83%, 91:9, er)
We explored also the β-keto acid 4 scope with chiral imine 3a under the optimized reaction
conditions. The decarboxylative Mannich condensation with 3-oxopentanoic acid (4b) and 3-
oxohexanoic acid (4c) leading to compounds 5i and 5j took place in 96 and 79% yield, respectively
(Scheme 3). Unfortunately, the subsequent organocatalyzed intramolecular Mannich condensation
proceeded in low yield at room temperature. Pleasingly, we found that the expected 2,3,6-
trisubstituted piperidin-4-ones 8 were obtained in reasonable yields by performing the reaction at
6
0 ºC for 6 h. In addition, compounds 8 displayed almost exclusively 2,6-cis-2,3-trans relative
configuration (Scheme 3).
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7
8
9
Scheme 3. Synthesis of 2,3,6-trisubstituted piperidin-4-ones 8
O
O
R3
LiOH/MeOH
(2M, 0.5 mmol)
S
O
O
N
t-Bu
R3
+
HO
THF, 0 to 23 ºC
NH
S
H
O
t-Bu
(
0.2 mmol)
(0.4 mmol)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
3a
4b (R = Me)
5i (R = Me, 96%, >95:5 dr)
3
3
4c (R = Et)
5j (R = Et, 79%, >95:5 dr)
HCl/Et O
2
(
10 equiv)
MeOH, 0 ºC
O
O
O
R3
Ph
H
R3
NH ·HCl
2e (1 equiv)
L-Proline (20 mol%), Et N (1 equiv)
3
N
H
MgSO (1 equiv), EtOH, 60 ºC, 6 h
2
4
3
8
a (R = Me, 68%, 94:6 er)
6
3
8
b (R = Et, 37%, 91:9 er)
A mechanism has been proposed in order to rationalize the stereochemical outcome. Thus, the
cyclization proceeded in an iminium-enamine intermediate 9 which is formed by double
condensation involving on one side the aldehyde 2 and the primary amine group of compounds 6,
8
and on the other side L-proline and the ketone functionality of 6. The nucleophilic attack of the
enamine moiety to the iminium took place through a Zimmerman-Traxler six-membered transition
1
2
3
state A, with the bulky R , R and R groups placed in equatorial positions in a chair-like
conformation, in order to minimized destabilizing steric interactions. The resulting cyclic iminium
compounds 10 was further hydrolyzed to yield the expected piperidin-4-ones 7 and 8, releasing L-
proline, which would be prone to participate in a new cyclization process. Formation of the
corresponding enantiomers ent-7 and ent-8 could be explained by considering that isomerization of
1
iminium 9 to give 9’ could take place in some extension, being facilitated the process when R and
2
R are aromatic rings. In this isomerization occurrs, the stereochemical integrity is not maintained at
the stereogenic center of compounds 6 (Scheme 4).
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9
1
1
1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. Rationalization of the stereochemical outcome of the organocatalyzed intramolecular
Mannich reaction
_
O C
2
‡
H
N
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R1
R3
+N
R2
H
H
O
R3
A
Et N
L-Proline
_
3
R1 NH ·HCl
O C
_
+
H O
2
2
N
2
O
O C
2
N
6
+
O
R3
R2
R3
R2
R3
+
N
R1
H O
R1
L-Proline
2
N
H
R1
N
R2
R2
H
Et3N·HCl
H
9
H
2
10
7 and 8
_
_
O C
2
O C
2
O
N
N
R3
R3
R3
+
+
R1
R2
R1
R2
R1
R2
N
H
N
N
H
H
ent-9
ent-7 and ent-8
9'
In addition to natural product (−)-epimyrtine (7k), enantiomerically pure piperidin-4-ones 7 could
be also interesting precursors of alkaloids with potential biological activity. For instance,
compounds 7f and ent-7j were transformed into natural alkaloids (+)-241D4a,5b,11g,15 (11) and (−)-
1
6
lasubine II (12), respectively, by stereoselective reduction of the carbonyl group. Thus, alkaloid
+)-241D (11), isolated from the methanolic skin extracts of the Panamanian poison frog
(
1
7
18
Dendrobates speciosus, was synthesized by reduction of 7f with lithium borohydride in MeOH
at 0 ºC, in 69% yield after column chromatography purification, as a single stereoisomer (Scheme
5
). Opposite relative facial-selectivity was observed in the reduction of compound ent-7j with L-
19
selectride at low temperature, leading in this case to (−)-lasubine II (12) in 70% yield, a natural
2
0
product isolated from plants of the Lythraceae family (Scheme 5).
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 5. Synthesis of (+)-241D (11) and (−)-lasubine II (12) from piperidin-4-ones 7f and ent-7j,
respectively
O
OH
LiBH (2.0 equiv), MeOH, 0 ºC, 30 min
4
Me
Me
Me
O
N
H
( )8
Me
N
H
( )8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7f
(+)-241D (11, 69%, 95:5 er)
OH
OMe
OMe
L-selectride (1.2 equiv), THF, -78 ºC, 1 h
OMe
N
N
OMe
ent-7j
()-Lasubine II (12, 70%, 90:10 er)
CONCLUSIONS
We have developed a methodology for the enantioselective synthesis of cis-2,6-disubstituted
piperidin-4-ones. Decarboxylative Mannich reaction of a chiral N-tert-butanesulfinyl imine with a
β-keto acid, followed by a L-proline organocatalyzed intramolecular Mannich reaction of the
resulting β-amino ketone derivative with an aldehyde, allowed access to either enantiomer of the
possible disubstituted piperidinones using the same precursors, including the chiral auxiliary. The
configuration of the reaction products is determined by order of the reactions of carbonyl
compounds 2 involved in the formation of the chiral imine 3 and in the intramolecular
organocatalyzed condensation. Finally, the straightforward synthesis of alkaloids (+)-241D, (−)-
epimyrtine and (−)-lasubine II demonstrated the potential in synthesis of this procedure.
EXPERIMENTAL SECTION
General Remarks: tert-Butanesulfinamides 1 (R and S) were a gift of Medalchemy (> 99% ee by
chiral HPLC on a Chiracel AS column, 90:10 n-hexane/i-PrOH, 1.2 mL/min, =222 nm). TLC was
performed on silica gel 60 F , using aluminum plates and visualized with phosphomolybdic acid
254
and potassium permanganate stain. Flash chromatography was carried out on handpacked columns
of silica gel 60 (230- 400 mesh). Melting points are uncorrected. Optical rotations were measured
using a polarimeter with a thermally jacketted 5 cm cell at approximately 20 ºC and concentrations
(c) are given in g/100 mL. Infrared analyses were performed with a spectrophotometer equipped
-1
with an ATR component; wavenumbers are given in cm . Low-resolution mass spectra (EI) were
obtained at 70 eV; and fragment ions in m/z with relative intensities (%) in parentheses. High-
resolution mass spectra (HRMS) were also carried out in the electron impact mode (EI) at 70 eV
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
using a quadrupole mass analyzer or in the electrospray ionization mode (ESI) using a TOF
1
13
analyzer. NMR Spectra were recorded at 300 or 400 MHz for H NMR and 75 or 100 MHz for C
NMR, using CDCl as the solvent, and TMS as internal standard (0.00 ppm). The data are being
3
reported as: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet or unresolved, br s =
1
3
1
broad signal, coupling constant(s) in Hz, integration. C NMR spectra were recorded with H-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
decoupling at 100 MHz and referenced to CDCl at 77.16 ppm. DEPT-135 experiments were
3
1
21
1
22
performed to assign CH, CH and CH . Compounds 3a , ent-3a [R = Ph(CH ) ], 3b (R = Me),
2
3
2 2
1
10
1
23
1
10
1
24
1
25
3
c (R = i-Pr), 3d [R = Me(CH ) ], 3e (R = Ph), 3f (R = 4-BrC H ), 3g [R = Br(CH ) ]
2
8
6
4
2 4
1
26
and ent-3h [R = Cl(CH ) ] were prepared from the corresponding aldehyde and (R)- or (S)-tert-
2
4
butanesulfinamide 1 in THF, in the presence of two equivalents of titanium tetraethoxide.
Compounds 4a-c were prepared by hydrolysis of the corresponding commercially available β-keto
ester.
General Procedure for the Reaction of β-Keto Acids 4 with N-tert-Butanesulfinyl Imines 3.
Synthesis of Compounds 5: These compounds were prepared by the previously published method
in reference 7. Yields, physical and spectroscopic data for new compounds 5 follow.
(
4R,R )-4-Amino-N-(tert-butanesulfinyl)pentan-2-one (5b): The representative procedure was
S
followed by using β-keto acid 4a (81.6 mg, 0.8 mmol) and imine 3b (59.0 mg, 0.4 mmol).
Purification by column chromatography (hexane/AcOEt, 1:2) yielded 5a (74.0 mg, 0.36 mmol,
9
3
0%) as a yellow liquid; [α]D20 –93.7 (c = 1.03; CH Cl ); R 0.10 (hexane/EtOAc, 1:3); IR ν (neat)
2 2 f
–
1 1
220, 2966, 2872, 1710, 1457, 1410, 1363, 1172, 1044, 796 cm ; H NMR (300 MHz, CDCl ) 
3
4.07 (d, J = 6.6 Hz, 1H), 3.74–3.70 (m, J = 6.5 Hz, 1H), 2.78 (dd, J = 17.6, 5.4 Hz, 1H), 2.69 (dd, J
1
3
1
=
17.6, 6.0 Hz, 1H), 2.13 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H), 1.16 (s, 9H); C{ H} NMR (100 MHz,
CDCl )  207.8 (C), 55.4 (C), 50.6 (CH ), 48.1 (CH), 30.8 (CH), 22.5 (CH ), 21.4 (CH ); LRMS
3
2
3
3
+
(
EI) m/z 205 (M , 2%), 149 (11), 111 (13), 91 (36), 85 (9), 70 (16), 61 (14), 57 (32), 45 (15), 44
+
(10), 43 (100), 42 (10), 41 (14); HRMS (ESI) m/z (M − C H ) calcd for C H NO S 149.0510,
4
8
5
11
2
found 149.0515.
(4S,S )-4-Amino-8-chloro-N-(tert-butanesulfinyl)octan-2-one (ent-5h): The representative
S
procedure was followed by using β-keto acid 4a (81.6 mg, 0.8 mmol) and imine ent-3h (107.2 mg,
0
.4 mmol). Purification by column chromatography (hexane/AcOEt, 1:2) yielded ent-5h (137.7 mg,
0.392 mmol, 98%) as a colorless oil; [α]D20 +45.9 (c = 1.09, CH Cl ); R 0.19 (hexane/EtOAc, 1:3);
2
2
f
–
1 1
IR ν (neat) 2955, 1710, 1457, 1411, 1363, 1169, 1048, 899, 734 cm ; H NMR (400 MHz, CDCl )
3

4.01 (d, J = 9.1 Hz, 1H), 3.54 (t, J = 6.5 Hz, 3H), 2.92 (dd, J = 17.9, 5.6 Hz, 1H), 2.81 (dd, J =
13
1
1
7.9, 4.6 Hz, 1H), 2.16 (s, 3H), 1.84–1.71 (m, 2H), 1.69–1.41 (m, 4H), 1.21 (s, 9H); C{ H} NMR
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(
100 MHz, CDCl )  208.1 (C), 55.9 (C), 53.5 (CH), 49.0 (CH ), 44.8 (CH ), 34.7 (CH ), 32.0
3
2
2
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(CH ), 31.0 (CH), 23.4 (CH ), 22.6 (CH ); LRMS (EI) m/z 225 (M – C H , 12%) 169 (36), 167
2
2
3
4
8
+
(
100), 161 (8), 57 (35), 43 (35), 41 (11); HRMS (EI) m/z (M – C H ) calcd for C H ClNO S
4 8 8 16 2
2
25.0590, found 225.0593.
(
6R,R )-6-Amino-N-(tert-butanesulfinyl)-8-phenyloctan-4-one (5j): The representative procedure
S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was followed by using β-keto acid 4c (52.0 mg, 0.4 mmol) and imine 3a (48 mg, 0.2 mmol).
Purification by column chromatography (hexane/AcOEt, 1:2) yielded 5j (51.3 mg, 0.158 mmol,
7
3
9%) as a colorless wax; [α]D20 –38.3 (c = 1.02, CH Cl ); R 0.33 (hexane/EtOAc, 1:3); IR ν (neat)
2 2 f
–
1 1
270, 2960, 2875, 1692, 1454, 1409, 1372, 1130, 1075, 1065, 947, 750, 703 cm ; H NMR (400
MHz, CDCl )  7.32–7.23 (m, 2H), 7.22–7.12 (m, 3H), 4.24 (d, J = 9.2 Hz, 1H), 3.60–3.47 (m, 1H),
3
2.90 (dd, J = 17.7, 5.6 Hz, 1H), 2.84–2.70 (m, 1H), 2.75 (dd, J = 17.6, 4.4 Hz, 1H), 2.67–2.56 (m,
1
1
1
3
H), 2.34 (td, J = 7.3, 4.2 Hz, 2H), 2.05–1.90 (m, 1H), 1.85–1.72 (m, 1H), 1.57 (q, J = 7.4 Hz, 2H),
1
3
1
.23 (s, 9H), 0.89 (t, J = 7.4 Hz, 3H); C{ H} NMR (100 MHz, CDCl )  210.7 (C), 141.5 (C),
3
28.5 (CH), 128.4 (CH), 126.0 (CH), 56.0 (C), 53.4 (CH), 48.05 (CH ), 45.7 (CH ), 37.4 (CH ),
2
2
2
+
2.5 (CH ), 22.75 (CH ), 17.0 (CH ), 13.7 (CH ); LRMS (EI) m/z 267 (M  C H , 5%), 181 (9),
2
3
2
3
4
8
159 (30), 131 (13), 117 (25), 116 (15), 92 (9), 91 (100), 71 (15), 57 (26); HRMS (EI) m/z (M –
+
C H ) calcd for C H NO S 267.1293, found 267.1291.
4
8
14 21
2
General Procedure for the Reaction of β-Keto Amine Derivatives 5 with Aldehydes 2.
Synthesis of Compounds 7 and 8: To a solution of the corresponding β-keto amine derivative 5
(
0.2 mmol) in MeOH (2.0 mL) was added a 2M solution of HCl in Et O (1.0 mL, 2.0 mmol) at 0
2
ºC. The reaction mixture was stirred at the same temperature for 30 min. Complete formation of the
corresponding free amine hydrochloride 6 was followed by TLC. After that, solvents were
evaporated (15 Torr), and to the resulting residue was successively added L-proline (0.04 mmol),
MgSO (0.2 mmol), EtOH (2.0 mL), Et N (0.2 mmol) and the corresponding aldehyde 2 (0.2
4
3
mmol). The resulting mixture was stirred for 6 h at rt (compounds 5a-h) or at 60 ºC (compounds
i,j). Then it was hydrolyzed with a saturated aqueous solution of NaHCO (10 mL), and extracted
5
3
with AcOEt (3 × 15 mL). The organic phase was extracted with 0.15M HCl (3 × 15 mL), and the
resulting acidic aqueous phase was basified with a 1M NaOH aqueous solution (pH 9-10), and
extracted with AcOEt (3 × 15 mL). The new organic phase was dried with anhydrous MgSO , and
4
the solvent evaporated (15 Torr). The residue was purified by column chromatography (silica gel,
hexane/EtOAc) to yield products 7 and 8. Yields, physical and spectroscopic data follow.
(
2R,6R)-2-Phenethyl-6-phenylpiperidin-4-one (7a): The representative procedure was followed
by using β-keto amine derivative 5a (59.0 mg, 0.2 mmol) and benzaldehyde (2e, 21.2 mg, 20.4 μL,
.2 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 7a (43.0 mg,
0
2
2
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2
2
2
2
2
2
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4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0.154 mmol, 77%) as a yellow oil; 90:10 er [HPLC (Chiralpak AS-H column, hexane/i-PrOH =
0/10, 1.0 mL/min, 220 nm): tminor = 14.13 min, tmajor = 16.22 min]; [α]D20 +40.1.8 (c = 1.01,
CH Cl ); R 0.30 (hexane/EtOAc, 5:1); IR ν (neat) 3032, 2916, 1710, 1601, 1495, 1454, 1308, 1136,
9
2
2
f
–1
1
1
030, 750, 697 cm ; H NMR (300 MHz, CDCl )  7.43–7.13 (m, 10H), 3.90 (dd, J = 7.4, 7.2 Hz,
3
1H), 3.08–2.93 (m, 1H), 2.70 (t, J = 7.9 Hz, 2H), 2.56–2.43 (m, 3H), 2.34–2.22 (m, 1H), 1.97–1.81
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
(m, 2H); C{ H} NMR (75 MHz, CDCl )  208.7 (C), 142.7 (C), 141.4 (C), 128.9 (CH), 128.6
3
(CH), 128.4 (CH), 128.0 (CH), 126.6 (CH), 126.2 (CH), 61.0 (CH ), 56.3 (CH), 50.4 (CH ), 48.2
2 2
+
(
CH ), 38.6 (CH ), 32.1 (CH ); LRMS (EI) m/z 279 (M , 5%), 175 (30), 174 (62), 146 (14), 145
2
2
2
(11), 133 (10), 132(67), 131 (67), 117 (11), 116 (14), 105 (24), 104 (40), 103 (27), 91 (100), 78
+
(
10), 77 (21), 65 (11), 51 (10); HRMS (EI) m/z M calcd for C H NO 279.1623, found 279.1612.
19 21
(2S,6S)-2-Phenethyl-6-phenylpiperidin-4-one (ent-7a): The representative procedure was
followed by using β-keto amine derivative 5e (53.4 mg, 0.2 mmol) and 3-phenylpropanal (2a, 26.8
mg, 27.0 μL, 0.2 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded
2
2
ent-7a (17.3 mg, 0.062 mmol, 31%), 88:12 er [HPLC (Chiralpak AS-H column, hexane/i-PrOH =
90/10, 1.0 mL/min, 220 nm): tmajor = 15.33 min, tminor = 17.90 min]. Physical and spectroscopical
data were found to be the same as for 7a. [α]D20 +34.6 (c = 1.47, CH Cl ).
2
2
(2S,6S)-2-Phenethyl-6-phenylpiperidin-4-one (ent-7a): The representative procedure was
followed by using β-keto amine derivative ent-5a (59.0 mg, 0.2 mmol) and benzaldehyde (2e, 21.2
mg, 20.4 μL, 0.2 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded
2
2
ent-7a (46.3 mg, 0.166 mmol, 83%), 91:9 er [HPLC (Chiralpak AS-H column, hexane/i-PrOH =
0/10, 1.0 mL/min, 220 nm): tmajor = 15.65 min, tminor = 18.42 min]. Physical and spectroscopical
data were found to be the same as for 7a. [α]D20 +35.4 (c = 1.09, CH Cl ).
9
2
2
(
2R,6R)-6-(2-Methylphenyl)-2-phenethylpiperidin-4-one (7b): The representative procedure was
followed by using β-keto amine derivative 5a (59.0 mg, 0.2 mmol) and 2-methylbenzaldehyde (2h,
4.0 mg, 23.0 μL, 0.2 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1)
2
2
2
yielded 7b (40.4 mg, 0.138 mmol, 69%) as an orange oil; 94:6 er [HPLC (Chiralpak AS column,
hexane/i-PrOH = 95/5, 1.0 mL/min, 220 nm): tmajor = 15.05 min, tminor = 17.25 min]; [α]D20 +31.7 (c
=
1.08, CH Cl ); R 0.35 (hexane/EtOAc, 5:1); IR ν (neat) 2925, 2858, 1710, 1601, 1494, 1454,
2 2 f
–1
1
1
287, 1044, 751, 699 cm ; H NMR (300 MHz, CDCl )  7.57 (d, J = 7.4 Hz, 1H), 7.34–7.11 (m,
3
8H), 4.12 (dd, J = 9.6, 5.1 Hz, 1H), 3.09–2.94 (m, 1H), 2.71 (dd, J = 9.3, 6.7 Hz, 2H), 2.53–2.38
1
3
1
(
m, 4H), 2.34 (s, 3H), 2.30–2.22 (m, 1H), 1.94–1.84 (m, 2H); C{ H} NMR (75 MHz, CDCl ) 
3
2
09.0 (C), 141.4 (C), 140.7 (C), 135.1 (C), 130.7 (CH), 128.6 (CH), 128.4 (CH), 127.5 (CH), 126.7
(
(
CH), 126.2 (CH), 125.6 (CH), 56.7 (CH), 56.45 (CH), 49.2 (CH ), 48.3 (CH ), 38.6 (CH ), 32.1
2
2
2
+
CH ), 19.2 (CH ); LRMS (EI) m/z 293 (M , 3%), 188 (13), 146 (25), 145 (50), 131 (9), 118 (14),
2
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117 (24), 116 (24), 115 (21), 92 (10), 91 (100), 65 (12); HRMS (EI) m/z M calcd for C H NO
20 23
2
93.1780, found 293.1778.
(2R,6R)-2-(4-Methoxyphenyl)-6-phenethylpiperidin-4-one (7c): The representative procedure
was followed by using β-keto amine derivative 5a (59.0 mg, 0.2 mmol) and 4-
methoxybenzaldehyde (2i, 27.2 mg, 22.8 μL, 0.2 mmol). Purification by column chromatography
0
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2
3
4
5
6
7
8
9
0
1
2
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7
8
9
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
(CH Cl /MeOH, 99:1) yielded 7c (39.5 mg, 0.128 mmol, 64%) as an orange oil; 88:12 er [HPLC
2 2
(Chiralpak AD-H column, hexane/i-PrOH = 90/10, 1.0 mL/min, 220 nm): tminor = 10.01 min, tmajor
=
1
1
7
1.93 min]; [α]D20 +23.1 (c = 1.01, CH Cl ); R 0.16 (hexane/EtOAc, 5:1); IR ν (neat) 2918, 2849,
2 2 f
–
1
1
711, 1610, 1512, 1454, 1246, 1176, 1032, 831, 748, 699 cm ; H NMR (300 MHz, CDCl ) 
3
.35–7.12 (m, 7H), 6.89 (d, J = 8.7 Hz, 2H), 3.89–3.82 (m, 1H), 3.80 (s, 3H), 3.06–2.91 (m, 1H),
1
3
1
2.70 (t, J = 8.0 Hz, 2H), 2.53–2.41 (m, 2H), 2.33–2.18 (m, 2H), 1.95–1.80 (m, 2H); C{ H} NMR
(
(
(
75 MHz, CDCl )  208.9 (C), 159.3 (C), 141.4 (C), 134.9 (C), 128.6 (CH), 128.4 (CH), 127.75
3
CH), 126.2 (CH), 114.2 (CH), 60.4 (CH), 56.3 (CH ), 55.4 (CH), 50.45 (CH ), 48.1 (CH ), 38.6
3
2
2
+
CH ), 32.1 (CH ); LRMS (EI) m/z 309 (M , 2%), 205 (9), 162 (28), 161 (41), 135 (12), 134 (22),
2
2
+
133 (13), 131 (9), 116 (17), 92 (10), 91 (100), 65 (11); HRMS (EI) m/z M calcd for C H NO
2
2
0
23
3
09.1729, found 309.1711.
(2S,6R)-2-Nonyl-6-phenethylpiperidin-4-one (7d): The representative procedure was followed by
using β-keto amine derivative 5a (59.0 mg, 0.2 mmol) and decanal (2d, 31.0 mg, 37.6 μL, 0.2
mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 7d (27.0 mg, 0.082
2
2
mmol, 41%) as a yellow solid; mp 41–42 ºC (hexane/CH Cl ); 89:11 er [HPLC (Chiralcel OJ
2
2
column, hexane/i-PrOH = 95/5, 1.0 mL/min, 210 nm): tminor = 10.38 min, tmajor = 25.50 min]; [α]D20
–
1
1.7 (c = 1.04, CH Cl ); R 0.23 (hexane/EtOAc, 5:1); IR ν (neat) 2922, 2852, 1709, 1602, 1495,
2 2 f
–1
1
455, 1324, 1071, 747, 697 cm ; H NMR (300 MHz, CDCl )  7.35–7.13 (m, 5H), 2.91–2.74 (m,
3
2H), 2.70 (t, J = 7.0 Hz, 2H), 2.49–2.32 (m, 2H), 2.24–2.01 (m, 2H), 1.98–1.75 (m, 2H), 1.61–1.39
1
3
1
(m, 2H), 1.27 (s, 14H), 0.88 (t, J = 6.8 Hz, 3H); C{ H} NMR (100 MHz, CDCl )  209.4 (C),
3
1
3
41.4 (C), 128.6 (CH), 128.35 (CH), 126.15 (CH), 56.6 (CH), 56.1 (CH), 48.7 (CH ), 48.6 (CH ),
2 2
8.5 (CH ), 37.05 (CH ), 32.3 (CH ), 31.9 (CH ), 29.7 (CH ), 29.6 (CH ), 29.4 (CH ), 25.75 (CH ),
2
2
2
2
2
2
2
2
+
22.7 (CH ), 14.2 (CH ); LRMS (EI) m/z 329 (M , 2%), 225 (8), 224 (50), 203 (10), 202 (73) 182
2
3
+
(24), 160 (21), 116 (16), 97 (11), 92 (8), 91 (100), 71 (8), 55 (15); HRMS (EI) m/z M calcd for
C H NO 329.2719, found 329.2697.
2
2
35
(2R,6S)-2-Nonyl-6-phenethylpiperidin-4-one (ent-7d): The representative procedure was
followed by using β-keto amine derivative 5d (63.4 mg, 0.2 mmol) and 3-phenylpropanal (2a, 26.8
mg, 27.0 μL, 0.2 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded
2
2
ent-7d (40.8 mg, 0.124 mmol, 62%), 93:7 er [HPLC (Chiralcel OJ column, hexane/i-PrOH = 95/5,
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1.0 mL/min, 210 nm): tmajor = 11.22 min, tminor = 25.92 min]. Physical and spectroscopical data were
found to be the same as for 7d. [α]D20 +0.9 (c = 1.05, CH Cl ).
2
2
(2S,6R)-2-Butyl-6-phenethylpiperidin-4-one (7e): The representative procedure was followed by
using β-keto amine derivative 5a (56.1 mg, 0.19 mmol) and pentanal (2j, 17.2 mg, 21.5 μL, 0.2
mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 7e (27.6 mg, 0.106
2
2
0
1
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3
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6
7
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2
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4
5
6
7
8
9
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5
6
7
8
9
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mmol, 56%) as an orange oil; 93:7 er [HPLC (Chiralpak AS-H column, hexane/i-PrOH = 90/10, 1.0
mL/min, 210 nm): tminor = 7.94 min, tmajor = 9.46 min]; [α]D20 –0.7 (c = 1.03, CH Cl ); R 0.16
2
2
f
–
1
(
hexane/EtOAc, 5:1); IR ν (neat) 2927, 2859, 1711, 1603, 1496, 1454, 1275, 1030, 748, 699 cm ;
1
H NMR (300 MHz, CDCl )  7.35–7.12 (m, 5H), 2.89–2.62 (m, 2H), 2.71 (t, J = 7.8 Hz, 1H),
3
2
.44–2.32 (m, 1H), 2.28–1.98 (m, 2H), 1.93–1.71 (m, 2H), 1.58–1.40 (m, 2H), 1.40–1.15 (m, 6H),
1
3
1
0.91 (t, J = 6.9 Hz, 3H); C{ H} NMR (75 MHz, CDCl )  209.5 (C), 141.4 (C), 128.65 (CH),
3
1
3
1
28.4 (CH), 126.2 (CH), 56.6 (CH), 56.2 (CH), 48.7 (CH ), 48.7 (CH ), 38.5 (CH ), 36.8 (CH ),
2 2 2 2
+
2.3 (CH ), 28.0 (CH ), 22.8 (CH ), 14.1 (CH ); LRMS (EI) m/z 259 (M , 2%) 203 (9), 202 (68),
2
2
2
3
60 (33), 154 (55), 117 (11), 116 (13), 112 (36), 111 (9), 92 (8), 91 (100), 65 (9), 55 (15); HRMS
+
(EI) m/z M calcd for C H NO 259.1936, found 259.1915.
1
7
25
(2R,6S)-2-Methyl-6-nonylpiperidin-4-one (7f): The representative procedure was followed by
using β-keto amine derivative 5b (61.5 mg, 0.3 mmol) and decanal (2d, 46.8 mg, 56.4 μL, 0.3
mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 7f (42.3 mg, 0.177
2
2
mmol, 59%) as a yellow wax; 90:10 er [GC (CP-Chirasil-Dex CB column, Tinjector= 275 ºC, Tdetector
=
250 ºC, Tcolumn= 100 ºC (10 min) and 100-200 ºC (2.5 ºC/min), P = 101 kPa): tmajor = 42.49 min,
tminor = 42.70 min]; [α]D20 –2.9 (c = 1.42, CH Cl ); R 0.24 (EtOAc); IR ν (neat) 2924, 2853, 1718,
2
2
1
f
–
1
1
2
3
542, 1460, 1377, 1280, 1142, 1077, 722 cm ; H NMR (300 MHz, CDCl )  3.06–2.88 (m, 1H),
3
.92–2.76 (m, 1H), 2.41–2.30 (m, 2H), 2.14–1.99 (m, 2H), 1.59–1.23 (m, 16H), 1.22 (d, J = 6.2 Hz,
13
1
H), 0.88 (t, J = 6.8 Hz, 3H); C{ H} NMR (100 MHz, CDCl )  209.6 (C), 52.3 (CH), 50.2 (CH),
3
48.1 (CH ), 37.1 (CH ), 32.0 (CH ), 29.7 (CH ), 29.6 (CH ), 29.4 (CH ), 25.8 (CH ), 22.8 (CH ),
2
2
2
2
2
2
2
2
+
2
2.7 (CH ), 14.2 (CH ); LRMS (EI) m/z 224 (M – CH , 2%), 182 (7), 113 (7), 112 (100), 70 (30);
3 3 3
+
HRMS (EI) m/z M calcd for C H NO 239.2249, found 239.2247.
1
5
29
(2R,6R)-2-Isopropyl-6-methylpiperidin-4-one (7g): The representative procedure was followed
by using β-keto amine derivative 5b (61.5 mg, 0.3 mmol) and isobutyraldehyde (2c, 25.5 mg, 31.9
μL, 0.35 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 7g (33.5
2
2
mg, 0.216 mmol, 72%) as a yellow oil; 92:8 er [GC (CP-Chirasil-Dex CB column, Tinjector= 275 ºC,
Tdetector= 250 ºC, Tcolumn= 100 ºC (10 min) and 100-200 ºC (2.5 ºC/min), P = 101 kPa): tminor = 15.36
min, tmajor = 15.79 min]; [α]D20 –3.0 (c = 0.62, CH Cl ); R 0.28 (hexane/EtOAc, 1:1); IR ν (neat)
2
2
f
–
1 1
2
961, 2928, 2874, 1718, 1464, 1377, 1308, 1287, 1117, 751 cm ; H NMR (400 MHz, CDCl ) 
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6
2.95 (dqd, J = 12.2, 6.2, 2.9 Hz, 1H), 2.63 (ddd, J = 11.9, 6.0, 2.8 Hz, 1H), 2.41–2.29 (m, 2H),
2
3
5
.14–2.03 (m, 2H), 1.80–1.64 (m, J = 6.5 Hz, 1H), 1.22 (d, J = 6.2 Hz, 3H), 0.97 (d, J = 6.8 Hz,
1
3
1
H), 0.94 (d, J = 6.8 Hz, 3H); C{ H} NMR (100 MHz, CDCl )  210.3 (C), 62.3 (CH), 52.3 (CH),
3
+
0.2 (CH ), 45.0 (CH ), 33.2 (CH), 22.7 (CH ), 19.1 (CH ), 18.4 (CH ); LRMS (EI) m/z 154 (M –
2
2
3
3
3
+
H, 1%), 112 (100), 98 (13), 70 (97); HRMS (EI) m/z (M – H) calcd for C H NO 154.1232, found
9
16
0
1
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0
1
54.1227.
(2S,6R)-2-Isopropyl-6-phenylpiperidin-4-one (7h): The representative procedure was followed by
using β-keto amine derivative 5c (65.2 mg, 0.28 mmol) and benzaldehyde (2e, 29.7 mg, 30.0 μL,
0
.28 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 7h (46.2 mg,
2 2
0
.213 mmol, 76%) as an orange oil; 72:28 er [HPLC (Chiralpak AS column, hexane/i-PrOH = 95/5,
1.0 mL/min, 210 nm): tminor = 13.49 min, tmajor = 17.20 min]; [α]D20 +27.8 (c = 1.02, CH Cl ); R
f
2
2
–
1 1
0
.46 (hexane/EtOAc, 5:1); IR ν (neat) 2961, 2876, 1714, 1456, 1365, 1249, 1030, 756, 699 cm ; H
NMR (400 MHz, CDCl )  7.45–7.24 (m, 5H), 3.90 (dd, J = 9.7, 5.2 Hz, 1H), 2.77 (ddd, J = 11.7,
3
5
.7, 2.9 Hz, 1H), 2.52–2.44 (m, 2H), 2.46–2.37 (m, 1H), 2.30–2.19 (m, 1H), 1.83–1.69 (m, 1H),
1
3
1
0.99 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H); C{ H} NMR (100 MHz, CDCl )  209.7 (C),
3
1
43.1 (C), 128.8 (CH), 127.9 (CH), 126.6 (CH), 62.4 (CH), 61.1 (CH), 50.6 (CH ), 45.0 (CH ), 33.2
2 2
+
(
CH), 18.8 (CH ), 18.3 (CH ); LRMS (EI) m/z 217 (M , 2%) 175 (12), 174 (100), 132 (53), 131
3 3
+
(
88), 105 (17), 104 (28), 103 (26), 77 (12), 70 (13); HRMS (EI) m/z M calcd for C H NO
14 19
217.1467, found 217.1465.
(
2R,6S)-2-Isopropyl-6-phenylpiperidin-4-one (ent-7h): The representative procedure was
followed by using β-keto amine derivative 5e (47.6 mg, 0.178 mmol) and isobutyraldehyde (2c,
3.0 mg, 16.4 μL, 0.18 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1)
1
2
2
yielded ent-7h (28.2 mg, 0.130 mmol, 73%), 78:22 er [HPLC (Chiralpak AS column, hexane/i-
PrOH = 95/5, 1.0 mL/min, 210 nm): tmajor = 13.16 min, tminor = 17.05 min]. Physical and
spectroscopical data were found to be the same as for 7h. [α]D20 –42.8 (c = 0.93, CH Cl ).
2
2
(2R,6S)-2-(4-Bromophenyl)-6-phenylpiperidin-4-one (7i): The representative procedure was
followed by using β-keto amine derivative 5e (53.4 mg, 0.2 mmol) and 4-bromobenzaldehyde (2f,
3
7.0 mg, 0.2 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 7i
2 2
(50.2 mg, 0.152 mmol, 76%) as an orange wax; 56:44 er [HPLC (Chiralpak IA column, hexane/i-
PrOH = 90/10, 1.0 mL/min, 220 nm): tmajor = 14.57 min, tminor = 17.60 min]; [α]D20 +1.4 (c = 1.03,
CH Cl ); R 0.49 (hexane/EtOAc, 5:1); IR ν (neat) 2964, 2834, 1709, 1487, 1455, 1296, 1239, 1071,
2
2
f
–
1 1
1
2
1
010, 828, 757, 699 cm ; H NMR (300 MHz, CDCl )  7.53–7.25 (m, 9H), 4.10–4.00 (m, 2H),
3
13
1
.63–2.48 (m, 4H); C{ H} NMR (75 MHz, CDCl )  207.6 (C), 142.6 (C), 141.8 (C), 132.0 (CH),
3
28.9 (CH), 128.4 (CH), 128.1 (CH), 126.7 (CH), 121.75 (CH), 61.2 (CH), 60.6 (CH), 50.4 (CH2);
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5
5
5
5
5
5
5
5
5
6
+
LRMS (EI) m/z 331 (M , 15%), 329 (14), 211 (53), 209 (52), 184 (69), 183 (36), 182 (50), 181 (23),
1
7
46 (49), 145 (90), 132 (21), 131 (67), 106 (35), 105 (36), 104 (100), 103 (93), 102 (80), 78 (20),
+
7 (60), 76 (27), 75 (25); HRMS (EI) m/z M calcd for C H BrNO 329.0415, found 329.0394.
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7
16
(
2S,6R)-2-(4-Bromophenyl)-6-phenylpiperidin-4-one (ent-7i): The representative procedure was
followed by using β-keto amine derivative 5f (44.8 mg, 0.13 mmol) and benzaldehyde (2e, 13.8 mg,
3.8 μL, 0.13 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded ent-7i
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
2
(31.2 mg, 0.095 mmol, 73%), 53:47 er [HPLC (Chiralpak IA column, hexane/i-PrOH = 90/10, 1.0
mL/min, 220 nm): tminor = 14.56 min, tmajor = 17.70 min]. Physical and spectroscopical data were
found to be the same as for 7i. [α]D20 –5.1 (c = 1.03, CH Cl ).
2
2
(
4R,9aR)-4-(3,4-Dimethoxyphenyl)octahydro-2H-quinolizin-2-one (7j): The representative
procedure was followed by using β-keto amine derivative 5g (65.0 mg, 0.2 mmol) and 3,4-
dimethoxybenzaldehyde (2k, 33.2 mg, 0.2 mmol). Purification by column chromatography
(
CH Cl /MeOH, 99:1) yielded 7j (17.9 mg, 0.062 mmol, 31%) as a yellow oil; 93:7 er [HPLC
2 2
(
Chiralcel OJ column, hexane/i-PrOH = 90/10, 1.0 mL/min, 220 nm): tminor = 10.58 min, tmajor
=
1
6.10 min]; [α]D20 +54.3 (c = 0.87, CH Cl ); R 0.18 (hexane/EtOAc, 1:1); IR ν (neat) 2933, 1719,
2
2
f
–
1 1
1594, 1511, 1463, 1264, 1138, 1027 cm ; H NMR (400 MHz, CDCl )  6.92 (s, 1H), 6.88–6.78
3
(
m, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.21 (dd, J = 12.2, 3.2 Hz, 1H), 2.79 (d, J = 11.5 Hz, 1H), 2.70
(
t, J = 13.7 Hz, 1H), 2.52 (t, J = 13.2 Hz, 1H), 2.46–2.23 (m, 3H), 1.78–1.64 (m, 2H), 1.66–1.60 (m,
13
1
1
H), 1.60–1.41 (m, 3H), 1.38–1.24 (m, 1H); C{ H} NMR (100 MHz, CDCl )  208.0 (C), 149.45
3
(C), 148.5 (C), 135.15 (C), 119.7 (CH), 111.1 (CH), 109.9 (CH), 70.1 (CH), 62.6 (CH), 56.1 (CH3),
6.0 (CH ), 52.9 (CH ), 50.9 (CH ), 48.8 (CH ), 34.4 (CH ), 25.9 (CH ), 24.3 (CH ); LRMS (EI)
5
3
2
2
2
2
2
2
+
m/z 289 (M , 22%) 247 (16), 209 (16), 208 (39), 207 (62), 206 (43), 192 (62), 191 (100), 177 (16),
1
76 (27), 175 (17), 165 (47), 164 (85), 163 (18), 84 (49), 83 (27), 82 (24), 55 (44); HRMS (EI) m/z
+
M calcd for C H NO 289.1678, found 289.1671.
1
7
23
3
(
4S,9aS)-4-(3,4-Dimethoxyphenyl)octahydro-2H-quinolizin-2-one (ent-7j): The representative
procedure was followed by using β-keto amine derivative ent-5h (56.2 mg, 0.2 mmol) and 3,4-
dimethoxybenzaldehyde (2k, 33.2 mg, 0.2 mmol). Purification by column chromatography
(
CH Cl /MeOH, 99:1) yielded ent-7j (37.6 mg, 0.130 mmol, 65%), 93:7 er [HPLC (Chiralcel OJ
2 2
column, hexane/i-PrOH = 90/10, 1.0 mL/min, 220 nm): tmajor = 10.45 min, tminor = 16.32 min].
Physical and spectroscopical data were found to be the same as for 7j. [α]D20 –56.9 (c = 0.89,
CH Cl ).
2
2
(
−)-Epimyrtine Hydrochloride (7k·HCl): The representative procedure was followed by using β-
keto amine derivative 5b (41.0 mg, 0.2 mmol) and 5-chloropentanal (2l, 30.1 mg, 0.25 mmol). Final
extraction in this case was carried out with CH Cl (3 × 10 mL). The organic phase containing (−)-
2
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epimyrtine [GC-MS: single peak, m/z 167 (M , 26%)] was treated with a 2M HCl solution in Et O
2
(0.5 mL, 1.0 mmol) for 15 min, and after that the solvents were evaporated (15 Torr) to yield ()-
epimyrtine hydrochloride as a white solid (26.8 mg, 0.132 mmol, 66%); 93:7 er (7k) [GC (CP-
Chirasil-Dex CB column, Tinjector= 275 ºC, Tdetector= 250 ºC, Tcolumn= 100 ºC (10 min) and 100-200
ºC (2.5 ºC/min), P = 101 kPa): tminor = 25.23 min, tmajor = 25.81 min]; [α]D20 −13.4 (c = 0.40, CHCl3)
[lit.11a [α]D20 –17.4 (c = 0.7, CHCl )]; H NMR (500 MHz, CDCl )  12.92 (s, 1H), 3.94 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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0
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2
1.3 Hz, 1H), 3.58 – 3.44 (m, 1H), 3.45 – 3.25 (m, 2H), 3.22 – 3.00 (m, 1H), 2.61 – 2.47 (m, 3H),
13
1
.43 – 2.21 (m, 2H), 2.03 – 1.84 (m, 2H), 1.65 (d, J = 5.7 Hz, 3H), 1.60 – 1.43 (m, 2H); C{ H}
NMR (75 MHz, CDCl )  201.45(C), 63.74 (CH), 61.50 (CH), 51.45 (CH ), 46.49 (CH ), 45.46
3
2
2
+
(CH ), 30.84 (CH ), 23.09(CH ), 22.37 (CH ), 17.70 (CH ); LRMS (EI) m/z 167 (7k, M , 26%) 153
2
2
2
2
3
(10), 152 (100), 124 (34), 110 (71), 84 (9), 83 (31), 82 (14), 69 (15), 55 (16).
(2R,3S,6R)-3-methyl-6-phenethyl-2-phenylpiperidin-4-one (8a): The representative procedure
was followed by using β-keto amine derivative 5i (52.5 mg, 0.17 mmol) and benzaldehyde (2e, 21.2
mg, 20.4 μL, 0.2 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 8a
2
2
(33.9 mg, 0.116 mmol, 68%) as a white solid; mp 71–72 ºC (hexane/CH Cl ); 94:6 er [HPLC
2
2
Chiralpak AS-H column, hexane/i-PrOH = 95/5, 1.0 mL/min, 220 nm): tminor = 9.28 min, tmajor
( =
1
1
1.60 min]; [α]D20 +21.5 (c = 1.02, CH Cl ); R 0.42 (hexane/EtOAc, 5:1); IR ν (neat) 2928, 1703,
2 2 f
–1
1
602, 1494, 1451, 1332, 1238, 934, 835, 748, 696 cm ; H NMR (400 MHz, CDCl )  7.43–7.12
3
(m, 10H), 3.46 (d, J = 10.5 Hz, 1H), 3.07–2.95 (m, 1H), 2.67 (t, J = 8.0 Hz, 2H), 2.59 (dq, J = 10.7,
6
.5 Hz, 1H), 2.54 (dd, J = 13.2, 2.9 Hz, 1H), 2.39 (t, J = 12.4 Hz, 1H), 1.91–1.80 (m, 2H), 0.77 (d, J
1
3
1
=
6.6 Hz, 3H); C{ H} NMR (100 MHz, CDCl )  210.1 (C), 141.9 (C), 141.4 (C), 128.8 (CH),
3
1
28.6 (CH), 128.4 (CH), 128.1 (CH), 127.8 (CH), 126.2 (CH), 68.4 (CH), 56.8 (CH), 51.7 (CH),
+
48.6 (CH ), 38.6 (CH ), 32.0 (CH ), 10.3 (CH ); LRMS (EI) m/z 293 (M , 10%), 188 (16), 160 (11),
2
2
2
3
1
59 (30), 132 (38), 117 (23), 116 (18), 115 (18), 105 (14), 104 (16), 91 (100), 65 (10); HRMS (ESI)
+
m/z M calcd for C H NO 293.1780, found 293.1779.
2
0
23
(
2R,3S,6R)-3-Ethyl-6-phenethyl-2-phenylpiperidin-4-one (8b): The representative procedure was
followed by using β-keto amine derivative 5j (64.6 mg, 0.2 mmol) and benzaldehyde (2e, 48 mg,
.2 mmol). Purification by column chromatography (CH Cl /MeOH, 99:1) yielded 8b (22.7 mg,
0
2
2
0.074 mmol, 37%) as a yellow oil; 91:9 er [HPLC (Chiralpak AS-H column, hexane/i-PrOH = 95/5,
1
.0 mL/min, 220 nm): tminor = 7.08 min, tmajor = 8.68 min]; [α]D20 +16.7 (c = 0.89, CH Cl ); R 0.49
2
2
f
–1
1
(
hexane/EtOAc, 5:1); IR ν (neat) 2927, 1708, 1495, 1455, 1307, 1207, 1029, 748, 698 cm ; H
NMR (300 MHz, CDCl )  7.45–7.24 (m, 7H), 7.26–7.13 (m, 3H), 3.60 (d, J = 10.7 Hz, 1H), 3.10–
3
2.95 (m, 1H), 2.75–2.63 (m, 2H), 2.60–2.47 (m, 1H), 2.47–2.34 (m, 1H), 1.97–1.80 (m, 3H), 1.62–
1
3
1
1
.41 (m, 1H), 1.22–1.03 (m, 1H), 0.76 (t, J = 7.4 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) 
3
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209.8 (C), 141.9 (C), 141.5 (C), 128.8 (CH), 128.6 (CH), 128.4 (CH), 128.1 (CH), 127.9 (CH),
1
26.15 (CH), 66.7 (CH), 58.5 (CH), 57.0 (CH), 49.3 (CH ), 38.6 (CH ), 32.05 (CH ), 18.1 (CH ),
2 2 2 2
+
1
2.3 (CH ); LRMS (EI) m/z 307 (M , 9%), 292 (15), 202 (10), 159 (31), 132 (27), 131 (14), 117
3
+
(
11), 116 (16), 106 (9), 105 (15), 104 (17), 91 (100); HRMS (ESI) m/z M calcd for C H NO
2
1
25
307.1936, found 307.1932.
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Synthesis of Alkaloid (+)-241D (11) from Piperidin-4-one 7f: To solution of piperidin-4-one 7f
(71.7 mg, 0.3 mmol) in MeOH (5 mL) was added a 2M LiBH solution in MeOH (0.5 mL, 1.0
4
mmol) at 0 ºC. The reaction mixture was stirred for 1 h at the same temperature. Then it was
hydrolyzed with a 2M NaOH aqueous solution (10 mL), and extracted with CH Cl (4 × 15 mL).
2
2
The organic phase was dried with anhydrous MgSO , and the solvent evaporated (15 Torr). The
4
residue was purified by recrystallization with petroleum ether to give (−)-241D (11) (48.2 mg, 0.20
1
5b
mmol, 69%) as a white solid; mp 103-106 ºC (hexane/CH Cl ) (lit. mp 106 ºC); >95:5 er [GC
2
2
(
CP-Chirasil-Dex CB column, Tinjector= 275 ºC, Tdetector= 250 ºC, Tcolumn= 100 ºC (10 min) and 100-
200 ºC (2.5 ºC/min), P = 101 kPa): tmajor = 45.14 min]; [α]D20 +5.2 (c = 0.52, MeOH) [lit.15c [α]D20
5.4 (c = 0.5, MeOH)]; R 0.35 (CH Cl /MeOH, 10:1); IR ν (neat) 3268, 3175, 2919, 2850,1469,
+
f
2
2
–
1 1
1
2
379, 1320, 1156, 1111, 1035, 838 cm ; H NMR (300 MHz, CDCl )  3.74–3.58 (m, 1H), 2.77–
3
.60 (m, 1H), 2.62–2.47 (m, 1H), 2.05–1.88 (m, 2H), 1.56–1.47 (m, 2H), 1.44–1.36 (m, 2H), 1.34–
1
3
1
1.20 (m, 14H), 1.12 (d, J = 6.3 Hz, 3H), 1.08–0.92 (m, 2H), 0.88 (t, J = 6.8 Hz, 3H); C{ H} NMR
(
100 MHz, CDCl )  69.55 (CH), 55.0 (CH), 50.3 (CH), 44.05 (CH ), 41.9 (CH ), 36.95 (CH ),
3
2
2
2
3
2.0 (CH ), 29.9 (CH ), 29.7 (CH ), 29.7 (CH ), 29.45 (CH ), 26.2 (CH ), 22.8 (CH ), 22.6 (CH ),
2 2 2 2 2 2 2 3
+
1
4.3 (CH ); LRMS (EI) m/z 226 (M -CH , 3%) 182 (29), 115 (8), 114 (100), 107 (11), 70 (27), 69
3
3
(7), 55 (6).
Synthesis of (−)-Lasubine II (12) from Piperidin-4-one ent-7j: To solution of piperidin-4-one
ent-7j (28.9 mg, 0.1 mmol) y dry THF (2 mL) was added dropwise a 2M L-Selectride solution in
THF (0.075 mL, 0.15 mmol) at -78 ºC. The reaction mixture was stirred for 1 h at the same
temperature. Then it was hydrolyzed with a saturated aqueous solution of NaHCO (10 mL), and
3
extracted with CH Cl (3 × 20 mL). The organic phase was dried with anhydrous MgSO , and the
2
2
4
solvent evaporated (15 Torr). The residue was purified by column chromatography (silica gel,
CH Cl /MeOH, 96:4) to give (−)-lasubine II (12) (20.4 mg, 0.07 mmol, 70%) as a yellow oil; 89:11
2
2
er [HPLC (Chiralcel OD-H column, hexane/i-PrOH = 90/10, 1.0 mL/min, 220 nm): tminor = 8.56
min, tmajor = 11.61 min]; [α]D20 –32.4 (c = 0.28, MeOH) [lit. [α] –34.7 (c = 0.32, MeOH); lit.27
20
20
D
[
α]D20 –51.0 (c = 0.12, MeOH)]; R 0.44 (CH Cl /MeOH, 10:1); IR ν (neat) 3340, 2932, 1516, 1464,
f 2 2
–
1 1
1
4
261, 1142, 1026, 749 cm ; H NMR (400 MHz, CDCl )  7.12 (s, 1H), 6.99–6.89 (m, 2H), 4.17–
3
.09 (m, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 2.96 (s, 1H), 2.82 (d, J = 12.1 Hz, 1H), 2.26–2.07 (m, 2H),
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.95–1.27 (m, 10H); C{ H} NMR (100 MHz, CDCl )  151.25 (C), 150.8 (C), 122.2 (CH), 113.8
3
4
5
6
7
8
9
1
1
1
1
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(CH), 113.3 (CH), 65.6 (CH), 64.4 (CH), 59.8 (CH), 56.9 (CH ), 56.8 (CH ), 53.9 (CH ), 41.8
3 3 2
+
(
CH ), 40.0 (CH ), 33.2 (CH ), 25.9 (CH ), 24.8 (CH ); LRMS (EI) m/z 291 (M , 100%) 290 (34),
2 2 2 2 2
2
48 (20), 246 (30), 232 (21), 191 (26), 190 (21), 165 (36), 164 (86), 163 (11), 154 (79), 151 (22),
149 (13), 126 (26), 110 (26), 96 (17), 91 (13), 84 (23), 55 (13).
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ASSOCIATED CONTENT
1
13
Supporting Information. Copies of H, C NMR and DEPT spectra for compounds 5b, ent-5h, 5j,
, 8, 11 and 12. Copies of chiral HPLC and GC chromatograms for compounds 7, 8, 11 and 12.
7
ACKNOWLEDGMENTS
We acknowledge the continued financial support from the Spanish Ministerio de Economía y
Competitividad (MINECO; projects CTQ2014-53695-P, CTQ2014-51912-REDC, CTQ2016-
8
1797-REDC,
CTQ2017-85093-P),
FEDER,
the
Generalitat
Valenciana
(PROMETEOII/2014/017), and the University of Alicante.
References
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1
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and food animal teratogens. Food Chem. Toxicol. 2012, 60, 2049−2055.
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2,3-Dihydropyridin-4(1H)-ones and 3-Aminocyclohex-2-enones: Synthesis, Functionalization, and
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Thomas, N.; Troin, Y. Stereoselective strategies for the construction of polysubstituted piperidinic
compounds and their applications in natural products’ synthesis. Org. Chem. Front. 2017, 4,
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655−1704.
3
. For selected examples, see: (a) Kumar, R. S. C.; Reddy, G. V.; Shankaraiah, G.; Babu, K. S.;
Rao, J. M. Stereoselective synthesis of dendrobate alkaloid (+)-241D and its C-4 epimer.
Tetrahedron Lett. 2010, 51, 1114−1116. (b) Murali, R. V. N. S.; Chandrasekhar, S. Stereocontrolled
synthesis of piperidine alkaloids, (−)-241D and (−)-isosolenopsin. Tetrahedron Lett. 2012, 53,
0
1
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0
3
467−3470. (c) Damodar, K.; Das, B. (N-tert-Butanesulfinyl)imines in Alkaloid Synthesis: Concise
Formal Syntheses of the Dendrobate Alkaloid (+)-241D and Its C-4 Epimer. Synthesis 2012, 44,
8
3−86.
4
. For selected examples, see: (a) Gnamm, G.; Krauter, C. M.; Brödner, K.; Helmchen, G.
Stereoselective Synthesis of 2,6‐Disubstituted Piperidines Using the Iridium‐Catalyzed Allylic
Cyclization as Configurational Switch: Asymmetric Total Synthesis of (+)‐241ꢀD and Related
Piperidine Alkaloids. Chem. – Eur. J. 2009, 15, 2050−2054. (b) Hande, S. M.; Kawai, N.; Uenishi,
II
J. An Efficient Synthesis of 2- and 2,6-Substituted Piperidines Using Pd -Catalyzed 1,3-Chirality
Transfer Reaction. J. Org. Chem. 2009, 74, 244−253. (c) Guerinot, A.; Serra-Muns, M.; Gnamm,
C.; Bensoussan, C.; Reymond, S.; Cossy, J. FeCl -Catalyzed Highly Diastereoselective Synthesis of
3
Substituted Piperidines and Tetrahydropyrans. Org. Lett. 2010, 12, 1808−1811. (d) Kurugome, Y.;
Kogiso, M.; Looi, K. K.; Hattori, Y.; Konno, H.; Hirota, M.; Makabe, H. Total synthesis of (+)-
azimine via diastereoselective aminopalladation. Tetrahedron 2013, 69, 8349−8352. (e) Katsuyama,
M.; Furuta, M.; Kobayashi, K.; Teruya, K.; Makabe, H.; Akaji, K.; Hattori, Y. Heterocycles 2015,
9
1, 959−969.
5. For selected examples, see: (a) Gouault, N.; Le Roch, M.; Cheignon, A.; Uriac, P.; David, M.
Enantiospecific Synthesis of Pyridinones as Versatile Intermediates toward Asymmetric
Piperidines. Org. Lett. 2011, 13, 4371−4373. (b) Gouault, N.; Le Roch, M.; Campos Pinto, G.;
David, M. Total synthesis of dendrobate alkaloid (+)-241D, isosolenopsin and isosolenopsin A:
application of a gold-catalyzed cyclization. Org. Biomol. Chem. 2012, 10, 5541−5546. (c)
Abrunhosa-Thomas, I.; Plas, A.; Kandepedu, N.; Chalard, P.; Troin, Y. Efficient synthesis of β’-
amino-α,β-unsaturated ketones. Beilstein J. Org. Chem. 2013, 9, 486−495. (d) Abrunhosa-Thomas,
I.; Plas, A.; Vogrig, A.; Kandepedu, N.; Chalard, P.; Troin, Y. Access to 2,6-Disubstituted
Piperidines: Control of the Diastereoselectivity, Scope, and Limitations. Applications to the
Stereoselective Synthesis of (−)-Solenopsine A and Alkaloid (+)-241D. J. Org. Chem. 2013, 78,
2
511−2526.
6. For selected examples, see: (a) Guo, F.; Dieter, R. K. Conjugate Addition Reactions of N-
Carbamoyl-4-Pyridones with Organometallic Reagents. J. Org. Chem. 2009, 74, 3843−3848. (b)
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Guo, F.; Dhakal, R. C.; Dieter, R. K. Conjugate Addition Reactions of N-Carbamoyl-4-pyridones
and 2,3-Dihydropyridones with Grignard Reagents in the Absence of Cu(I) Salts. J. Org. Chem.
2
013, 78, 8451−8464. (c) Tsukanov, S. V.; Comins, D. L. Total Synthesis of Alkaloid 205B. J. Org.
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