A general approach for the asymmetric synthesis of densely substituted piperidines and fully substituted piperidinones employing the asymmetric Mannich reaction as key step

Article abstract of DOI:10.1039/c3ra45110k

Two efficient and alternative protocols for the preparation of highly enantioenriched piperidine structures are reported. We have also developed a simple route to access to fully diastereo- and enantioenriched substituted piperidinones. The key step of al

Full text of DOI:10.1039/c3ra45110k

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A general approach for the asymmetric synthesis of
densely substituted piperidines and fully substituted
piperidinones employing the asymmetric Mannich
reaction as key step†
Cite this: RSC Adv., 2013, 3, 25800
*
*
´
Ainara Iza, Uxue Uria, Efraım Reyes, Luisa Carrillo and Jose L. Vicario
Two efficient and alternative protocols for the preparation of highly enantioenriched piperidine structures
are reported. We have also developed a simple route to access to fully diastereo- and enantioenriched
substituted piperidinones. The key step of all this synthesis relies on a diastereoselective Mannich
reaction, employing the readily available aminoalcohol (+)-(S,S)-pseudoephedrine as a chiral auxiliary,
which allows the preparation of b-aminocarbonyl compounds in high yield, diastereo and
enantioselectivity and using easy-to-scale protocols.
Received 17th July 2013
Accepted 30th September 2013
DOI: 10.1039/c3ra45110k
www.rsc.org/advances
obtained by (iv) stereoselective nucleophilic addition to pyr-
idinium salts.
Introduction
Piperidines represent one of the most common building blocks
found in natural products and pharmaceuticals, the piperidine
ring being a privileged structure in medicinal chemistry which
has generated intensive research, focused on exploiting their
interesting attributes as potential drugs.1 Furthermore, these
heterocyclic rings are also of interest in synthetic organic
chemistry as chiral auxiliaries and ligands.2 These facts have
raised a lot of synthetic interest, focussed especially on many
important efforts directed towards the development of stereo-
controlled approaches for the preparation of this class of
compound.3 The typical strategies for building up the piperi-
dine framework are mainly based on ring closing processes,
starting from a conveniently functionalized acyclic chiral non-
racemic starting material by means of intramolecular reactions.
In this context, most common approaches to piperidines
involve (i) C–N bond formation by intramolecular lactamiza-
tion, an aza-Michael reaction or reductive amination, or (ii) C–C
bond formation by means of intramolecular Michael-type
additions, Mannich reactions, ring-closing metathesis or
radical cyclization. Alternatively, other methods have been
reported in which the piperidine ring is built up by (iii) the
simultaneous formation of two different bonds by classical
Diels–Alder cycloaddition chemistry or, in a different approach,
enantiopure mono- or disubstituted piperidines can also be
In this context, and in connection with our ongoing program
directed toward the design and implementation of new meth-
odologies for the asymmetric synthesis of nitrogen heterocy-
cles,4 we became interested in developing a direct and modular
approach for the enantioselective preparation of piperidines
with different substitution patterns by applying the stereo-
controlled Mannich reaction using (+)-(S,S)-pseudoephedrine as
a chiral auxiliary.5,6 We suggested that this methodology which
had been previously developed in our group could be a
successful key step with regard to the stereocontrol in the
synthesis of the target compounds (Scheme 1).
In particular, we wish to report herein our synthetic studies
toward the direct access to 2,3-disubstituted piperidines and to
3,4,5,6-tetrasubstituted piperidin-2-ones starting from the cor-
responding Mannich adducts, prepared by our previously
mentioned methodology.5 To access 2,3-disubstituted piperi-
dines, we will present two alternative approaches which involve
the use of either ring-closing metathesis or lactamization/
reduction reactions for building up the piperidine skeleton and
with the two substituents of the nal piperidine ring incorpo-
rated initially in the stereocontrolled Mannich reaction. Alter-
natively, we have also developed a more elaborated route to
form densely functionalized tetrasubstituted piperidin-2-ones,
starting from the same Mannich adducts by using a diaster-
eoselective intramolecular Michael reaction for the construc-
tion of the heterocyclic ring, in an approach which has not been
reported in the literature for the preparation of piperidines.
This second synthetic route has also allowed us to carry out
the preparation of both 3,4,5,6-tetrasubstituted and 3,4,5-
trisubstituted piperidin-2-ones as highly diastereo- and enan-
tioenriched compounds by carefully selecting the nature of the
´
´
´
Departamento de Quımica Organica II, Facultad de Ciencia y Tecnologıa, Universidad
´
del Paıs Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), P.O. Box 644, E-48080
Bilbao, Spain. E-mail: marisa.carrillo@ehu.es; joseluis.vicario@ehu.es; Fax: (+34)
946012748
† Electronic supplementary information (ESI) available: 1H and 13C-NMR spectra
of all prepared compounds. See DOI: 10.1039/c3ra45110k
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shown in Scheme 2. Our rst approach (route A) consisted of
building up the piperidine skeleton from a conveniently
substituted d-amino ester intermediate by means of a lactam
formation/reduction protocol. This d-amino ester should be
accessible from a b-amino aldehyde precursor, by simple Wittig-
type olenation followed by hydrogenation, and this compound
could be obtained starting from the corresponding Mannich
adduct, the latter being accessible through our previously
mentioned methodology which involves the use of (S,S)-
(+)-pseudoephedrine as
a chiral auxiliary. An alternative
approach to the same piperidine compounds (route B) could
also be envisaged by applying a ring-closing metathesis reaction
for the construction of the piperidine framework, for which a
conveniently functionalized N-allyl amine incorporating an
olen moiety at the correct position could be used as the key
intermediate. This intermediate should also be, in principle,
readily accessible from the same b-amino aldehyde used in the
previous synthetic route via olenation and N-alkylation.
We started our work by carrying out the Mannich reaction
between (S,S)-(+)-pseudoephedrine propionamide 1 and imine
2. Under our reported conditions, adduct 3 was isolated in an
excellent yield and as a single anti diastereoisomer with a very
high facial selectivity (Scheme 3).7 We next faced the conversion
of the b-amino amide adduct 3 into the corresponding b-amino
aldehyde, which was proposed as the key compound for the two
synthetic approaches proposed in Scheme 2. The direct
controlled reduction of the amide moiety, in order to obtain a
formyl group, by using different reducing systems was unsuc-
cessful, so we moved to an alternative procedure that involved a
hydrolysis/reduction sequence. Thus, acid hydrolysis of
b-amino amide 3 under known conditions followed by standard
borane-mediated reduction led to the formation of the g-amino
alcohol 5 in good yield aer ash column chromatography
purication and with no epimerization at any stereocentre, as
NMR analysis of the crude reaction mixture indicated. At this
point, we were also able to check the optical purity of the
obtained amino alcohol by HPLC analysis on a chiral stationary
phase under conditions previously optimized for a racemic
standard (see the ESI† for details). The next step involved the
oxidation of g-amino alcohol 5 to the target amino aldehyde,
but aer several unsuccessful attempts using various reaction
conditions we were not able to obtain the desired aldehyde due
to extensive product decomposition. In order to overcome this
stability problem attributed to the presence of a secondary
amino group, we proceeded to carry out the N-methylation of 5,
obtaining derivative 6 in an excellent yield, which was next
subjected to IBX-mediated oxidation under conditions previ-
ously optimized in our group.8 Under these conditions, a clean
reaction took place, delivering the b-amino aldehyde 7 in an
excellent yield.
Scheme
1
Asymmetric synthesis of differently substituted pyrrolidines by
applying the stereocontrolled Mannich reaction using (+)-(S,S)-pseudoephedrine
as chiral auxiliary in the key step.
Scheme
2
Two alternative retrosynthetic plans for the synthesis of
2,3-disubstituted piperidines.
reagents used in the intramolecular Michael reaction that
builds up the heterocyclic framework.
At this point, we proceeded rst to evaluate the synthetic
route which involved the formation of the piperidine ring by
lactamization/reduction, as planned in route A, shown in
Scheme 2. We therefore subjected b-amino aldehyde 7 to a
Results and discussion
Asymmetric synthesis of 2,3-disubstituted piperidines
As mentioned in the introduction, access to the target disub- Wittig olenation reaction with the suitable and commercially
stituted piperidines was planned according to two possible available Ph3P]CHCO2Et, which allowed us to obtain the cor-
approaches which are depicted in the retrosynthetic analysis responding conjugated a,b-unsaturated d-amino ester 8 in an
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excellent yield and as a single E diastereoisomer (Scheme 4). A
subsequent standard hydrogenation in the presence of 10 mol%
PtO2 delivered the d-amino ester 9. Next, we proceeded to
remove the p-methoxyphenyl group under oxidative conditions,
which proceeded smoothly and delivered directly the piper-
idinone 10 aer an intramolecular amide formation, which
took place in situ on the secondary amine intermediate aer
basication. Finally, the 2,3-disubstituted piperidine 11 was
obtained aer a reduction step using LAH in an overall yield of
54% starting from b-amino aldehyde 7 (4 steps) and of 25% if
calculated from (S,S)-(+)-pseudoephedrine propionamide 1
(9 steps). It should be pointed out that NMR analysis of the
crude reaction mixtures of all the transformations carried out
from 7 indicated that no epimerization had taken place at any
stereocentre present in these compounds. In addition, we also
measured the optical purity of the nal piperidine 11 by chiral
HPLC, under conditions optimized for a racemic standard,
observing that it had been obtained in 98% ee which matched
with the optical purity of the previous g-amino alcohol 5.
We next evaluated the second approach to piperidine 11
according to the alternative route B depicted in Scheme 2, which
involved ring construction by ring closing metathesis (Scheme 5).
We started by surveying the Wittig methylenation of b-amino
aldehyde 7 using methylenetriphenylphosphorane, which should
be generated in situ starting from the commercially available
phosphonium salt and a suitable base. However, all our attempts
were unsuccessful, which was attributed in this case to the
incompatibility of the starting b-amino aldehyde with the pres-
ence of a strongly basic reagent such as the phosphorous ylide
employed. For this reason, we moved to the Julia-Kocienski
protocol9 and therefore we proceeded to prepare the required
tetrazolyl sulfone anion as described in the literature10 and
reacted this with aldehyde 7, furnishing the target olenation
product 12 in an excellent 90% yield. Removal of the PMP group
and subsequent N-allylation reaction furnished the diene 14 in an
excellent yield. With this compound in hand, we proceeded to
carry out the ring-closing metathesis reaction under different
reaction conditions, which included the use of both rst and
second generation Grubbs catalysts. However, in all our attempts
no reaction was observed and the starting material was recovered
unchanged under all the conditions tested, which also involved
carrying out the reaction in boiling solvents and for prolonged
reaction times. We attributed this lack of reactivity to catalyst
poisoning by the tertiary amine moiety, because of its ability to
coordinate to the intermediate metal–alkylidene complex and
consequently, we decided to carry out the metathesis reaction on
the corresponding ammonium hydrochloride,11 obtained aer
treating amine 14 with excess HCl in Et2O and removal of the
volatiles. Gratifyingly, under these conditions, tetrahydropiper-
idine 15 was obtained in a 70% yield aer reaction in the pres-
ence of the second generation Grubbs catalyst in reuxing
dichloromethane. Finally, the hydrogenation of 15 furnished 2,3-
disubstitutedpiperidine 11 in a 30% overall yield from the
b-amino aldehyde 7 (5 steps) and in 13% from 1 (10 steps). In
light of these data, we concluded that our initial approach
involving the piperidine ring formation by lactamization/reduc-
tion was much more effective than this second approach.
Scheme 3 Reagents and Conditions: (i) (1) LDA, LiCl, THF, ꢀ78 ꢁC; (2) PhCH]
NPMP (2), 0 ꢁC. (ii) H2SO4 (4 M), 1,4-dioxane, 0 ꢁC to reflux. (iii) BH3–Me2S, THF, r.t.
(iv) (1) HCHO, CH3CN, r.t.; (2) NaBH4, TFA, 0 ꢁC to r.t. (v) IBX, EtOAc, reflux, 3 h.
Scheme 4 Reagents and Conditions: (i) Ph3P]CHCO2Et, CH2Cl2, r.t., 5 h. (ii) H2,
PtO2 (10 mol%), EtOAc, r.t., 1 h. (iii) (1) CAN, H2SO4 (concd.), CH3CN–H2O (3 : 1),
0
ꢁC, 90 min. (2) NaOH, r.t., 2 h. (iv) LAH, Et2O, 0 ꢁC, 1 h.
Scheme 5 Reagents and Conditions: (i) 5-methylsulfonyl-1-phenyl-1H-tetrazole,
KN(SiMe3)2, toluene, ꢀ20 ꢁC, 90 min. (ii) CAN, H2SO4 (concd.), CH3CN–H2O (3 : 1),
0
ꢁC, 90 min. (iii) CH2]CHCH2I, K2CO3, CH3CN, reflux, 4 h. (iv) (1) HCl (concd.),
Et2O, 30 min. (2) 2nd generation Grubbs cat. (5 mol%), CH2Cl2, reflux, 1 h. (v) H2,
PtO2 (10 mol%), EtOAc, r.t., 1 h.
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performed in this alternative synthesis also proceeded with no
epimerization in any of the stereogenic centres present in any of
the compounds employed. In addition, we also veried that the
nal piperidine 11 had been obtained with the same enantio-
meric excess as the one found for the b-amino aldehyde precursor
6 (98% ee).
Asymmetric synthesis of 3,4,5,6-tetrasubstituted piperidin-2-
ones
Complex and polysubstituted piperidines and piperidinones
are difficult targets to be accessible by classical methods and for
this reason we have envisaged a novel synthesis according to
retrosynthetic analysis shown in Scheme 6 in which the key step
for building up the piperidine skeleton relies on a diaster-
eoselective intramolecular Michael reaction step by using a
conveniently substituted N-acyl d-amino a,b-unsaturated ester.
This intramolecular reaction would lead to the formation of a
piperidin-2-one nal compound, together with the concomitant
generation of two additional stereocentres and therefore, suit-
able reaction conditions should be found in order to achieve the
highest stereocontrol in their formation. As it can be seen in the
following scheme, this key substrate on which the intra-
molecular Michael reaction was planned to take place can be
easily accessed from the d-amino a,b-unsaturated ester 8,
obtained previously during the synthesis of 2,3-disubstituted
piperidines and which is prepared in a diastereo- and enan-
tioselective fashion by our protocol for carrying out the Man-
nich reaction using (S,S)-(+)-pseudoephedrine as a chiral
auxiliary.5
Scheme 6 Retrosynthetic plan for the synthesis of a fully substituted piper-
idinone ring.
We started our work as depicted in Scheme 7 by removing
the PMP group from the d-amino a,b-unsaturated ester 8 using
the same reaction conditions as previously employed. Next, the
obtained secondary amine was acylated with n-butyric anhy-
dride, isolating N-butanoyl N-methyl d-amino a,b-unsaturated
ester 17a in excellent yield. Disappointingly, when this
compound was subjected to the projected intramolecular
Michael addition using different bases and conducting the
reaction at different temperatures in order to generate the
required enolate intermediate, no reaction was observed,
recovering the starting material unchanged in all cases. We
supposed that this lack of reactivity could be due to the diffi-
culties in the formation of the enolate intermediate and, in
order to verify this hypothesis, we proceeded to quench the
reaction with external highly reactive electrophiles such as MeI
or benzaldehyde, also recovering unchanged starting material.
Thus, we decided to generate the required nucleophilic species
by a halogen–lithium exchange, preparing the corresponding
a-bromo amide 18a by acylation of 16 with commercially
available 2-bromobutyric acid. Reacting this compound 18a
with n-BuLi in THF at low temperature resulted in a very fast
reaction, furnishing the desired piperidin-2-one 19 in a
moderate yield (52%) and as an 80 : 20 mixture of diastereo-
isomers, with regard to the relative conguration of the ster-
Scheme 7 Reagents and Conditions: (i) CAN, H2SO4 (concd.), CH3CN–H2O (3 : 1),
0
ꢁC, 2 h. (ii) (n-BuCO)2O, DMAP, CH2Cl2, r.t., 2 h.; (iii) 2-bromobutyric acid, DCC,
DMAP, CH2Cl2, r.t., 90 min. (iv) n-BuLi, LiCl, THF, ꢀ105 ꢁC, 5 min.
Scheme 8 Reagents and Conditions: (i) 2-bromoacetic acid, DCC, DMAP, CH2Cl2,
r.t., 90 min. (ii) n-BuLi, LiCl, THF, ꢀ105 ꢁC, 5 min. (iii) Ac2O, DMAP, CH2Cl2, r.t., 2 h.
As we did before, we also conrmed that piperidine 11 was eocentre at C3 (19 and 190). Importantly, other possible
obtained as single diastereoisomer (by NMR analysis of the crude diastereoisomers that could be eventually produced were not
mixture of 11), which indicated that all the transformations detected aer NMR analysis of the crude reaction mixture.
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clean and efficient intramolecular Michael reaction upon
treatment with sodium hydride, delivering piperidin-2-one 21
in an excellent yield (81%) and as almost diastereopure
material, as NMR analysis of the crude reaction mixture
indicated. Finally, the target trisubstituted pyrrolidin-2-one 22
was achieved by desulfonylation using Mg in MeOH as the
corresponding methyl ester.12
Conclusions
To sum up, we have demonstrated that the Mannich reaction
could be a reliable tool for the asymmetric synthesis of
nitrogen containing six-membered heterocycles such as
piperidines and piperidinones, starting from b-amino
carbonyl compounds. We have shown two efficient and
straightforward routes to access diastereo- and enantio-
merically pure piperidines, employing simple trans-
formations in an excellent overall yield and maintaining the
excellent diastereo- and enantiopurity obtained during the
Mannich reaction. Furthermore, we have accessed a poly-
substituted piperidinone core, in which two new stereogenic
centres are formed in a highly diastereoselective way,
demonstrating the ability of the preexisting stereogenic
centres to control the stereochemical outcome of this reac-
tion in a very efficient way. Importantly, these methodologies
constitute important alternatives to the classical strategies
for the construction of such heterocycles.
Scheme 9 Reagents and Conditions: (i) NaSO2Ph, DMF, r.t., 1 h. (ii) NaH, THF,
ꢀ40 ꢁC, 3 h. (iii) Mg, MeOH, 0 ꢁC to r.t., 5 h.
Moreover, the diastereoselectivity of the reaction could be
signicantly improved by incorporating LiCl as an additive
to the reaction scheme, leading to the formation of piper-
idin-2-one 19 almost as a single diastereoisomer in a 54%
yield (19/190 ratio: 92 : 8 by NMR analysis of crude reaction
mixture).
Asymmetric synthesis of 4,5,6-trisubstituted piperidin-2-ones
In light of the results obtained when trying to access to the
piperidine skeleton by an intramolecular Michael reaction, we
also decided to survey the possibility of optimizing a synthetic
Experimental section
General information
ꢁ
route to 4,5,6-trisubstituted piperidin-2-ones, by using the NMR spectra were recorded at 20–25 C, running at 300 MHz
corresponding N-bromoacetyl d-amino a,b-unsaturated ester for 1H and at 75 MHz for 13C in CDCl3 solutions and the
as a substrate for undergoing the cyclization step (Scheme 8). resonances are reported in ppm relative to tetramethylsilane,
In this context, acylation of 16 with bromoacetic acid under unless otherwise stated. The following abbreviations were
the same reaction conditions led to the formation of the used to designate the chemical shi multiplicities: s ¼ singlet,
required N-bromoacetamide 18b but, when we tested the d ¼ doublet, t ¼ triplet, m ¼ multiplet, bs ¼ broad signal. All
subsequent intramolecular Michael reaction through forma- rst-order splitting patterns were assigned on the basis of the
tion of the nucleophile via a lithium–halogen exchange, no appearance of the multiplet. Splitting patterns that could not
cyclization reaction was observed, isolating the debrominated be easily interpreted are designated as multiplet (m) or broad
N-acetyl derivative 17b, almost quantitatively. This compound signal (bs). Assignments of individual signals were carried out
could also be easily obtained from 16 in an 86% yield by using COSY, HMQC and DEPT experiments. IR spectra were
acetylation. In addition, we tried the cyclization reaction measured in the interval between 4000 and 400 cmꢀ1
,
starting from 17b, by forming the required enolate through obtained by depositing a lm on a KBr plate and only the
conventional deprotonation procedures, without any success characteristic bands are given. Mass spectra were recorded
in all our attempts.
under electron impact (EI) or chemical ionization (CI) at 70 eV.
Therefore, we modied our synthetic approach by acti- The obtained data are presented in mass units (m/z) and the
vating the Michael donor site of the starting material by values found in the brackets belong to the relative intensities,
incorporating a second electron-withdrawing group which compared to the base peak (100%). Optical rotations were
would enhance the acidity of the a-protons and hence would measured at 20 ꢁC and recorded on solution on a 1 dm length
favour the formation of the nucleophile participating in the cell using a Na lamp (589 nm) in the solvent and concentration
intramolecular Michael reaction. In particular, we decided to indicated in each case. TLC was carried out with 0.2 mm thick
introduce a sulfone moiety which, aer the cyclization step, silica gel plates and visualization was accomplished by ultra-
could be easily removed by conventional reductive cleavage violet irradiation light or by spraying with phosphomolybdic
methods (Scheme 9). Therefore, we started with the conver- acid. Flash column chromatography on silica gel was per-
sion of the previously synthesized bromoamide 18b into formed with silica gel (230–400 mesh). All solvents used in the
sulfone 20 by reaction with NaSO2Ph, sulfone 20 underwent a reactions were dried and puried according to standard
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procedures. All other reagents were used as purchased. All air-
or moisture-sensitive reactions were performed under an
argon atmosphere. The glassware was oven dried (140 ꢁC)
overnight and purged with argon prior to use. Enantiomeric
excesses (ee) were determined by HPLC under the conditions
specied in each case.
(2R,3S)-3-[N-(4-Methoxyphenyl)-N-methylamino]-2-methyl-3-
phenylpropan-1-ol (6)
Formaldehyde (1.79 mL, 22.14 mmol) was added to a solution of
alcohol 5 (1.27 g, 4.70 mmol) in CH3CN (20 mL). The reaction
was maintained stirring for 2 h at r.t. aer which water was
added to quench the reaction and it was extracted with CH2Cl2
(3 ꢂ 15 mL). The combined organic extracts were dried over
Na2SO4, ltered and the solvent removed under reduced pres-
sure, affording pure (4S,5R)-3-(4-methoxyphenyl)-5-methyl-4-
phenyl-1,3-oxazinane (1.34 g, 4.70 mmol) aer ash column
(2R,3S)-3-(4-Methoxyphenylamino)-2-methyl-3-phenylpropanoic
acid (4)
4 M H2SO4 (10 mL) was slowly added to a cooled (0 ꢁC) solution
of amide 3 (0.25 g, 0.58 mmol) in 1,4-dioxane (10 mL). The
reaction was reuxed for 6 h aer which it was cooled down to
r.t. Water (20 mL) was added and the mixture was carefully
basied to pH ¼ 4 and extracted with CH2Cl2 (3 ꢂ 20 mL). The
combined organic extracts were dried over Na2SO4, ltered and
the solvent removed under reduced pressure affording b-amino
acid 4 (0.13 g, 0.45 mmol) as a colorless oil, without further
purication. Yield: 79%. [a]2D0 ¼ ꢀ112.0 (c ¼ 1.0, CH2Cl2). IR
(neat): 1510 (C]O), 3418 (OH + NH) cmꢀ1. 1H-NMR (300 MHz,
CDCl3): d 1.10 (d, 3H, J ¼ 7.0 Hz, CH3CH), 2.75–293 (m, 1H,
CHCO), 3.68 (s, 3H, CH3O), 4.38 (d, 1H, J ¼ 9.1 Hz, CHN), 5.80–
6.50 (br, 2H, NH + OH), 6.53–6.62 (m, 2H, Carom–H), 6.63–6.73
(m, 2H, Carom–H), 7.15–7.35 (m, 5H, Carom–H). 13C-NMR (75
MHz, CDCl3): d 15.0 (CH3CH), 45.9 (CHCO), 55.6 (CHN), 63.1
(CH3O), 114.6, 116.9, 127.1, 127.7, 128.7 (Carom–H), 139.3, 140.1,
153.3 (Carom–C), 179.5 (CO). MS (EI) [m/z (rel. abundance)]: 285
(M+, 100), 212 (49), 197 (69), 168 (35), 122 (73), 91 (79), 77 (79), 58
(3). HRMS: m/z calculated for [C17H19NO3]+: 285.1365; found:
285.1387.
chromatography (hexanes–EtOAc 9 : 1). Yield: 99%. [a]D20
¼
+27.4 (c ¼ 1.0, CH2Cl2. 1H-NMR (300 MHz, CDCl3): d 0.68 (d, 3H,
J ¼ 6.7 Hz, CH3CH), 2.09–2.30 (m, 1H, CHCH3), 3.41 (dd, 1H, J ¼
11.0, 11.0 Hz, CHCHaHbO), 3.66 (s, 3H, CH3O), 3.73 (d, 1H, J ¼
9.2 Hz, CHN), 4.13 (dd, 1H, J ¼ 4.4, 11.0 Hz, CHCHaHbO), 4.40
(d, 1H, J ¼ 8.7 Hz, CHaHbN), 4.81 (d, 1H, J ¼ 8.7 Hz, CHaHbN),
6.64 (d, 2H, J ¼ 8.8 Hz, Carom–H), 6.94 (d, 2H, J ¼ 8.8 Hz, Carom
–
H), 7.06–7.32 (m, 5H, Carom–H). 13C-NMR (75 MHz, CDCl3): d
13.8 (CH3CH), 36.5 (CHCH3), 55.2 (CHNH), 70.9 (CH3O), 73.7
(CHCH2O), 87.0 (CH2N), 113.8, 126.0, 127.0, 128.0, 128.6 (Carom
–
H), 140.4, 140.6, 156.0 (Carom–C). MS (CI) [m/z (rel. abundance)]:
283 [((M + H)+, 100), 269 (16), 265 (20), 211 (32), 136 (22). HRMS:
m/z calculated for [C18H21NO2]+: 283.1572 [(M + H)+]; found:
283.1566.
Next, a solution of (4S,5R)-3-(4-methoxyphenyl)-5-methyl-4-
phenyl-1,3-oxazinane (1.34 g, 4.70 mmol) in CH2Cl2 (20 mL) was
carefully added to a cooled (0 ꢁC) suspension of NaBH4 (0.89 g,
23.60 mmol) and triuoroacetic acid (10.9 mL, 141.50 mmol).
The reaction was warmed to r.t. and maintained for 2 h aer
which it was cooled down to 0 ꢁC. The mixture was carefully
basied with NaOH 4 M to pH ¼ 14 and extracted with CH2Cl2 (3
ꢂ 20 mL). The combined organic extracts were dried over
Na2SO4, ltered and the solvent was removed under reduced
pressure affording alcohol 6 (1.20 g, 4.20 mmol) as a pure
compound aer ash column chromatography (hexanes–EtOAc
9 : 1). Yield: 88%. [a]D20 ¼ ꢀ208.3 (c ¼ 1.0, CH2Cl2). IR (neat):
3398 (OH + NH) cmꢀ1. 1H-NMR (300 MHz, CDCl3): d 0.73 (d, 3H,
J ¼ 6.7 Hz, CH3CH), 2.45 (s, 3H, CH3N), 2.56–2.77 (m, 1H,
CHCH3), 3.76 (s, 3H, CH3O), 3.84–3.97 (m, 2H, CH2O), 4.33 (d,
1H, J ¼ 11.2 Hz, CHN), 6.75–6.95 (m, 6H, Carom–H), 7.19–7.29
(m, 3H, Carom–H). 13C-NMR (75 MHz, CDCl3): d 15.2 (CH3CH),
33.1 (CHCH3), 33.4 (CH3N), 55.5 (CHN), 69.7 (CH2O), 75.6
(CH3O), 114.2, 121.0, 127.4, 127.8, 128.7 (Carom–H), 135.0, 145.1,
154.2 (Carom–C). MS (EI) [m/z (rel. abundance)]: 285 (M+, 9), 227
(18), 226 (100), 211 (12), 196 (16), 136 (7), 122 (8), 117 (5), 91 (16).
HRMS: m/z calculated for [C18H23NO2]+: 285.1729 (M+); found:
285.1718.
(2R,3S)-3-(4-Methoxyphenylamino)-2-methyl-3-phenylpropan-
1-ol (5)
Borane-dimethyl sulde complex (2.0 M in THF) (0.52 mL, 1.05
mmol) was added to a solution of b-amino acid 4 (0.10 g, 0.35
mmol) in THF (10 mL). The reaction was maintained stirring for
4 h at r.t. aer which water was added to quench the reaction
and it was extracted with CH2Cl2 (3 ꢂ 15 mL). The combined
organic extracts were dried over Na2SO4, ltered and the solvent
removed under reduced pressure affording pure g-amino
alcohol 5 (0.07 g, 0.27 mmol) as a yellowish oil aer ash
column chromatography (hexanes–EtOAc 6 : 4). Yield: 80% (dr:
>95 : 5). The ee was determined by HPLC using Chiralpak IA
column, [n-hexane–i-PrOH (95 : 5)]; ow rate 1.00 mL minꢀ1
;
smajor (2R,3S) isomer ¼ 24.40 min; sminor (2S,3R) isomer ¼ 23.05
min (98% ee). [a]2D0 ¼ ꢀ67.8 (c ¼ 1.0, CH2Cl2). IR (neat): 3376
(OH + NH) cmꢀ1. 1H-NMR (300 MHz, CDCl3): d 0.82 (d, 3H, J ¼
6.9 Hz, CH3CH), 2.00–2.23 (m, 1H, CHCH3), 3.60–3.98 (m, 5H,
CH3O + CH2OH), 4.20 (d, 1H, J ¼ 7.8 Hz, CHN), 6.50–6.60 (m,
2H, Carom–H), 6.64–6.73 (m, 2H, Carom–H), 7.15–7.35 (m, 5H,
(2R,3S)-3-[N-(4-Methoxyphenyl)-N-methylamino]-2-methyl-3-
phenylpropanal (7)
C
arom–H). 13C-NMR (75 MHz, CDCl3): d 14.7 (CH3CH), 41.2
(CHCH2), 55.7 (CHN), 65.2 (CH3O), 67.4 (CH2O), 114.7, 116.3, IBX (1.35 g, 4.84 mmol) was added to a solution of alcohol 6
127.0, 127.1, 128.5 (Carom–H), 142.3, 143.1, 153.0 (Carom–C). MS (0.46 g, 1.61 mmol) in EtOAc (20 mL) and the reaction mixture
(EI) [m/z (rel. abundance)]: 271 (M+, 88), 213 (100), 212 (94), 197 was reuxed. Aer 2 h it was cooled to r.t., ltered and the
(77), 168 (67), 134 (79), 108 (55), 91 (97), 77 (40), 57 (51). HRMS: solvent removed under reduced pressure. The crude mixture
m/z calculated for [C17H21NO2]+: 271.1572 (M+); found: was puried by ash column chromatography (hexanes–EtOAc
271.1566.
9 : 1) affording pure product 6 (0.37 g, 1.30 mmol) as a colorless
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oil. Yield: 81%. [a]2D0 ¼ ꢀ145.6 (c ¼ 1.0, CH2Cl2). IR (neat): 1507 127.9, 128.1 (Carom–H), 137.9, 145.5, 152.3 (Carom–C), 173.9 (CO).
(C]O) cmꢀ1. 1H-NMR (300 MHz, CDCl3): d 1.01 (d, 3H, J ¼ 6.8 MS (EI) [m/z (rel. abundance)]: 355 (M+, 5), 226 (100), 196 (11), 83
Hz, CH3CH), 2.51 (s, 3H, CH3N), 3.17–3.35 (m, 1H, CHCH3), 3.76 (12). HRMS: m/z calculated for [C22H29NO3]+: 355.2147 (M+);
(s, 3H, CH3O), 4.79 (d, 1H, J ¼ 11.3 Hz, CHN), 6.79–6.84 (m, 4H, found: 355.2139.
C
arom–H), 6.98–7.06 (m, 2H, Carom–H), 7.20–7.35 (m, 3H, Carom–
H), 9.78 (d, 1H, J ¼ 4.4 Hz, CHO). 13C-NMR (75 MHz, CDCl3): d
12.6 (CH3CH), 33.0 (CH3N), 46.6 (CHCH3), 55.5 (CHN), 68.9
(CH3O), 114.3, 119.7, 127.7, 128.2 (Carom–H), 134.7, 144.6, 153.8
(Carom–C), 203.4 (CHO). MS (EI) [m/z (rel. abundance)]: 283 (M+,
9), 265 (11), 226 (24), 147 (100), 137 (84), 129 (15), 123 (30), 107
(13). HRMS: m/z calculated for [C18H21NO2]+: 283.1572 (M+);
found: 283.1581.
(5S,6S)-1,5-Dimethyl-6-phenylpiperidin-2-one (10)
Cerium ammonium nitrate (0.46 g, 0.85 mmol) and H2SO4
(60 mL) were added to a cooled (0 ꢁC) solution of 9 (0.10 g, 0.28
mmol) in a mixture of CH3CN–H2O 3 : 1 (20 mL) and it was
stirred for 90 minutes at this temperature, aer which NaOH
4 M was added until pH ¼ 12. Aer stirring the biphasic mixture
at r.t. for further 2 h, it was extracted with CH2Cl2 (3 ꢂ 15 mL).
The combined organic layers were collected, dried over anhy-
drous Na2SO4, ltered and the solvent removed under reduced
(4S,5S,E)-Ethyl 5-[N-(4-methoxyphenyl)-N-methylamino]-4-
methyl-5-phenylpent-2-enoate (8)
Carbethoxymethylene triphenylphosphorane (0.54 g, 1.69 pressure. Compound 10 (0.06 g, 0.28 mmol) was obtained as a
mmol) was added to a solution of aldehyde 7 (0.09 g, 0.34 mmol) colorless oil aer ash column chromatography purication
in CH2Cl2 (20 mL). The reaction was maintained stirring for 5 h (hexanes–EtOAc 2 : 8). Yield: 99%. [a]2D0 ¼ ꢀ11.7 (c ¼ 1.0,
at r.t. aer which water was added to quench the reaction and it CH2Cl2). IR (neat): 1631 (C]O) cmꢀ1 1H-NMR (300 MHz,
.
was extracted with CH2Cl2 (3 ꢂ 15 mL). The combined organic CDCl3): d 0.95 (d, 3H, J ¼ 6.6 Hz, CH3CH), 1.40–1.60 (m, 1H,
extracts were dried over Na2SO4, ltered and the solvent CHCH3), 1.72–1.95 (m, 2H, CH2CH), 2.35–2.60 (m, 2H, CH2CO),
removed under reduced pressure affording pure ester 8 (0.10 g, 2.64 (s, 3H, CH3N), 3.91 (d, 1H, J ¼ 7.3 Hz, CHN), 7.05–7.20 (m,
0.28 mmol) aer ash column chromatography (hexanes– 2H, Carom–H), 7.21–7.40 (m, 3H, Carom–H). 13C-NMR (75 MHz,
EtOAc 8 : 2). Yield: 85% (E–Z ¼ >15 : 1). [a]2D0 ¼ ꢀ98.3 (c ¼ 1.0, CDCl3): d 18.4 (CH3CH), 26.6 (CH2CH), 31.0 (CH2CO), 33.6
CH2Cl2). IR (neat): 1716 (C]O) cmꢀ1 1H-NMR (300 MHz, (CHCH3), 37.0 (CH3N), 71.1 (CHN), 127.0, 127.7, 128.7 (Carom
. –
CDCl3): d 0.99 (d, 3H, J ¼ 6.6 Hz, CH3CH), 1.28 (t, 3H, J ¼ 7.1 Hz, H), 141.1 (Carom–C), 170.8 (CO). MS (EI) [m/z (rel. abundance)]:
CH3CH2), 2.52 (s, 3H, CH3N), 3.13–3.32 (m, 1H, CHCH3), 3.75 203 (M+, 3), 118 (3), 87 (8), 85 (55), 83 (100), 83 (3). HRMS: m/z
(s, 3H, CH3O), 4.18 (q, 2H, J ¼ 7.1 Hz, CH2CH3), 4.48 (d, 1H, J ¼ calculated for [C13H17NO]+: 203.1310 (M+); found: 203.1314.
10.7 Hz, CHN), 5.95 (dd, 1H, J ¼ 0.84, 14.8 Hz, CH]CHCO),
6.74–6.84 (m, 4H, Carom–H), 7.05–7.35 (m, 6H, Carom–H +
CHCO). 13C-NMR (75 MHz, CDCl3): d 14.3 (CH3CH), 17.9
(1S,2S)-N,2-Dimethyl-N-(4-methoxyphenyl)-1-phenylbut-3-en-
(CH3CH2), 32.8 (CH3N), 37.5 (CHCH3), 55.6 (CHN), 60.2
(CH2CH3), 71.2 (CH3O), 114.3 (CH]CHCO), 118.5 (CHCO),
1-amine (12)
Potassium hexamethyldisilazide (0.5 M in toluene, 3.3 mL, 1.65
mmol) was added dropwise for 30 minutes to a cooled (ꢀ20 ꢁC)
solution of 7 (0.13 g, 0.46 mmol) and sulfone (0.14 g, 0.63
mmol)9 in THF (10 mL) and it was stirred for 1 h at this
temperature, aer which H2O (20 mL) was added. The mixture
was extracted with EtOAc (3 ꢂ 15 mL) and the combined
organic layers were collected, dried over anhydrous Na2SO4,
ltered and the solvent removed under reduced pressure.
120.7, 127.3, 128.0, 128.1 (Carom–H), 136.8, 145.2, 152.9 (Carom
–
C), 166.6 (CO). MS (EI) [m/z (rel. abundance)]: 353 (M+, 2), 227
(14), 226 (100), 196 (14), 91 (2). HRMS: m/z calculated for
[C22H27NO3]+: 353.1991 (M+); found: 353.1985.
(4S,5S)-Ethyl 5-[N-(4-methoxyphenyl)-N-methylamino]-4-
methyl-5-phenylpentanoate (9)
A solution of ester 8 (0.10 g, 0.28 mmol) in EtOAc (10 mL) was Compound 12 (0.11 g, 0.41 mmol) was obtained as a colorless
stirred in the presence of PtO2 (10 mg, 10 mol%) under a H2 oil aer ash column chromatography purication (hexanes–
atmosphere (balloon) at r.t. for 1 h. Next, the mixture was EtOAc 9.5 : 0.5). Yield: 90%. [a]2D0 ¼ ꢀ205.7 (c ¼ 1.0, CH2Cl2).
ltered and the solvent removed under reduced pressure. 1H-NMR (300 MHz, CDCl3): d 0.98 (d, 3H, J ¼ 6.6 Hz, CH3CH),
Compound 9 (0.09 g, 0.26 mmol) was obtained as a colorless oil 2.59 (s, 3H, CH3N), 3.00–3.17 (m, 1H, CHCH3), 3.77 (s, 3H,
aer ash column chromatography purication (hexanes– CH3O), 4.47 (d, 1H, J ¼ 10.7 Hz, CHN), 5.07 (d, 1H, Jcis ¼ 10.3 Hz,
EtOAc 9 : 1). Yield: 92%. [a]2D0 ¼ ꢀ130.4 (c ¼ 1.0, CH2Cl2). IR CHcis
trans]CH), 5.19 (d, 1H, Jtrans ¼ 17.2 Hz, CHcisHtrans]CH),
H
(neat): 1639 (C]O) cmꢀ1. 1H-NMR (300 MHz, CDCl3): d 0.83 (d, 6.05 (ddd, 1H, J ¼ 7.7, 10.3, 17.2 Hz, CH2]CH), 6.75–6.87 (m,
3H, J ¼ 6.5 Hz, CH3CH), 1.27 (t, 3H, J ¼ 7.1 Hz, CH3CH2), 1.42– 4H, Carom–H), 7.10–7.19 (m, 2H, Carom–H), 7.20–7.34 (m, 3H,
1.60 (m, 1H, CHCH3), 2.22–2.54 (m, 4H, CH2CH2), 2.54 (s, 3H,
C
arom–H). 13C-NMR (75 MHz, CDCl3): d 18.5 (CH3CH), 32.4
CH3N), 3.76 (s, 3H, CH3O), 4.15 (q, 2H, J ¼ 7.1 Hz, CH2CH3), 4.30 (CH3N), 38.5 (CHCH3), 55.6 (CHN), 70.6 (CH3O), 113.8 (CH2),
(d, 1H, J ¼ 10.6 Hz, CHN), 6.70–6.86 (m, 4H, Carom–H), 7.00–7.10 114.4 (CH2CH), 117.0, 127.0, 128.0, 128.1 (Carom–H), 138.0
(m, 2H, Carom–H), 7.15–7.30 (m, 3H, Carom–H). 13C-NMR (75 (Carom–C), 142.5 (Carom–H), 145.4, 152.2 (Carom–C). MS (EI) [m/z
MHz, CDCl3):
d
14.3 (CH3CH), 17.1 (CH3CH2), 29.0 (rel. abundance)]: 281 (M+, 2), 226 (100), 211 (14), 196 (19), 167
(CH2CH2CO), 32.0 (CH2CO), 32.4 (CH3N), 55.6 (CHN), 55.6 (4), 129 (4), 122 (4). HRMS: m/z calculated for [C19H23NO]+:
(CHCH3), 60.3 (CH2CH3), 71.2 (CH3O), 114.4, 117.5, 126.9, 281.1780 (M+); found: 281.1792.
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amine hydrochloride. A solution of this adduct and second
generation Grubbs catalyst (14 mg, 5 mol%) in dry CH2Cl2
(30 mL) was reuxed for 1 h. Next, the mixture was warmed
and basied carefully with NaOH 4 M until pH ¼ 12. The
mixture was extracted with CH2Cl2 (3 ꢂ 15 mL) and the
combined organic layers were collected, dried over anhy-
drous Na2SO4, ltered and the solvent removed under
reduced pressure. Piperidine 14 (0.05 g, 0.26 mmol) was
obtained as a colorless oil aer ash column chromatog-
raphy purication (EtOAc). Yield: 70%. [a]2D0 ¼ ꢀ98.5 (c ¼ 1.0,
CH2Cl2). 1H-NMR (300 MHz, CDCl3): d 0.75 (d, 3H, J ¼ 7.0 Hz,
CH3CH), 2.00 (s, 3H, CH3N), 2.40–2.60 (m, 1H, CHCH3), 2.68
(d, 1H, J ¼ 8.9 Hz, CHN), 2.79–2.92 (m, 1H, CHaHbN), 3.30–
(1S,2S)-N,2-Dimethyl-1-phenylbut-3-en-1-amine (13)
Cerium ammonium nitrate (0.70 g, 1.24 mmol) and H2SO4 (77
ꢁ
mL) were added to a cooled (0 C) solution of 12 (0.12 g, 0.41
mmol) in a mixture of CH3CN–H2O 3 : 1 (20 mL) and it was
stirred for 90 minutes at this temperature, aer which NaOH 4
M was added until pH ¼ 12. Aer stirring the biphasic mixture
at r.t. for further 2 h, it was extracted with CH2Cl2 (3 ꢂ 15 mL).
The combined organic layers were collected, dried over anhy-
drous Na2SO4, ltered and the solvent was removed under
reduced pressure. Pure compound 13 (0.06 g, 0.33 mmol) was
obtained as a yellowish oil without further purication. Yield:
82%. 1H-NMR (300 MHz, CDCl3): d 0.78 (d, 3H, J ¼ 6.8 Hz,
CH3CH), 1.60–2.00 (bs, 1H, NH), 2.17 (s, 3H, CH3N), 2.26–2.45
(m, 1H, CHCH3), 3.13 (d, 1H, J ¼ 8.9 Hz, CHN), 5.07 (dd, 1H, J ¼
10.1, 1.6 Hz, CHcisHtrans), 5.16 (dd, 1H, J ¼ 17.1, 1.1 Hz,
3.44 (m, 1H, CHaHbN), 5.60–5.80 (m, 2H, CHCH2N
+
CHCHCH3), 7.20–7.40 (m, 5H, Carom–H). 13C-NMR (75 MHz,
CDCl3): d 18.4 (CH3CH), 38.6 (CH3N), 43.7 (CHCH3), 55.9
(CH2N), 74.0 (CHN), 123.8 (CHCHCH3), 127.2 (CHCH2N),
128.3, 128.6, 131.7 (Carom–H), 142.2 (Carom–C). MS (EI) [m/z
(rel. abundance)]: 187 (M+, 27), 172 (11), 168 (7), 120 (29), 118
(100), 108 (6), 91 (9), 77 (6), 68 (8). HRMS: m/z calculated for
[C13H17N]+: 187.1361 (M+); found: 187.1361.
CHcisHtrans), 5.71 (ddd, 1H, CH2]CH), 7.18–7.38 (m, 5H, Carom
–
H). 13C-NMR (75 MHz, CDCl3): d 17.9 (CH3CH), 34.7 (CH3N),
45.6 (CHCH3), 70.1 (CHN), 115.9 (CH2), 127.1, 128.1, 128.2
(Carom–H), 142.2 (Carom–C), 142.3 (CH2CH). MS (CI) [m/z (rel.
abundance)]: 176 [(M + H)+, 18), 174 (23), 145 (62), 121 (13), 120
(100), 98 (5). HRMS: m/z calculated for [C12H18N]+: 176.1439
[(M + H)+]; found: 176.1444.
(2S,3S)-1,3-Dimethyl-2-phenylpiperidine (11)
A approach: LAH (0.05 g, 1.30 mol) was added to a cooled (0 ꢁC)
solution of 10 (0.05 g, 0.26 mmol) in Et2O (10 mL). The mixture
was stirred for 90 minutes at this temperature, aer which H2O
(10 mL) was added to quench the reaction. The mixture was
extracted with CH2Cl2 (3 ꢂ 15 mL) and the combined organic
layers were collected, dried over anhydrous Na2SO4, ltered and
the solvent removed under reduced pressure. Piperidine 11
(0.04 g, 0.18 mmol) was obtained as a colorless oil aer ash
column chromatography purication (hexanes–EtOAc 1 : 9).
Yield: 70%. The ee was determined by HPLC using a Chiralcel
OD column, (n-hexane); ow rate 0.50 mL minꢀ1; smajor (2S,3S)
isomer ¼ 11.72 min; sminor (2R,3R) isomer ¼ 10.48 min (98% ee).
[a]2D0 ¼ ꢀ99.6 (c ¼ 1.0, CH2Cl2).
(1S,2S)-N-Allyl-N,2-dimethyl-1-phenylbut-3-en-1-amine (14)
A solution of 13 (0.06 g, 0.33 mmol) in dry CH3CN (10 mL) was
added to a suspension of K2CO3 (0.15 g, 1.08 mmol) in the same
solvent (10 mL) and the mixture was reuxed for 2 h, aer which
allyl iodide (0.12 mL, 1.35 mmol) was added at once. Reuxing
was maintained for further 2 h and next the reaction was cooled
down to r.t. and diluted with water (20 mL). The mixture was
extracted with CH2Cl2 (3 ꢂ 15 mL) and the combined organic
layers were collected, dried over anhydrous Na2SO4, ltered and
the solvent removed under reduced pressure. Compound 14
(0.05 g, 0.21 mmol) was obtained as a colorless oil aer ash
column chromatography purication (hexanes–EtOAc 9.5 : 0.5)
isolating it as a colorless oil. Yield: 64%. [a]2D0 ¼ ꢀ26.6 (c ¼ 1.0,
1
B approach: A solution of the piperidine 15 (0.04 g,
0.23 mmol) in EtOAc (10 mL) was stirred in the presence of PtO2
(10 mg, 10 mol%) under a H2 atmosphere (balloon) at r.t. for
90 minutes. Next, the mixture was ltered and the solvent was
removed under reduced pressure. Compound 11 (0.04 g, 0.21
mmol) was obtained as a colorless oil aer ash column chro-
matography purication (hexanes–EtOAc 1 : 9). Yield: 90%. The
ee was determined by HPLC using a Chiralcel OD column,
(n-hexane); ow rate 0.50 mL minꢀ1; smajor (2S,3S) isomer ¼
CH2Cl2). H-NMR (300 MHz, CDCl3): d 0.82 (d, 3H, J ¼ 6.7 Hz,
CH3CH), 2.12 (s, 3H, CH3N), 2.70 (dd, 1H, J ¼ 13.7, 7.6 Hz,
CHaHbN), 2.76–2.95 (m, 1H, CHCH3), 3.10 (dd, 1H, J ¼ 13.7, 5.0
Hz, CHaHbN), 3.37 (d, 1H, J ¼ 9.8 Hz, CHN), 4.98–5.22 (m, 4H, 2
ꢂ CH2]CH + CH2]CH), 5.70–6.00 (m, 2H, CH2]CH + CH2]
CH), 7.12–7.22 (m, 2H, Carom–H), 7.23–7.42 (m, 3H, Carom–H).
13C-NMR (75 MHz, CDCl3): d 17.7 (CH3CH), 37.8 (CH3N), 39.1
(CHCH3), 56.8 (CH2N), 72.4 (CHN), 112.9 (CH2]CH), 116.7
(CH2]CH), 126.9, 127.7, 129.3 (Carom–H), 136.7 (Carom–C),
143.4 (CH2]CH), 136.7 (CH2]CH). MS (CI) [m/z (rel. abun-
dance)]: 160 (M+ ꢀ C4H8, 90), 125 (5), 117 (13), 84 (100), 71 (19),
57 (21). HRMS: m/z calculated for [C11H14N]+: 160.1126 (M+ ꢀ
C4H8); found: 160.1134.
11.72 min; sminor (2R,3R) isomer ¼ 10.48 min (98% ee). [a]D20
ꢀ105.4 (c ¼ 0.5, CH2Cl2).
¼
1H-NMR (300 MHz, CDCl3): d 0.56 (d, 3H, J ¼ 6.7 Hz, CH3CH),
1.00–1.19 (m, 1H, CHaHbCH), 1.62–1.89 (m, 4H, CHaHbCH +
CH2CH2N + CHCH3), 1.93 (s, 3H, CH3N), 2.02–2.17 (m, 1H,
CHaHbN), 2.34 (d, 1H, J ¼ 9.7 Hz, CHN), 2.95–3.08 (m, 1H,
CHaHbN), 7.10–7.50 (m, 5H, Carom–H). 13C-NMR (75 MHz,
(2S,3S)-1,3-Dimethyl-2-phenyl-1,2,3,6-tetrahydropyridine (15)
HCl concd. (0.1 mL) was added to a cooled (0 ꢁC) solution of 14 CDCl3): d 19.4 (CH3CH), 25.7 (CH2CH2N), 33.7 (CH2CH), 37.8
(0.08 g, 0.37 mmol) in Et2O (5 mL) and the mixture was stirred at (CHCH3), 44.8 (CH3N), 57.5 (CH2N), 78.0 (CHN), 126.9, 128.2,
this temperature for 30 minutes aer which the solvent was 128.2 (Carom–H), 143.0 (Carom–C). MS (EI) [m/z (rel. abundance)]:
removed under reduced pressure obtaining the corresponding 189 (M+, 27), 174 (16), 146 (41), 132 (23), 118 (100), 112 (80), 91
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(26), 77 (7), 65 (3). HRMS: m/z calculated for [C13H19N]+: 149.2*, 150.7 (CH]CHCO), 165.9*, 166.2 (COO), 172.6*, 173.2
189.1517 (M+); found: 189.1523.
(CON). MS (CI) [m/z (rel. abundance)]: 318 [(M + H)+, 71], 272
(22), 245 (20), 217 (100), 202 (38), 190 (97), 171 (11), 143 (13),
120 (44). HRMS: m/z calculated for [C19H28NO3]+: 318.2076
[(M + H)+]; found: 318.2069.
(4S,5S,E)-Ethyl 4-methyl-5-methylamino-5-phenylpent-2-
enoate (16)
Cerium ammonium nitrate (3.68 g, 6.71 mmol) and H2SO4 (100
mL) were added to a cooled (0 ꢁC) solution of 8 (0.79 g, 2.24
mmol) in a mixture of CH3CN–H2O 3 : 1 (40 mL) and it was
(4S,5S,E)-Ethyl 4-methyl-5-(N-methylacetamido)-5-
phenylpent-2-enoate (17b)
stirred for 90 minutes at this temperature, aer which NaOH Ac2O (0.24 mL, 0.23 mmol) was added to a solution of 16 (0.51 g,
4 M (10 mL) was added in order to basify it. Aer stirring the 2.06 mmol) and DMAP (13 mg, 0.1 mmol) in dry CH2Cl2 (10 mL)
biphasic mixture at r.t. for a further 2 h, it was extracted with at r.t. Aer stirring at this temperature for 2 h, water (10 mL)
EtOAc (3 ꢂ 15 mL). The combined organic layers were collected, was added and the mixture was extracted with CH2Cl2 (3 ꢂ 15
dried over anhydrous Na2SO4, ltered and the solvent removed mL). The combined organic layers were collected, dried over
under reduced pressure. Pure compound 16 (0.51 g, 2.06 mmol) anhydrous Na2SO4, ltered and the solvent removed under
was obtained as a yellowish oil, without any purication. Yield: reduced pressure. Compound 17b (0.53 g, 1.84 mmol) was
93%. [a]2D0 ¼ ꢀ103.6 (c ¼ 1.0, CH2Cl2). IR (neat): 1714 (C]O) obtained as a colorless oil aer ash column chromatography
cmꢀ1
.
1H-NMR (300 MHz, CDCl3): d 0.82 (d, 3H, J ¼ 6.8 Hz, purication (hexanes–EtOAc 6 : 4). Yield: 89%. [a]D20 ¼ ꢀ158.3
CH3CH), 1.29 (t, 3H, J ¼ 7.1 Hz, CH3CH2), 1.50–1.58 (bs, 1H, (c ¼ 1.0, CH2Cl2). IR (neat): 1645 (C]O), 1716 (C]O) cmꢀ1. 1H-
NH), 2.17 (s, 3H, CH3N), 2.45–2.62 (m, 1H, CHCH3), 3.29 (d, 1H, NMR (300 MHz, CDCl3): d (5 : 1 rotamer ratio; * indicates minor
J ¼ 8.6 Hz, CHN), 4.20 (q, 2H, J ¼ 7.1 Hz, CH2), 5.91 (d, 1H, J ¼ rotamer signals) 0.99 (d, 3H, J ¼ 6.6 Hz, CH3CH), 1.25 (t, 3H, J ¼
15.6 Hz, CHCO), 6.91 (dd, 1H, J ¼ 9.1, 15.6 Hz, CH]CHCO), 7.1 Hz, CH3CH2), 1.96 (s, 3H, CH3CO), 2.03* (s, 3H, CH3CO),
7.20–7.38 (m, 5H, Carom–H). 13C-NMR (75 MHz, CDCl3): d 14.2 2.64 (s, 3H, CH3N), 2.67* (s, 3H, CH3N), 3.00–3.30 (m, 1H,
(CH3CH), 17.2 (CH3CH2), 34.6 (CH3N), 43.9 (CHCH3), 60.3 CHCH3), 4.15 (q, 2H, J ¼ 7.1 Hz, CH2), 5.77 (d, 1H, J ¼ 11.4 Hz,
(CH2), 69.8 (CHN), 122.2 (CHCO), 127.3, 128.0, 128.3 (Carom–H), CHN), 5.89 (d, 1H, J ¼ 15.6 Hz, CHCO), 5.92* (d, 1H, J ¼ 15.5 Hz,
141.4 (Carom–C), 151.8 (CH]CHCO), 166.5 (CO). MS (CI) [m/z CHCO), 6.87 (dd, 1H, J ¼ 9.1, 15.6 Hz, CH]CHCO), 7.17–7.42
(rel. abundance)]: 248 [(M + H)+, 20], 217 (5), 202 (4), 143 (22), (m, 5H, Carom–H). 13C-NMR (75 MHz, CDCl3): d (5 : 1 rotamer
120 (100), 101 (2). HRMS: m/z calculated for [C15H22NO2]+: ratio; * indicates minor rotamer signals) 14.2 (CH3CH), 17.9*,
248.1651 [(M + H)+]; found: 248.1649.
18.0 (CH3CH2O), 22.0, 22.2* (CH3CO), 27.8*, 30.4 (CH3N), 36.7,
37.3* (CHCH3), 59.4, 66.2* (CHN), 60.3, 60.5* (CH2), 121.6,
122.4* (CHCO), 127.8, 127.9*, 128.3*, 128.5, 128.6, 128.9*
(Carom–H), 137.0*, 137.5 (Carom–C), 149.0*, 150.5 (CH]CHCO),
165.9*, 166.2 (COO), 170.1*, 170.8 (CON). MS (CI) [m/z (rel.
abundance)]: 290 [(M + H)+, 31], 245 (20), 217 (100), 202 (44), 171
(15), 162 (64), 143 (15), 120 (27), 74 (3). HRMS: m/z calculated for
[C17H24NO3]+: 290.1756 [(M + H)+]; found: 290.1767.
(4S,5S,E)-Ethyl 4-methyl-5-(N-methylbutyramido)-5-
phenylpent-2-enoate (17a)
Butyric anhydride (0.10 mL, 0.64 mmol) was added to a solution
of 16 (0.13 g, 0.53 mmol) and DMAP (3.3 mg, 0.02 mmol) in dry
CH2Cl2 (10 mL) at r.t. Aer stirring at this temperature for 2 h,
water (10 mL) was added and the mixture was extracted with
CH2Cl2 (3 ꢂ 15 mL). The combined organic layers were
collected, dried over anhydrous Na2SO4, ltered and the solvent
removed under reduced pressure. Compound 17a (0.17 g, 0.52
(4S,5S,E)-Ethyl 5-(2-bromo-N-methylbutyramido)-4-methyl-5-
phenylpent-2-enoate (18a)
mmol) was obtained as a colorless oil aer ash column chro- DCC (1.23 g, 5.94 mmol) and 2-bromobutyric acid (0.63 mL,
matography purication (hexanes–EtOAc 7 : 3). Yield: 98%. 5.94 mmol) were added to a solution of 16 (0.16 g, 0.66 mmol)
[a]2D0 ¼ ꢀ149.4 (c ¼ 1.0, CH2Cl2). IR (neat): 1637 (C]O), 1718 and DMAP (4 mg, 0.03 mmol) in dry CH2Cl2 (10 mL) at r.t. Aer
(C]O) cmꢀ1. 1H-NMR (300 MHz, CDCl3): d (8 : 1 rotamer ratio; stirring at this temperature for 90 minutes, water (10 mL) was
* indicates minor rotamer signals) 0.88 (t, 3H, J ¼ 7.4 Hz, added and the mixture was ltered and extracted with CH2Cl2
CH3CH2CH2), 0.95* (t, 3H, J ¼ 7.4 Hz, CH3CH2CH2), 1.01 (d, 3H, (3 ꢂ 15 mL). The combined organic layers were washed with a
J ¼ 6.6 Hz, CH3CH), 1.26 (t, 3H, J ¼ 7.1 Hz, CH3CH2O), 1.50–1.72 saturated NaHCO3 solution (10 mL) and H2O (10 mL),
(m, 2H, CH2CH2CO), 2.10–2.29 (m, 2H, CH2CO), 2.30–2.37* (m, collected, dried over anhydrous Na2SO4, ltered and the
2H, CH2CO), 2.64, 2.70* (s, 3H, CH3N), 3.00–3.24 (m, 1H, solvent removed under reduced pressure. Compound 18a
CHCH3), 4.15 (q, 2H, J ¼ 7.1 Hz, CH2O), 5.83 (d, 1H, J ¼ 11.4 Hz, (0.26 g, 0.65 mmol) was obtained as a yellowish oil aer ash
CHN), 5.89 (d, 1H, J ¼ 15.6 Hz, CHCO), 6.87 (dd, 1H, J ¼ 9.2, 15.6 column chromatography purication (hexanes–EtOAc 9 : 1).
Hz, CH]CHCO), 7.19–7.44 (m, 5H,
C
arom–H). 13C-NMR Yield: 98% (dr: >95 : 5). IR (neat): 1649 (C]O), 1718 (C]O)
1H-NMR (300 MHz, CDCl3): d (20 : 1 rotamer ratio; *
(75 MHz, CDCl3): d (8 : 1 rotamer ratio; * indicates minor cmꢀ1
.
rotamer signals) 13.6*, 13.8 (CH3CH2CH2), 14.1*, 14.2 (CH3CH), indicates minor rotamer signals) 0.94 (t, 3H, J ¼ 7.3 Hz,
17.8*, 18.0 (CH3CH2O), 18.3*, 18.5 (CH2CH2CO), 28.0*, 29.7 CH3CH2CH), 1.10 (d, 3H, J ¼ 6.5 Hz, CH3CH), 1.28 (t, 3H, J ¼
(CH3N), 35.7, 35.9* (CH2CO), 36.8, 36.9* (CHCH3), 59.3 (CHN), 7.1 Hz, CH3CH2O), 1.95–2.06 (m, 1H, CHaHbCH), 2.19–2.31 (m,
60.3, 60.5* (OCH2CH3), 67.0* (CHN), 121.6, 122.4* (CHCO), 1H, CHaHbCH), 2.72 (s, 3H, CH3N), 2.95* (s, 3H, CH3N), 3.10–
127.7, 128.0*, 128.6, 128.9* (Carom–H), 137.2*, 137.6 (Carom–C), 3.25 (m, 1H, CHCH3), 4.10–4.23 (m, 3H, CHBr + OCH2), 5.85 (d,
25808 | RSC Adv., 2013, 3, 25800–25811
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1H, J ¼ 11.4 Hz, CHN), 5.93 (d, 1H, J ¼ 15.6 Hz, CHCOO), 6.89 92 : 8). [a]2D0 ¼ +41.3 (c ¼ 1.0, CH2Cl2). IR (neat): 1637 (C]O),
1
(dd, 1H, J ¼ 15.6, 9.3 Hz, CH]CHCO), 7.26–7.42 (m, 5H, 1734 (C]O) cmꢀ1. H-NMR (300 MHz, CDCl3): d (92 : 8 dia-
C
arom–H). 13C-NMR (75 MHz, CDCl3): d 12.1 (CH3CH2CH), 14.2 stereoisomer ratio;
* indicates minor diastereoisomer
(CH3CH), 18.0 (CH3CH2O), 28.4 (CH2CH), 29.6 (CH3N), 36.6 signals) 0.85* (d, 3H, J ¼ 6.4 Hz, CH3CH), 0.97 (d, 3H, J ¼ 6.9
(CHCH3), 45.4 (CHBr), 60.0 (CHN), 60.3 (CH2O), 121.8 Hz, CH3CH), 1.02 (t, 3H, J ¼ 7.4 Hz, CH3CH2CH), 1.15 (t, 3H,
(CHCOO), 128.0, 128.6, 128.7 (Carom–H), 136.5 (Carom–C), J ¼ 7.1 Hz, CH3CH2O), 1.22* (t, 3H, J ¼ 7.1 Hz, CH3CH2O),
150.3 (CH]CHCO), 166.0 (COO), 168.8 (CON). MS (CI) [m/z 1.75–1.99 (m, 2H, CH3CH2CH), 2.13–2.22 (m, 1H, CHCH3),
(rel. abundance)]: 396 [(M + H)+, 11], 350 (13), 316 (15), 270 2.23–2.40 (m, 4H, CH2CO + CHCHCON), 2.58* (s, 3H, CH3N),
(42), 245 (16), 217 (100), 202 (33), 171 (11), 143 (13), 120 (17). 2.72 (s, 3H, CH3N), 3.64–3.74* (m, 1H, CHaHbO), 3.78* (d, 1H,
HRMS: m/z calculated for [C19H27NO3Br]+: 396.1174 [(M + H)+]; J ¼ 9.7 Hz, CHN), 4.00 (d, 1H, J ¼ 6.8 Hz, CHN), 4.02–4.10 (m,
found: 396.1183.
2H, CH2O), 4.11–4.19* (m, 1H, CHaHbO), 7.08–7.15 (m, 2H,
C
C
arom–H), 7.15–7.19* (m, 2H, Carom–H), 7.25–7.31* (m, 3H,
arom–H), 7.32–7.39 (m, 3H, Carom–H). 13C-NMR (75 MHz,
(4S,5S,E)-Ethyl 5-(2-bromo-N-methylacetamido)-4-methyl-5-
CDCl3): d (92 : 8 diastereoisomer ratio; * indicates minor
diastereoisomer signals) 11.5, 13.5* (CH3CH2CH), 14.1, 14.2*
(CH3CH2O), 14.7, 15.8* (CH3CH), 21.3*, 23.7 (CH2CHCO),
32.9*, 33.3 (CHCH2CO), 34.1 (CH3N), 34.5 (CH2CO), 35.5*
(CH3N), 35.6 (CHCH3), 37.4* (CH2CO), 38.2* (CHCH3), 46.4
(CHCO), 60.5, 60.7* (OCH2CH3), 68.8, 71.6* (CHN), 126.8,
127.6*, 127.8, 127.9*, 128.7, 128.8* (Carom–H), 140.7, 141.2*
(Carom–C), 172.2 (COO), 172.4, 173.1* (CON). MS (CI) [m/z (rel.
abundance)]: 318 [(M + H)+, 100], 289 (5), 272 (7), 202 (5),
147 (5). HRMS: m/z calculated for [C19H28NO3]+: 318.2069
[(M + H)+]; found: 318.2058.
phenylpent-2-enoate (18b)
DCC (1.19 g, 5.79 mmol) and 2-bromoacetic acid (0.42 mL,
5.79 mmol) were added to a solution of 16 (0.16 g, 0.64 mmol)
and DMAP (4 mg, 0.03 mmol) in dry CH2Cl2 (10 mL) at r.t. Aer
stirring at this temperature for 90 minutes, water (10 mL) was
added and the mixture was ltered and extracted with CH2Cl2
(3 ꢂ 15 mL). The combined organic layers were washed with a
saturated NaHCO3 solution (10 mL) and H2O (10 mL),
collected, dried over anhydrous Na2SO4, ltered and the
solvent removed under reduced pressure. Compound 18b
(0.20 g, 0.55 mmol) was obtained as a yellowish oil aer ash
column chromatography purication (hexanes–EtOAc 7 : 3).
Yield: 86%. [a]2D0 ¼ ꢀ145.2 (c ¼ 1.0, CH2Cl2). IR (neat): 1651
(C]O), 1716 (C]O) cmꢀ1. 1H-NMR (300 MHz, CDCl3): d (8 : 1
rotamer ratio; * indicates minor rotamer signals) 1.04 (d, 3H,
J ¼ 6.6 Hz, CH3CH), 1.27 (t, 3H, J ¼ 7.1 Hz, CH3CH2), 2.75 (s,
3H, CH3N), 2.78* (s, 3H, CH3N), 3.09–3.30 (m, 1H, CHCH3),
3.73 (d, 1H, J ¼ 10.6 Hz, CHaHbBr), 3.78 (d, 1H, J ¼ 10.6 Hz,
CHaHbBr), 4.17 (q, 2H, J ¼ 7.1 Hz, OCH2CH3), 5.70 (d, 1H, J ¼
11.4 Hz, CHN), 5.93 (d, 1H, J ¼ 15.6 Hz, CHCO), 6.88 (dd, 1H,
J ¼ 15.6, 9.2 Hz, CH]CHCO), 6.98* (dd, 1H, J ¼ 15.8, 8.6 Hz,
CH]CHCO), 7.26–7.42 (m, 5H, Carom–H). 13C-NMR (75 MHz,
CDCl3): d 14.3 (CH3CH), 18.0 (CH3CH2), 26.5 (CH2Br), 30.4
(CH3N), 36.8 (CHCH3), 60.1 (CHN), 60.4 (OCH2CH3), 122.2
(CHCO), 128.1, 128.6, 128.8 (Carom–H), 136.7 (Carom–C), 149.6
(CH]CHCO), 166.0 (COO), 166.8 (CON). MS (CI) [m/z (rel.
abundance)]: 368 [(M + H)+, 12], 324 (24), 288 (29), 245 (19),
242 (58), 217 (100), 202 (11), 171 (30), 143 (15), 120 (13). HRMS:
m/z calculated for [C17H23NO3Br]+: 368.0869 [(M + H)+]; found:
368.0861.
(4S,5S,E)-Ethyl 4-methyl-5-(N-methyl-2-
phenylsulfonylacetamido)-5-phenylpent-2-enoate (20)
Sodium benzenesulnate (0.04 g, 0.23 mmol) was added to a
solution of 18b (0.09 g, 0.23 mmol) in DMF (10 mL) at r.t. for a
period of 30 minutes. Aer stirring at this temperature for 1 h,
H2O (10 mL) was added and the mixture was extracted with
Et2O (3 ꢂ 15 mL). The combined organic layers were washed
with a saturated NaHCO3 solution (10 mL) and H2O (10 mL),
collected, dried over anhydrous Na2SO4, ltered and the
solvent removed under reduced pressure. Compound 20 (0.09
g, 0.20 mmol) was obtained as a yellowish oil aer ash
column chromatography purication (hexanes–EtOAc 6 : 4).
Yield: 86%. [a]2D0 ¼ ꢀ104.0 (c ¼ 1.0, CH2Cl2). IR (neat): 1152
(SO2), 1318 (SO2), 1654 (C]O), 1720 (C]O) cmꢀ1 1H-NMR
.
(300 MHz, CDCl3): d (13 : 1 rotamer ratio; * indicates minor
rotamer signals) 1.00 (d, 3H, J ¼ 6.5 Hz, CH3CH), 1.06* (d, 3H,
J ¼ 6.6 Hz, CH3CH), 1.27 (t, 3H, J ¼ 7.1 Hz, CH3CH2), 2.77* (s,
3H, CH3N), 2.88 (s, 3H, CH3N), 3.07–3.27 (m, 1H, CHCH3),
4.02–4.25 (m, 4H, CH2O + CH2S), 5.63 (d, 1H, J ¼ 11.5 Hz,
CHN), 5.99 (d, 1H, J ¼ 15.6 Hz, CHCO), 6.89 (dd, 1H, J ¼ 15.6,
9.1 Hz, CH]CHCO), 7.12 (dd, 1H, J ¼ 15.6, 9.0 Hz, CH]
(3S,4R,5S,6S)-4-Ethoxycarbonylmethyl-3-ethyl-1,5-dimethyl-6-
phenyl-piperidin-2-one (19/190)
Compound 18a (0.08 g, 0.19 mmol) was slowly added to a CHCO), 7.21–7.46 (m, 5H, Carom–H), 7.47–7.60 (m, 2H, Carom
–
cooled (ꢀ105 ꢁC) suspension of LiCl (0.02 g, 0.57 mmol) in H), 7.60–7.73 (m, 1H, Carom–H), 7.78–7.91 (m, 2H, Carom–H),
THF (10 mL). n-BuLi 1.1 M (0.19 mL, 0.21 mmol) was then 7.91–8.01* (m, 2H, Carom–H). 13C-NMR (75 MHz, CDCl3): d 14.2
added dropwise and the mixture stirred for 15 min at this (CH3CH), 18.0 (CH3CH2O), 31.1 (CH3N), 36.6 (CHCH3), 60.1
temperature. H2O was added and the reaction was warmed to (CH2S), 60.4 (CH2O), 60.5 (CHN), 122.4 (CHCOO), 128.2, 128.5,
r.t. and extracted with EtOAc (3 ꢂ 15 mL). The combined 128.7, 128.8, 129.0, 134.1 (Carom–H), 136.7, 138.5 (Carom–C),
organic extracts were dried over Na2SO4, ltered and the 149.4 (CH]CHCO), 161.7 (COO), 166.2 (CON). MS (CI) [m/z
solvent removed under reduced pressure. Piperidinone 19/ (rel. abundance)]: 430 [(M + H)+, 100], 384 (9), 365 (26), 288
190 (0.03 g, 0.10 mmol) was obtained as a colorless oil aer (14), 278 (9), 200 (2). HRMS: m/z calculated for [C23H28NO5S]+:
ash column chromatography purication. Yield: 54% (dr: 430.1707 [(M + H)+]; found: 430.1688.
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(Carom–C), 169.5 (CON), 172.2 (COO). MS (CI) [m/z (rel. abun-
dance)]: 276 [(M + H)+, 100], 244 (17), 147 (7), 118 (4). HRMS: m/z
calculated for [C16H22NO3]+: 276.1599 [(M + H)+]; found:
276.1611.
(3S,4R,5S,6S)-4-Ethoxycarbonylmethyl-1,5-dimethyl-6-phenyl-
3-phenylsulfonylpiperidin-2-one (21)
A solution of compound 20 (0.07 g, 0.16 mmol) in dry THF
(5 mL) was added to a cooled (ꢀ40 ꢁC) solution of sodium
hydride (0.19 g, 0.80 mmol) in the same solvent. The mixture
was stirred for 3 h at this temperature, aer which H2O (10 mL)
was added to quench the reaction. The mixture was extracted
with EtOAc (3 ꢂ 15 mL) and the combined organic layers were
collected, dried over anhydrous Na2SO4, ltered and the solvent
removed under reduced pressure. Piperidinone 21 (0.05 g, 0.12
mmol) was obtained as a colorless oil aer ash column chro-
matography purication (hexanes–EtOAc 1 : 1). Yield: 81% (dr:
92 : 8). [a]2D0 ¼ ꢀ8.0 (c ¼ 1.0, CH2Cl2). IR (neat): 1146 (SO2), 1306
Acknowledgements
The authors thank the Spanish MICINN (CTQ2011-22790), the
Basque Government (Grupos IT328-10 and fellowship to U.U.)
and UPV/EHU (UFI QOSYC 11/22 and fellowship to A.I.) for
nancial support. The authors also acknowledge PETRONOR,
S.A. for the generous gi of solvents.
(SO2), 1650 (C]O), 1728 (C]O) cmꢀ1 1H-NMR (300 MHz,
.
Notes and references
CDCl3): d (92 : 8 diastereoisomer ratio; * indicates minor dia-
stereoisomer signals) 0.92 (d, 3H, J ¼ 6.7 Hz, CH3CH), 1.26
(t, 3H, J ¼ 7.3 Hz, CH3CH2), 2.13–2.43 (m, 1H, CHaHbCO), 2.66
(s, 3H, CH3N), 2.73 (dd, 1H, J ¼ 16.8, 3.8 Hz, CHaHbCO), 2.78–
2.92 (m, 1H, CHCH3), 3.26–3.42 (m, 1H, CHCH2), 3.89 (d, 1H, J ¼
10.3 Hz, CHN), 4.09–4.18 (m, 2H, OCH2), 4.30 (d, 1H, J ¼ 1.8 Hz,
CHS), 7.29–7.49 (m, 5H, Carom–H), 7.50–7.72 (m, 3H, Carom–H),
7.92–7.97* (m, 2H, Carom–H), 7.97–8.07 (m, 2H, Carom–H).
13C-NMR (75 MHz, CDCl3): d (92 : 8 diastereoisomer ratio; *
indicates minor diastereoisomer signals) 14.1 (CH3CH2), 15.4
(CH3CH), 31.2 (CH2CO), 33.6 (CH3N), 33.7 (CHCH2), 33.8*
(CH2CO), 35.7 (CHCH3), 36.9* (CH3N), 38.2* (CHCH3), 61.0
(CH2O), 68.3, 69.0* (CHN), 70.3, 72.1 (CHS), 127.9, 128.3, 128.8,
129.0, 133.8 (Carom–H), 139.1, 140.4 (Carom–C), 161.7 (COO),
171.3, 172.6* (CON). MS (CI) [m/z (rel. abundance)]: 430 [(M +
H)+, 100], 384 (6), 365 (26), 288 (14), 278 (9). HRMS: m/z calcu-
lated for [C23H28NO5S]+: 430.1703 [(M + H)+]; found: 430.1688.
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(4R,5S,6S)-4-Methoxycarbonylmethyl-1,5-dimethyl-6-
phenylpiperidin-2-one (22)
Mg (0.08 g, 0.33 mmol) was added to a cooled (0 ꢁC) solution of
compound 21 (0.10 g, 0.22 mmol) in MeOH (3 mL). The mixture
was stirred for 5 h at r.t., aer which the mixture was ltered
and the solvent was removed under reduced pressure. Piper-
idinone 22 (0.05 g, 0.18 mmol) was obtained as a colorless oil
aer ash column chromatography purication (hexanes–
EtOAc 1 : 1). Yield: 80% (dr: 92 : 8). [a]2D0 ¼ +27.1 (c ¼ 1.0,
CH2Cl2). IR (neat): 1641 (C]O), 1734 (C]O) cmꢀ1 1H-NMR
.
(300 MHz, CDCl3): d (92 : 8 diastereoisomer ratio; * indicates
minor diastereoisomer signals) 0.86* (d, 3H, J ¼ 6.5 Hz,
CH3CH), 1.07 (d, 3H, J ¼ 7.0 Hz, CH3CH), 1.96–2.12 (m, 1H,
CHCH3), 2.14–2.32 (m, 3H, CH2COO + CHaHbCON), 2.33–2.49
(m, 1H, CHCH2), 2.55–2.72 (m, 1H, CHaHbCON), 2.81 (s, 3H,
CH3N), 3.58 (s, 3H, CH3O), 3.67* (s, 3H, CH3O), 3.86 (d, 3H, J ¼
10.0 Hz, CHN), 4.20 (d, 3H, J ¼ 3.8 Hz, CHN), 7.05–7.15 (m, 2H,
C
C
arom–H), 7.15–7.21* (m, 2H, Carom–H), 7.23–7.45 (m, 3H,
arom–H). 13C-NMR (75 MHz, CDCl3): d (92 : 8 diastereoisomer
5 For some of our previous efforts in this eld, see: (a) A. Iza,
J. L. Vicario, D. Badia and L. Carrillo, Synthesis, 2006, 4065;
(b) J. L. Vicario, D. Badia and L. Carrillo, Org. Lett., 2001, 3,
773; (c) J. L. Vicario, D. Badia and L. Carrillo, J. Org. Chem.,
2001, 66, 9030.
ratio; * indicates minor diastereoisomer signals) 13.6, 15.4*
(CH3CH), 28.7, 32.9* (CHCH2), 34.3 (CH3N), 34.6 (CH2CON),
34.7* (CH3N), 36.4 (CH2COO), 37.6* (CH2CON), 38.4*
(CH2COO), 38.6, 42.3* (CHCH3), 51.6, 51.8* (CH3O), 69.8, 71.2*
(CHN), 126.4, 127.7, 128.1*, 128.9 (Carom–H), 140.5, 140.8*
6 For the rst use of pseudoephedrine as chiral auxiliary, see:
(a) A. G. Myers, B. H. Yang, H. Chen and J. L. Gleason, J. Am.
25810 | RSC Adv., 2013, 3, 25800–25811
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Chem. Soc., 1994, 116, 9361; (b) A. G. Myers, H. Chen,
L. McKinstry, D. J. Kopecky and J. L. Gleason, J. Am.
Chem. Soc., 1997, 119, 6496. For review, see: (c)
L. Carrillo and V. Yoldi, Eur. J. Org. Chem., 2001, 4343; (o)
A. G. Myers, J. K. Barbay and B. Zhong, J. Am. Chem. Soc.,
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Chem., 1996, 61, 2428.
a
A. G. Myers and M. G. Charest, Handbook of Reagents for
Organic Synthesis: Chiral Reagents for Asymmetric Synthesis,
ed. L. A. Paquette, Wiley Interscience, New York, 2003,
p. 485. For other examples, see: (d) M. Ocejo, L. Carrillo,
D. Badia, J. L. Vicario, N. Fernandez and E. Reyes, J. Org.
Chem., 2009, 74, 4404; (e) D. A. Kummer, W. J. Chain,
M. R. Morales, O. Quiroga and A. G. Myers, J. Am. Chem.
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L. Carrillo, U. Uria and A. Iza, J. Org. Chem., 2006, 71,
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A. Iza and U. Uria, Org. Lett., 2006, 8, 2535; (h)
J. Etxebarria, J. L. Vicario, D. Badia, L. Carrillo and
7 NMR analysis indicated the formation of
a single
diastereoisomer. Nevertheless, because of poor resolution
of NMR signals due to the presence of rotamer isomers,
crude reaction mixture was converted into alcohol 5 and at
this point both syn/anti ratio and ee, could be determined
by HPLC in a chiral stationary phase under conditions
optimized for a racemic standard.
8 M. Ocejo, J. L. Vicario, D. Badia, L. Carrillo and E. Reyes,
Synlett, 2005, 2110.
9 P. R. Blakemore, W. J. Cole, P. J. Kocienski and A. Morley,
Synlett, 1998, 26.
N. Ruiz, J. Org. Chem., 2005, 70, 8790; (i) J. Etxebarria, 10 M. E. Lebrum, P. L. Marquand and C. Berthelette, J. Org.
J. L. Vicario, D. Badia and L. Carrillo, J. Org. Chem., 2004, Chem., 2006, 71, 2009.
69, 2588; (j) J. H. Smitrovich, L. DiMichele, C. Qu, 11 For some examples which employ ammonium salts in this
G. N. Boice, T. D. Nelson, M. A. Huffman and J. Murry,
J. Org. Chem., 2004, 69, 1903; (k) J. H. Smitrovich,
G. N. Boice, C. Qu, L. Dimichelle, T. D. Nelson,
M. A. Huffman, J. Murry, J. McNamara and P. J. Reider,
Org. Lett., 2002, 4, 1; (l) P. C. Hutchison, T. D. Heightman
context: (a) A. Agosti, S. Britto and P. Renaud, Org. Lett.,
2008, 10, 1417; (b) S. H. Hong and R. H. Grubbs, J. Am.
Chem. Soc., 2006, 128, 3508; (c) R. Weihofen, O. Tverskoy
and G. Helmchen, Angew. Chem., Int. Ed., 2006, 45, 5546;
(d) V. Birman and V. H. Rawal, J. Org. Chem., 1998, 63, 9146.
and D. J. Procter, Org. Lett., 2002, 4, 4583; (m) 12 The transesterication process could not be avoided using
J. L. Vicario, D. Badia and L. Carrillo, J. Org. Chem., 2001,
66, 5801; (n) E. Anakabe, J. L. Vicario, D. Badia,
Mg-mediated desulfonylation reaction in EtOH for being
an extremely slow reaction.
This journal is ª The Royal Society of Chemistry 2013
RSC Adv., 2013, 3, 25800–25811 | 25811