Stereoselective access to fluorinated and non-fluorinated quaternary piperidines: Synthesis of pipecolic acid and iminosugar derivatives

Article abstract of DOI:10.1002/chem.201102351

The preparation of optically pure quaternary piperidines, both fluorinated and non-fluorinated, has been achieved from a chiral imino lactone derived from (R)-phenylglycinol. In the case of the fluorinated derivatives, the addition of (trifluoromethyl)trimethylsilane (TMSCF₃) followed by iodoamination and migration of the CF₃ group allowed access to four derivatives of α-(trifluoromethyl)pipecolic acid. A theoretical study of the CF ₃-group rearrangement has been carried out to help establish the reaction mechanism of this uncommon transformation. Moreover, a route to trifluoromethyl-substituted iminosugars was also developed through the diastereoselective dihydroxylation of suitable synthetic intermediates. Conversely, alkylation of the starting substrate and subsequent cross-metathesis and aza-Michael reactions led to α-alkyl derivatives of the target compounds. Copyright

Full text of DOI:10.1002/chem.201102351

FULL PAPER
DOI: 10.1002/chem.201102351
Stereoselective Access to Fluorinated and Non-fluorinated Quaternary
Piperidines: Synthesis of Pipecolic Acid and Iminosugar Derivatives
Santos Fustero,*[a, b] Laia Albert,[a, b] Natalia Mateu,[a, b] Gema Chiva,[b] Javier Mirꢀ,[a]
Javier Gonzꢁlez,[c] and Josꢂ Luis AceÇa*[b, d]
Abstract: The preparation of optically
pure quaternary piperidines, both fluo-
rinated and non-fluorinated, has been
achieved from a chiral imino lactone
derived from (R)-phenylglycinol. In the
case of the fluorinated derivatives, the
addition of (trifluoromethyl)trimethyl-
silane (TMSCF3) followed by iodoami-
nation and migration of the CF3 group
allowed access to four derivatives of a-
(trifluoromethyl)pipecolic acid. A theo-
retical study of the CF3-group rear-
rangement has been carried out to help
establish the reaction mechanism of
this uncommon transformation. More-
over, a route to trifluoromethyl-substi-
tuted iminosugars was also developed
through the diastereoselective dihy-
droxylation of suitable synthetic inter-
mediates. Conversely, alkylation of the
starting substrate and subsequent
cross-metathesis and aza-Michael reac-
tions led to a-alkyl derivatives of the
target compounds.
Keywords: amino acids
· density
functional calculations · fluorine ·
iminosugars · quaternary stereocen-
ters
Introduction
Nowadays fluorinated analogues of proteinogenic amino
acids are common synthetic targets due to their highly rec-
ognized biological properties.[1] Particularly, the selective in-
troduction of trifluoromethyl groups into peptidic com-
pounds may contribute to an enhancement of their chemical
and thermal stabilities and, as a result, to an improvement
of their bioavailability.[2] However, 3,3,3-trifluoroalanine-
containing peptides possess low chemical and configuration-
al stabilities at pH >7; therefore, the a-CF3 groups are usu-
ally located within a quaternary center to avoid these draw-
backs.[3] Acyclic derivatives such as a-(trifluoromethyl)ala-
nine (Scheme 1) have been widely used for the design of an-
Scheme 1. Quaternary a-(trifluoromethyl)amino acids.
titumor drugs[4] or as suitable molecular labels in 19F NMR
spectroscopic studies.[5] In contrast, the preparation of cyclic
analogues has been much scarcer, despite the importance of
quaternary cyclic amino acids in the discovery of new pepti-
domimetic structures.[6,7] The most representative example is
the synthesis of optically active a-(trifluoromethyl)proline
developed by Brigaud and co-workers,[8] whereas the prepa-
ration of a-(trifluoromethyl)pipecolic acid derivatives has
been achieved only in racemic form.[9,10]
We recently studied the nucleophilic trifluoromethyla-
tion[11] of chiral imino lactones such as 1 with the Ruppert–
Prakash reagent TMSCF3,[12] thus leading to trifluoromethyl
lactol 2 as a single diastereoisomer[13] (Scheme 2). As it
turned out, the cyclization of 2 by reaction with iodine and
NaH proceeded through a 6-exo-trig ring closure, although
the initially formed iodoamination product 3 underwent an
unexpected rearrangement toward trifluoromethyl lactone 4
by the addition of a second iodine atom in a one-pot pro-
cess, with the concomitant stereoselective creation of a qua-
ternary center containing a CF3 group.[14]
[a] Prof. Dr. S. Fustero, Dr. L. Albert, N. Mateu, J. Mirꢀ
Departmento de Quꢁmica Orgꢂnica
Universidad de Valencia
46100 Burjassot, Valencia (Spain)
Fax : (+34)963544939
E-mail: santos.fustero@uv.es
[b] Prof. Dr. S. Fustero, Dr. L. Albert, N. Mateu, Dr. G. Chiva,
Dr. J. L. AceÇa
Laboratorio de Molꢃculas Orgꢂnicas
Centro de Investigaciꢀn Prꢁncipe Felipe
46012 Valencia (Spain)
Fax : (+34)963289701
E-mail: sfustero@cipf.es
[c] Prof. Dr. J. Gonzꢂlez
Departmento de Quꢁmica Orgꢂnica e Inorgꢂnica
Universidad de Oviedo
33071 Oviedo (Spain)
Intrigued by the result of this unusual transformation,[15]
we decided to study the reaction mechanism in depth with
the aid of density functional calculations. Next, we envi-
sioned 4 as a versatile precursor to the synthesis of several
2,6-disubstituted 2-(trifluoromethyl)piperidines, such as pi-
[d] Dr. J. L. AceÇa
New address: Departamento de Quꢁmica Orgꢂnica I
Universidad del Paꢁs Vasco
20018 San Sebastiꢂn (Spain)
E-mail: joseluis.acena@ehu.es
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Table 1. Synthesis of trifluoromethyl lactol
3
and lactone 4.
Entry I2
[equiv]
Base (equiv)
Solvent
T
t
Yield
Yield
of
AHCTUNGTRENNUNG
[8C] [h] of
3 [%] 4 [%]
1
2
NaHCO3
(excess)
Et3N (2)
NaH (2)
NaH (2.5)
NaH (2.5)
none
CH2Cl2/
H2O
CHCl3
CHCl3
CHCl3
THF
25
15 46
9
Scheme 2. Iodoamination of imino lactol 2 and rearrangement of the CF3
group. TASF=tris(dimethylamino)sulfonium difluorotrimethylsilicate,
TMSCF3 =(trifluoromethyl)trimethylsilane.
2
3
4
5
6
7
3
4
5
5
1.5
5
25
25
48 40
60 25
18
39
60
80
–
60[a] 0.5
60[a] 0.5
CHCl3
THF
25
3
2
83
62
60[a]
–
pecolic acids 5, by functional-group manipulations and re-
moval of the chiral auxiliary (Scheme 3). Furthermore, the
stereoselective introduction of hydroxy groups within the pi-
peridine ring would afford iminosugars 6 containing a qua-
ternary CF3 group.
none
[a] The reaction was performed under microwave irradiation.
as the rearranged lactone 4. Further attempts to increase
the yield of 4 involved the use of other bases, such as Et3N
or NaH (Table 1, entries 2 and 3). In practice, the exclusive
formation of 4 was made possible by using NaH as the base,
a greater amount of I2 (5 equiv), and microwave heating
(Table 1, entry 4); although, the best yield was achieved
when the solvent was changed from CHCl3 to THF (Table 1,
entry 5). It should be mentioned that the reaction did not
proceed further in the absence of the base and enamino
lactol 3 was formed as the only product (Table 1, entries 6
and 7). Moreover, we confirmed that lactone 4 was also
formed from
(Scheme 4).
3 under the same reaction conditions
These experimental results seem to indicate that the [1,2]-
shift of the CF3 group takes place when sodium alkoxide 9
reacts with iodine, thus leading to the iminium ion 10, which
evolves to lactone 4 (Scheme 4). We carried out a theoreti-
cal study of these reactions by using density-functional
theory (DFT) to substantiate this mechanistic proposal. The
calculations were carried out with the B3LYP functional,
the 6-31G* basis set was employed for the carbon, hydro-
gen, oxygen, nitrogen, fluorine, and sodium atoms and the
Scheme 3. Synthetic plan for the preparation of quaternary pipecolic
acids 5 and 8 and iminosugars 6.
Based on our previous studies concerning the synthesis of
a-methyl quaternary dipeptide mimics,[16] we additionally
developed an alternative route to prepare the corresponding
non-fluorinated derivatives 8 (R’=alkyl). By starting again
from unsaturated imino lactone 1, key steps would include
the diastereoselective alkylation at the iminic carbon
atom[17] and a further cyclization based on a cross-metathe-
sis/intramolecular aza-Michael protocol.
Results and Discussion
Mechanism of the CF3 rearrangement: Iodocyclization of
imino lactol 2[13] was first tested using two equivalents of I2
and an excess of NaHCO3 in CH2Cl2/H2O (Table 1, entry 1).
A moderate yield of the expected product 3 was obtained
and isolated as a single diastereoisomer,[18] together with a
small amount of a new compound, which was characterized
Scheme 4. Transformation of enamino lactol 3 into lactone 4 and tenta-
tive mechanism.
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Preparation of Optically Pure Quaternary Piperidines
FULL PAPER
LANL2DZ pseudopotential was used for the iodine atoms.
All the stationary points located were fully optimized and
characterized as a minimum or first-order saddle point by
calculating their harmonic vibrational frequencies (full de-
tails of the geometries and energies of the located stationary
points are given in the Supporting Information).
First, the potential-energy surface that corresponds to the
6-exo-trig ring iodocyclization of imino lactol 1, in the ab-
sence of a base, to give bicyclic enamine 3 was studied, and
the transition structures TS1 and TS2 were located
(Figure 1). The predicted activation energies are 14.3 and
Figure 2. Transition structure located for the tautomerization of iminium
intermediate 10. Bond lengths are given in ꢅ.
frequency of TS3 corresponds to the stretching movement
À
À
of the breaking C H bond and the forming I H bond. Ac-
cording to these calculations, the rate-determining step for
the reaction of imino lactol 1 with iodine to give bicycle 3 is
the iodoamination reaction, which has an activation energy
of 14.3 kcalmolÀ1.
The treatment of bicyclic enamine 3 with sodium hydride
and iodine resulted in the rearranged bicycle 4 (Scheme 4).
It seems plausible that the reaction of 3 with NaH to give
sodium alkoxide 9 and molecular hydrogen (Scheme 4) is
faster than iodination of the double bond, so we propose
that the diiodinated alkoxide 10 is formed and then under-
goes a [1,2]-shift of the CF3 group. Thus, we found the tran-
sition-structure TS4 for the addition of iodine to the alkox-
ide 9 (Figure 3). The imaginary normal mode of TS4 corre-
Figure 1. Transition structures located for the iodocyclization of imino
lactol 2 to give iminium intermediates 11 and 12. Bond lengths and rela-
tive energies are given in ꢅ and kcalmolÀ1, respectively.
17.3 kcalmolÀ1, respectively. TS1, which leads to bicyclic imi-
nium intermediate 11, has an anti disposition between the
phenyl and the iodomethyl groups and is clearly favored by
3.0 kcalmolÀ1 relative to TS2, which leads to the syn imini-
um intermediate 12. The normal mode associated with the
imaginary frequency of the transition structures TS1 and
TS2 is dominated by the stretching movement that corre-
Figure 3. Transition structure located for the iodination of sodium alkox-
ide 9. Bond lengths are given in ꢅ.
À
À
sponds to the formation and breaking of the C I and I I
bonds, respectively. The coordination of the iodine molecule
with the sodium cation directs the addition of the iodine
atom to the double bond of 9, that is, anti to the CF3 group.
The potential-energy barrier for the iodination of 9 present-
ed a quite low value of 3.4 kcalmolÀ1.
À
sponds to the formation of the N C bond associated with
the ring closure. The comparison of both transition struc-
tures shows that TS1 is an earlier transition structure, as re-
À
flected in the bond lengths of the formed C N bonds: 1.891
and 1.782 ꢅ in TS1 and TS2, respectively. The preference of
TS1 appears to be related to the higher steric interaction be-
tween the phenyl ring and the iodomethyl group in TS2.
Although the alternative 7-endo-trig ring closure was also
favored according to the Baldwin rules,[19] the corresponding
transition structures were located, and, in agreement with
the experiments, this route was clearly unfavored relative to
the 6-exo-trig cyclization (see the Supporting Information
for details).
According to our calculations, iodinated alkoxide 10 is a
minimum on the potential-energy surface and can experi-
ence the [1,2]-shift of the CF3 group toward the electrophilic
iminium carbon atom through the transition-structure TS5
(Figure 4), which leads to lactone 4. The imaginary normal
Bicyclic enamine 3 was formed by tautomerization of the
iminium intermediate 11 promoted by the iodide anion. The
reaction takes place through transition-structure TS3
(Figure 2), which corresponds to a proton abstraction from
the a-methylene group by the iodide anion, and has a pre-
dicted activation energy of 13.9 kcalmolÀ1. The imaginary
Figure 4. Transition structure for the [1,2]-shift of the CF3 group. Bond
lengths are given in ꢅ.
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S. Fustero, J. L. AceÇa et al.
mode of TS5 corresponds to the simultaneous processes of
bond breaking and bond formation between the CF3 group
and the carbon atoms and the subsequent shortening of the
tion time could be efficiently decreased by using microwave
heating without affecting the yield (Table 2, entry 4). In the
event, the treatment of 4 with NaCN under extended reac-
tion times or microwave irradiation promoted both the elim-
ination and the introduction of a nitrile group to give 14 ex-
clusively (Table 2, entries 5 and 6).
Access to a target amino acid derivative was first evaluat-
ed by starting from nitrile 14. After hydrogenation of the
double bond, the CN group was reduced with BH2Cl·SMe2,
and the resulting crude amine was protected with a Boc
group (Scheme 5). In this transformation, the lactone ring
À1
À
C O bond. The barrier of the [1,2]-shift was 12.3 kcalmol .
The full reaction profile for the transformation of alkox-
ide 9 into lactone 4 is shown in Figure 5. According to these
data, the rate-determining step of the process is the CF3 re-
arrangement, and the whole transformation is exothermic.
Figure 5. Energy-reaction profile for the transformation of 9 into lactone
4.
Synthesis of a-(trifluoromethyl)pipecolic acid derivatives:
Starting from diiodide 4, we attempted the displacement of
the primary iodine atom with several nucleophilic reagents.
However, we soon found that elimination of the secondary
iodine atom was a faster process; for example, the reaction
with NaCN afforded a mixture of iodide 13, nitrile 14, and
starting material (Table 2, entry 1). When using non-nucleo-
philic basic reagents, such as NaH or DBU, 13 was obtained
as the only product (Table 2, entries 2 and 3), and the reac-
Scheme 5. Synthesis of amino ester 18. Boc=tert-butyloxycarbonyl,
TMSCHN2 =trimethylsilyldiazomethane.
also experienced a partial reduction to afford a mixture of
diastereomeric lactols 15, which were fully reduced with
LiBH4 to produce diol 16. The phenylglycinol moiety was
removed by hydrogenation in the presence of the Pearlman
catalyst, and finally alcohol 17 was converted into ester 18
in a three-step sequence, namely, the Swern oxidation[20] fol-
lowed by Pinnick oxidation[21] and esterification with
TMSCHN2 without purification of the corresponding inter-
mediates.
Table 2. Synthesis
of
bicyclic
lactones
13
and
14.
Nitrile 14 also served as the precursor to a diester deriva-
tive. Accordingly, reduction to diol 19 was followed by hy-
drolysis with HCl in EtOH to furnish ethyl ester 20
(Scheme 6). Interestingly, the chiral auxiliary was fully re-
À
moved probably due to the high lability of the benzylic C N
Entry
Base
t
T
[8C]
Yield of
13 [%]
Yield of
14 [%]
[h]
bond under acidic conditions, which is attributable to the
presence of the trifluoromethyl group.[22] Alcohol 20 was hy-
drogenated to afford its saturated derivative 21 and finally
transformed into diester 22.
1[a]
2
3
4
5
NaCN
NaH
DBU
DBU
NaCN
NaCN
12
12
12
1
48
1
25
25
63
65
85
92
–
16
–
–
–
95
84
25
60[b]
25
Two more derivatives containing aminomethyl or hydrox-
ymethyl substituents at the C2 position were obtained from
primary iodide 13. Thus, the treatment of 13 with either
sodium azide or silver acetate yielded substitution products
23 and 24, respectively, which were subsequently reduced
6
90[b]
–
[a] Starting material 4 was isolated in 12% yield. [b] The reaction was
performed under microwave irradiation. DBU=1,8-diazabicycloundec-7-
ene, DMSO=dimethyl sulfoxide.
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Preparation of Optically Pure Quaternary Piperidines
FULL PAPER
Scheme 6. Synthesis of amino diester 22.
with LiBH4 to give diols 25 and 26 (Scheme 7). Further hy-
drogenation of the phenylgylcinol species and the double
bond led to amino alcohols 27 and 28. In the case of 27, the
azido moiety was also converted into an amine group and
protected in situ with a Boc group. As above, a final oxida-
tion and esterification led to amino esters 29 and 30.
Scheme 8. Synthesis of fluorinated iminosugar 36. NMO=N-Methylmor-
pholine-N-oxide.
and 1H–19F NOE interaction studies carried out on triacetate
derivative 32 (see the Supporting Information). Disappoint-
ingly, the phenylglycinol moiety could not be effectively re-
moved from any of these compounds to reveal the target
iminosugar 35.
Next, we attempted the double-bond dihydroxylation of
the derived diol 26, which proved unsuccessful, and the
starting material was recovered. Access to the final product
was ultimately achieved when the phenylglycinol fragment
was removed prior to the double-bond functionalization.
Thus, treatment of 26 with acid furnished diol 33 by elimina-
tion of the chiral auxiliary and the acetyl group. The reac-
tion of 33 with OsO4 resulted again in full diastereoselectiv-
ity to give iminosugar 35, which was best isolated as its cor-
responding tetraacetyl derivative 36, albeit in low yield. A
more efficient sequence involved the osmylation of diacety-
lated olefin 34 to produce tetraacetate 36 finally and again
as a single diastereoisomer in good overall yield. Coupling-
constant analysis from the 1H NMR spectrum established
the stereochemical configuration of 36 because the origin of
this diastereoselectivity is attributable to the blocking effect
of the allylic trifluoromethyl group.
Scheme 7. Synthesis of amino esters 29 and 30.[a] The reaction was per-
formed in the presence of Boc2O.
Synthesis of an a-(trifluoromethyl)iminosugar: The versatili-
ty of our synthetic intermediates was demonstrated by the
straightforward access to a fluorinated analogue of an imi-
nosugar.[23] Although several fluorinated derivatives of imi-
nosugars have been described as glycosidase inhibitors,[24]
trifluoromethyl analogues have not been reported to date.
We first envisioned 24 as a suitable precursor for the syn-
thesis of (trifluoromethyl)iminosugar frameworks. For this
purpose, osmylation of 24 proceeded through the less steri-
cally demanding double-bond face to produce diol 31 as a
single diastereoisomer (Scheme 8). The stereochemistry of
this diol was confirmed by coupling-constant calculations
Synthesis of a-alkylpipecolic acid derivatives: As we had
achieved the preparation of several quaternary a-(trifluoro-
methyl)pipecolates, we considered access to their corre-
sponding non-fluorinated counterparts. Accordingly, our
previous synthesis of a-methyl quaternary dipeptide
mimics[16] was conveniently adapted to introduce diverse
alkyl substituents besides the methyl group at the quaterna-
ry center in a stereoselective manner, bearing in mind that
the volume of a trifluoromethyl moiety is significantly larger
than a methyl group.[25]
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S. Fustero, J. L. AceÇa et al.
Thus, starting again from imino lactone 1, alkylation at
the iminic carbon atom by reaction with methyl- or isobutyl-
magnesium bromide in the presence of BF3·OEt2 produced
amines 37 and 38, respectively, as single diastereoisomers
(Scheme 9). Removal of the phenylglycinol moiety by lac-
Conclusions
The synthetic potential of imino lactones derived from phe-
nylglycinol has been confirmed by the diastereoselective
preparation of several examples of polysubtituted piperi-
dines. In one case, the (trifluoromethyl)lactol that resulted
from the addition of TMSCF3 to the starting material expe-
rienced an unusual rearrangement of the CF3 group, which
served to produce a key diiodide intermediate for the syn-
thesis of a-(trifluoromethyl)pipecolic acid derivatives and
CF3-containing iminosugar analogues. A detailed study of
the rearrangement process was carried out with the aid of
theoretical DFT calculations, which established that migra-
tion of the CF3 group took place on an iminium ion inter-
mediate. In a different approach, non-fluorinated com-
pounds were also prepared from the same starting molecule
by using the alkylation of the iminic carbon atom, a cross-
metathesis reaction, and an intramolecular aza-Michael ad-
dition as key steps. The resulting final products in both
series are compounds with further potential utility as build-
ing blocks of more complex peptidomimetic structures.
Experimental Section
General methods: All the reactions were carried out in an argon or nitro-
gen atmosphere. The solvents were purified prior to use, that is, THF was
distilled from sodium/benzophenone and CH2Cl2 was distilled from calci-
um hydride. All the other solvents and reagents were used as received.
The reactions were monitored with the aid of TLC analysis on precoated
silica gel plates (0.25 mm; E. Merck). Visualization was carried out with
UV light and vainillin or potassium permanganate stains. Flash column
chromatography was performed with the indicated solvents on silica gel
60 (particle size: 0.040–0.063 mm). Melting points were measured on a
Bꢆchi B-540 apparatus and are uncorrected. Optical rotations were mea-
sured on a Jasco P-1020 polarimeter. 1H, 13C, and 19F NMR spectra were
recorded on a 300 MHz Bruker AC300 spectrometer. Chemical shifts (d)
are given in ppm and referenced to the residual proton resonances of the
solvents or fluorotrichloromethane in the 19F NMR spectroscopic experi-
ments. Coupling constants (J) are given in Hertzs (Hz). The letters m, s,
d, t, and q stand for multiplet, singlet, doublet, triplet, and quartet, re-
spectively, and br indicates that the signal is broad. High-resolution mass
spectra were carried out by the Universidad de Valencia Mass Spectrom-
etry Service. Microwave experiments were carried out in sealed vials
with an Initiator 2.0 (Biotage). The equipment contains an IR probe to
control the internal temperature of the reaction mixture. The solutions
were prestirred before irradiation was started. The absorbance of the sol-
vent was set as “normal” and the reaction time was initiated as soon as
the system reached the input temperature. After irradiation, the reaction
mixture was cooled to room temperature with air flow and the pressure
was vented with a needle before removing the vial cap.
Scheme 9. Synthesis of amino diesters 45 and 46. TFA=trifluoroacetic
acid.
tone opening and treatment with PbACTHNUTRGNENUG(OAc)4 revealed unsatu-
rated amino acids 39[26] and 40, which were further protected
to furnish 41 and 42. Next, a tandem cross-metathesis/intra-
molecular aza-Michael process[27] was first attempted on
amino ester 41 by reaction with ethyl acrylate under a varie-
ty of conditions,[28] but afforded only complex mixtures and
the cyclized product remained undetectable. Therefore, a
two-step sequence was carried out. Hence, cross-metathesis
of 41 and 42 with ethyl acrylate in the presence of a Grubbs
second-generation catalyst led to Michael acceptors 43 and
44, essentially as single trans isomers as shown by analysis of
their NMR spectroscopic data. The subsequent intramolecu-
lar aza-Michael reaction was unsuccessful with these Boc-
protected amines under various basic reaction conditions.
However, removal of the Boc group prior to treatment with
Et3N under microwave heating cleanly afforded methyl a-al-
kylpipecolates 45 and 46 with high diastereoselectivity
(80:20 as determined by GC analysis). The configuration of
the newly created stereocenter was deduced with the aid of
NOE interaction studies performed on the diastereoisomeric
pair 45/epi-45 (see the Supporting Information for details).
Therefore, the major diastereoisomers possess the same ste-
reochemical arrangement as the fluorinated amino diester
22.
(À)-(4R,6S,9aS)-6-(Iodomethyl)-4-phenyl-9a-(trifluoromethyl)-3,4,6,7-
tetrahydropyridoACHTUNGTNER[NNUG 2,1-c]ACHTUNRTGEG[NNUN 1,4]oxazin-1ACHTNUGTREN(GUNN 9aH)-one (13): DBU (0.23 mL,
1.52 mmol) was added to a solution of 4[13] (430 mg, 0.76 mmol) in
DMSO (3.8 mL). The reaction mixture was heated under microwave irra-
diation at 608C for 1 h and quenched with saturated aqueous NH4Cl. The
aqueous layer was extracted with EtOAc (3ꢇ), and the combined organic
layers were dried over Na2SO4. The filtrates were concentrated and puri-
fied by column chromatography on silica gel to afford 13 (305 mg, 92%)
as a colorless oil. Rf =0.17 (hexane/EtOAc, 15:1); [a]25D =À73.8 (c=0.2
1
in CHCl3); H NMR (300 MHz, CDCl3): d=2.21–2.29 (m, 2H), 3.00–3.09
(m, 1H), 3.20 (dd, J=10.0, 8.3 Hz, 1H), 3.29 (dd, J=10.1, 4.9 Hz, 1H),
4.35–4.41 (m, 1H), 4.57 (t, J=2.9 Hz, 1H), 5.05 (dd, J=11.4, 3.4 Hz,
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Preparation of Optically Pure Quaternary Piperidines
FULL PAPER
1H), 6.27 (dt, J=10.2, 4.5 Hz, 1H), 6.52 (d, J=10.2 Hz, 1H), 7.11–7.16
(300 MHz, CDCl3): d=0.62–0.79 (m, 1H), 1.43 (s, 9H), 1.47–2.07 (m,
7H), 2.65–2.93 (m, 2H), 3.11–3.26 (m, 1H), 3.61 (d, J=12.2 Hz, 1H),
3.70 (dd, J=10.7, 3.2 Hz, 1H), 3.94–4.06 (m, 1H), 4.19 (d, J=12.2 Hz,
1H), 4.23 (t, J=10.8 Hz, 1H), 4.55 (dd, J=10.0, 3.8 Hz, 1H), 7.22–
7.36 ppm (m, 5H); 13C NMR (75.5 MHz, CDCl3): d=15.0, 26.0, 26.4,
28.4, 35.3, 38.7, 47.2, 60.4, 61.7, 62.7, 63.3 (q, 2JCF =22.2 Hz), 79.2, 127.3
(q, 1JCF =291.4 Hz), 127.6, 128.2, 128.6, 139.8, 155.9 ppm; 19F NMR
(282.4 MHz, CDCl3): d=À73.3 ppm (s, 3F); HRMS (FAB): m/z calcd for
C22H33F3N2O4: 446.2392 [M+]; found: 446.2404.
(m, 2H), 7.30–7.40 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=11.1
5
(q, 5JCF =3.1 Hz), 26.8, 53.8, 59.7, 65.1 (q, 2JCF =28.4 Hz), 71.1 (q, JCF
=
3.4 Hz), 122.1 (q, 4JCF =1.0 Hz), 124.2 (q, 1JCF =290.1 Hz), 127.1, 128.5,
129.1, 129.6, 138.4, 165.1 ppm; 19F NMR (282.4 MHz, CDCl3): d=
À72.8 ppm (s, 3F); HRMS (EI): m/z calcd for C16H15F3INO2: 437.0100
[M+]; found: 437.0096.
(À)-(4R,6S,9aS)-6-(Cyanomethyl)-4-phenyl-9a-(trifluoromethyl)-3,4,6,7-
tetrahydropyridoACHTUNGTRENNUNG[2,1-c]ACHTUNGTRENNUNG[1,4]oxazin-1ACHTNUGTRENUN(GN 9aH)-one (14): NaCN (86 mg,
1.74 mmol) was added to a solution of 4[13] (246 mg, 0.44 mmol) in
DMSO (2.2 mL). The reaction mixture was heated under microwave irra-
diation at 908C for 1 h and quenched with saturated aqueous NaCl. The
aqueous layer was extracted with EtOAc (3ꢇ) and the combined organic
layers were dried over Na2SO4. The filtrates were concentrated and puri-
fied by column chromatography on silica gel to afford 14 (123 mg, 84%)
as a colorless oil. Rf =0.21 (hexane/EtOAc, 3:1); [a]25D =À171.4 (c=1.0
in CHCl3); 1H NMR (CDCl3): d=1.97–2.08 (m, 1H), 2.21–2.33 (m, 1H),
2.43 (dd, J=16.8, 7.2 Hz, 1H), 2.61 (dd, J=16.8, 7.3 Hz, 1H), 3.38 (qd,
J=7.2, 3.7 Hz, 1H), 4.36–4.42 (m, 1H), 4.63 (t, J=3.0 Hz, 1H), 5.06 (dd,
J=11.6, 3.5 Hz, 1H), 6.25 (ddd, J=10.4, 5.3, 3.5 Hz, 1H), 6.44 (d, J=
General procedure for the hydrogenation of N-protected amines (general
procedure B): Pd(OH)2 (0.7 equiv) was added to a solution of the corre-
sponding N-protected amine (1 equiv) in MeOH (0.04m). The reaction
mixture was stirred in a hydrogen atmosphere (5 atm) for the time indi-
cated, filtered, and concentrated under reduced pressure. The crude mix-
ture was purified by column chromatography on silica gel with the appro-
priate solvents as the eluent.
(+)-(2S,6S)-6-[2-(tert-Butoxycarbonylamino)ethyl]-2-(hydroxymethyl)-2-
(trifluoromethyl)piperidine (17): General procedure B and 16 (84 mg,
0.19 mmol) were employed with stirring for 6 h to obtain 17 (53 mg,
86%) as a white solid. Rf =0.34 (hexane/EtOAc, 3:1); m.p. 120–1218C;
[a]25D = +8.1 (c=0.9 in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.03–
1.19 (m, 1H), 1.41 (s, 9H), 1.40–1.75 (m, 5H), 2.36 (br, 1H), 2.66–2.76
(m, 1H), 2.95–3.08 (m, 1H), 3.30–3.48 (m, 1H), 3.61 (d, J=11.9 Hz, 1H),
3.74 (br, 1H), 3.92 (d, J=11.9 Hz, 1H), 4.99 ppm (br, 1H); 13C NMR
(75.5 MHz, CDCl3): d=19.9, 24.7, 28.3, 31.7, 36.4, 38.5, 46.6, 58.5, 59.9 (q,
2JCF =23.9 Hz), 79.8, 126.9 (q, 1JCF =282.9 Hz), 157.1 ppm; 19F NMR
(282.4 MHz, CDCl3): d=À79.9 ppm (s, 3F); HRMS (FAB): m/z calcd for
C14H26F3N2O3: 327.1896 [M+H+]; found: 327.1907.
10.3 Hz, 1H), 7.13–7.18 (m, 2H), 7.34–7.42 ppm (m, 3H); 13C NMR
2
(CDCl3): d=24.1 (q, 5JCF =3.3 Hz), 26.9, 49.8, 60.3, 64.6 (q, JCF
=
28.5 Hz), 71.0 (q, 5JCF =3.4 Hz), 117.7, 122.4 (c, 4JCF =1.1 Hz), 124.2 (q,
3
1JCF =291.4 Hz), 127.1, 128.4, 128.8. 129.2, 138.2, 164.7 ppm (q, JCF
=
1.3 Hz); 19F NMR (282.4 MHz, CDCl3): d=À72.4 ppm (s, 3F); HRMS
(EI): m/z calcd for C17H15F3N2O2: 336.1086 [M+]; found: 336.1092.
(4R,6S,9aS)-6-[2-(tert-Butoxycarbonylamino)ethyl]-4-phenyl-9a-
(trifluoromethyl)octahydropyrido
ACHUTGTNRNEUG[N 2,1-c]ACHTGNUTRENNUNG
wt, 46 mg, 0.044 mmol) was added to
a
General procedure for the oxidation and esterification of amino alcohols
(general procedure C): DMSO (6 equiv) was added dropwise to a stirred
solution of (COCl)2 (3 equiv) in CH2Cl2 (0.025m) cooled to À788C. After
0.086 mmol) in MeOH (0.9 mL). The reaction mixture was stirred in a
hydrogen atmosphere (1 atm) for 12 h, filtered, and concentrated under
reduced pressure. The crude mixture was dissolved in THF (1.7 mL), and
BH2Cl·SMe2 (0.027 mL, 0.261 mmol) was added dropwise. The reaction
mixture was stirred at under reflux for 12 h and cooled at room tempera-
ture. A solution of HCl in MeOH (1.25m, 0.695 mL, 0.869 mmol) was
added dropwise, and the reaction mixture was concentrated under re-
duced pressure. The residue was dissolved in EtOH and re-evaporated
three times until complete disappearance of residual borates. Et3N
(0.018 mL, 0.130 mmol) and Boc2O (28 mg, 0.130 mmol) were added to
the crude mixture dissolved in THF (1.7 mL). The reaction mixture was
stirred at room temperature for 3 h and concentrated under reduced
pressure. The crude reaction mixture was purified by column chromatog-
raphy on silica gel to afford a 7:1 mixture of diastereomeric lactols 15
(34 mg, 88%) as a colorless oil. Rf =0.23 (hexane/EtOAc, 5:1); data of
major diastereoisomer: 1H NMR (300 MHz, CDCl3): d=1.39 (s, 9H),
1.46–1.86 (m, 7H), 2.42–2.59 (m, 1H), 2.67–2.91 (m, 2H), 3.65 (dd, J=
11.4, 3.4 Hz, 1H), 3.84–3.94 (m, 1H), 4.01 (t, J=11.7 Hz, 1H), 4.16 (d,
10 min,
a solution of the corresponding amino alcohol (1 equiv) in
CH2Cl2 (0.1m) was added and the reaction mixture was stirred at À788C
for 1 h. Et3N (9 equiv) was added to the reaction mixture, which was al-
lowed to reach 08C. After 10 min, the reaction was quenched with satu-
rated aqueous NH4Cl. The aqueous phase was extracted with CH2Cl2
(3ꢇ), and the combined organic layers were dried over Na2SO4. The fil-
trates were concentrated under reduced pressure, and the residue was fil-
tered through a short pad of silica gel with 1:1 hexane/EtOAc as the
eluent. The resulting aldehyde was dissolved in 2:1 tBuOH/THF (0.03m).
2-Methyl-2-butene (30 equiv) was added to the reaction mixture followed
by a solution of NaClO2 (10 equiv) and NaH2PO4 (10 equiv) in H2O
(0.05m). The reaction mixture was stirred a room temperature for 30 min
and quenched with saturated aqueous NH4Cl. The aqueous phase was ex-
tracted with EtOAc (3ꢇ), and the combined organic layers were dried
over Na2SO4. The filtrates were concentrated under reduced pressure,
and the crude acid was dissolved in toluene/MeOH (2.5:1, 0.03m). The
solution was cooled to 08C and TMSCHN2 (2m in hexane, 1.5 equiv) was
added dropwise. The reaction mixture was stirred at 08C for 30 min and
quenched with some drops of AcOH and concentrated under reduced
pressure. The crude mixture was purified by column chromatography on
silica gel with the appropriate solvents as the eluent.
J=5.1 Hz, 1H), 4.61–4.71 (m, 1H), 5.03 (d, J=5.0 Hz, 1H), 7.29–
7.43 ppm (m, 5H); 13C NMR (75.5 MHz, CDCl3): d=15.5 (q, JCF
=
3
8.4 Hz), 25.4, 27.2, 27.3, 28.3, 38.3, 49.0, 57.6 (q, 4JCF =2.6 Hz), 61.6 (q,
2JCF =21.2 Hz), 63.8, 79.0, 90.9 (q, 3JCF =3.9 Hz), 128.1, 128.6, 128.7 (q,
1JCF =297.4 Hz), 129.1, 138.3 (q, 5JCF =0.9 Hz), 155.6 ppm; 19F NMR
(282.4 MHz, CDCl3): d=À64.1 ppm (s, 3F); data of minor diastereoiso-
mer: 19F NMR (282.4 MHz, CDCl3): d=À59.5 ppm (s, 3F); HRMS (EI):
m/z calcd for C22H31F3N2O4: 444.2236 [M+]; found: 444.2208.
(+)-(2S,6S)-6-[2-(tert-Butoxycarbonylamino)ethyl]-2-(methoxycarbonyl)-
2-(trifluoromethyl)piperidine (18): General procedure C and 17 (63 mg,
0.193 mmol) were employed to obtain 18 (51 mg, 74%) as a colorless oil.
1
Rf =0.30 (hexane/EtOAc, 5:1); [a]25D = +7.1 (c=0.8 in CHCl3); H NMR
General procedure for reduction with LiBH4 (general procedure A):
LiBH4 (3 equiv) was added to a solution of the corresponding lactol or
lactone (1 equiv) in THF (0.1m) and stirred at room temperature for the
time indicated in each case. The reaction was quenched with saturated
aqueous NH4Cl, the aqueous layer was extracted with Et2O (3ꢇ), and the
combined organic layers were dried over Na2SO4. The filtrates were con-
centrated and purified by column chromatography on silica gel with the
appropriate solvents as the eluent.
(300 MHz, CDCl3): d=1.11–1.35 (m, 2H), 1.44 (s, 9H), 1.53–1.72 (m,
4H), 1.76–1.87 (m, 1H), 2.30–2.38 (m, 1H), 2.56–2.69 (m, 1H), 3.09–3.33
(m, 2H), 3.83 (s, 3H), 4.80 ppm (br, 1H); 13C NMR (75.5 MHz, CDCl3):
d=20.8, 25.9 (q, 3JCF =1.5 Hz), 28.4, 29.9, 36.6, 37.0, 50.9, 53.1, 66.9 (q,
2JCF =26.3 Hz), 79.2, 124.1 (q, 1JCF =282.3 Hz), 155.9, 169.6 ppm;
19F NMR (282.4 MHz, CDCl3): d=À78.9 ppm (s, 3F); HRMS (EI): m/z
calcd for C15H26F3N2O4: 355.1845 [M+H+]; found: 355.1844.
(+)-(2S,6S)-6-[2-(tert-Butoxycarbonylamino)ethyl]-2-(hydroxymethyl)-1-
[(R)-2-hydroxy-1-phenylethyl]-2-(trifluoromethyl)piperidine (16): Gener-
al procedure A and 15 (144 mg, 0.32 mmol) were employed with stirring
for 36 h to obtain 16 (103 mg, 71%) as a white solid. Rf =0.14 (hexane/
EtOAc, 2:1); m.p. 51–538C; [a]25D = +2.4 (c=0.9 in CHCl3); 1H NMR
(+)-(2S,6S)-2-(Cyanomethyl)-6-(hydroxymethyl)-1-[(R)-2-hydroxy-1-phe-
nylethyl]-6-(trifluoromethyl)-1,2,3,6-tetrahydropyridine (19): General
procedure A and 14 (58 mg, 0.173 mmol) were employed with stirring for
3 h to obtain 19 (52 mg, 89%) as a white solid. Rf =0.34 (hexane/EtOAc,
1:4); m.p. 114–1168C; [a]25D = +33.7 (c=0.9 in CHCl3); 1H NMR
Chem. Eur. J. 2012, 18, 3753 – 3764
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3759

S. Fustero, J. L. AceÇa et al.
(300 MHz, CDCl3): d=1.33 (d, J=16.7 Hz, 1H), 2.27 (dd, J=16.7,
11.1 Hz, 1H), 2.34 (dd, J=16.7, 6.6 Hz, 1H), 2.45–2.58 (m, 1H), 3.57 (d,
J=12.1 Hz, 1H), 3.71 (dd, J=11.1, 3.4 Hz, 1H), 3.81 (br, 1H), 3.88–3.97
(m, 1H), 4.14 (d, J=12.1 Hz, 1H), 4.26 (t, J=10.4 Hz, 1H), 4.56 (dd, J=
10.5, 3.2 Hz, 1H), 4.77 (br, 1H), 5.71 (dd, J=10.2, 2.8 Hz, 1H), 6.21–6.29
(m, 1H), 7.31–7.49 ppm (m, 5H); 13C NMR (75.5 MHz, CDCl3): d=22.1
(q, 5JCF =4.4 Hz), 29.2, 46.4, 60.2, 60.4 (q, 5JCF =1.4 Hz), 62.3, 64.9 (q,
2JCF =23.3 Hz), 118.9 (q, 6JCF =1.3 Hz), 123.9 (q, 4JCF =2.7 Hz), 125.8 (q,
1JCF =289.1 Hz), 128.0 (q, 6JCF =1.4 Hz), 128.5, 129.1, 129.8, 137.6 ppm;
19F NMR (282.4 MHz, CDCl3): d=À72.0 ppm (s, 3F); HRMS (EI): m/z
calcd for C17H20F3N2O2: 341.1477 [M+H+]; found: 341.1471.
(m, 1H), 4.63 (t, J=3.1 Hz, 1H), 5.03 (dd, J=11.4, 3.3 Hz, 1H), 6.26 (dt,
J=10.2, 4.5 Hz, 1H), 6.42 (d, J=10.0 Hz, 1H), 7.12–7.22 (m, 2H), 7.28–
7.45 ppm (m, 3H); 13C NMR (75.5 MHz, CDCl3): d=25.1, 51.9, 54.6 (q,
5JCF =2.8 Hz), 60.2, 64.9 (q, 2JCF =28.5 Hz), 71.2 (q, 5JCF =3.2 Hz), 122.2,
124.1 (q, 1JCF =291.8 Hz), 127.2, 128.5, 129.0, 129.5, 138.5, 165.0 ppm (q,
3JCF =1.1 Hz); 19F NMR (282.4 MHz, CDCl3): d=À73.3 ppm (s, 3F);
HRMS (FAB): m/z calcd for C16H16F3N4O2: 353.1225 [M+H+]; found:
353.1232.
(À)-(4R,6S,9aS)-6-(Acetoxymethyl)-4-phenyl-9a-(trifluoromethyl)-
3,4,6,7-tetrahydropyrido[2,1-c]
N
U
(24):
AgOAc
(178 mg, 1.068 mmol) was added to a solution of 13 (47 mg, 0.107 mmol)
in toluene (1.6 mL), and the reaction mixture was stirred at room temper-
ature for 24 h. The reaction mixture was filtered through celite with
EtOAc as the eluent, concentrated under reduced pressure, and purified
by column chromatography on silica gel to afford 24 (35 mg, 89%) as a
white solid. Rf =0.19 (hexane/EtOAc, 7:1); m.p. 55–578C; [a]25D =À134.8
(c=0.7 in CHCl3); 1H NMR (300 MHz, CDCl3): d=2.04 (s, 3H), 2.14–
2.22 (m, 2H), 3.05–3.18 (m, 1H), 3.90 (dd, J=11.4, 4.6 Hz, 1H), 4.23 (dd,
J=11.3, 6.6 Hz, 1H), 4.35–4.42 (m, 1H), 4.67–4.72 (m, 1H), 4.99 (dd, J=
11.4, 3.4 Hz, 1H), 6.29 (dt, J=10.2, 4.5 Hz, 1H), 6.49 (d, J=10.2 Hz,
1H), 7.13–7.17 (m, 2H), 7.29–7.40 ppm (m, 3H); 13C NMR (75.5 MHz,
(À)-(2S,6S)-2-(Ethoxycarbonylmethyl)-6-(hydroxymethyl)-6-(trifluoro-
methyl)-1,2,3,6-tetrahydropyridine (20): AcCl (0.78 mL, 10.97 mmol) was
added dropwise to EtOH (2 mL) at room temperature (caution: exother-
mic reaction). An aliquot of the resulting solution of HCl in EtOH (4m,
0.60 mL, 2.35 mmol) was added to 19 (20 mg, 0.059 mmol). The reaction
mixture was stirred at 758C for 4 h, cooled to room temperature, and
then saturated aqueous NaHCO3 was added. The aqueous layer was ex-
tracted with EtOAc (3ꢇ), and the combined organic layers were dried
over Na2SO4. The filtrates were concentrated and purified by column
chromatography on silica gel to afford 20 (12 mg, 76%) as a white solid.
Rf =0.28 (hexane/EtOAc, 1:1); m.p. 82–838C; [a]25D =À25.8 (c=0.8 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.26 (t, J=7.1 Hz, 3H), 1.92–
2.08 (m, 2H), 2.42–2.56 (m, 2H), 2.67 (br, 2H), 3.28–3.37 (m, 1H), 3.77
(d, J=12.5 Hz, 1H), 3.84 (d, J=12.3 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H),
5.54 (ddd, J=10.2, 2.5, 1.4 Hz, 1H), 6.09 ppm (ddd, J=10.1, 5.2, 2.7 Hz,
1H); 13C NMR (75.5 MHz, CDCl3): d=14.1, 30.8, 40.0, 44.5, 60.9, 61.9 (q,
2JCF =25.3 Hz), 62.0, 121.5 (q, 4JCF =2.0 Hz), 125.9 (q, 1JCF =284.2 Hz),
131.2, 172.4 ppm; 19F NMR (282.4 MHz, CDCl3): d=À77.3 ppm (s, 3F);
HRMS (EI): m/z calcd for C11H17F3NO3: 268.1161 [M+H+]; found:
268.1159.
CDCl3): d=20.8, 25.0 (q, 5JCF =0.9 Hz), 51.2, 59.2, 64.9 (q, 5JCF =2.4 Hz),
1
65.0 (q, 2JCF =28.2 Hz), 71.4 (q, 5JCF =3.3 Hz), 123.0, 124.5 (q, JCF
=
289.4 Hz), 127.3, 128.2, 129.0, 130.1, 138.6, 165.3, 170.8 ppm; 19F NMR
(282.4 MHz, CDCl3): d=À73.6 ppm (s, 3F); HRMS (EI): m/z calcd for
C18H18F3NO4: 369.1188 [M+]; found 369.1196.
(À)-(2S,6S)-6-(Azidomethyl)-2-(hydroxymethyl)-1-[(R)-2-hydroxy-1-phe-
nylethyl]-2-(trifluoromethyl)-1,2,5,6-tetrahydropyridine (25): General
procedure A and 23 (100 mg, 0.28 mmol) were employed with stirring for
4 h to obtain 25 (87 mg, 86%) as a white solid. Rf =0.18 (hexane/EtOAc,
3:1); m.p. 169–1708C; [a]25D =À15.5 (c=1.2 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=2.21–2.42 (m, 3H), 2.92 (td, J=11.9, 1.0 Hz, 1H),
3.48–3.54 (m, 1H), 3.57 (d, J=12.1 Hz, 1H), 3.69 (dd, J=11.1, 3.7 Hz,
1H), 4.15 (d, J=12.0 Hz, 1H), 4.26 (t, J=10.9 Hz, 1H), 4.54 (dd, J=10.4,
3.3 Hz, 1H), 4.84 (br, 1H), 5.67 (dd, J=10.2, 2.5 Hz, 1H), 6.16–6.25 (m,
(+)-(2S,6S)-6-(Ethoxycarbonylmethyl)-2-(hydroxymethyl)-2-(trifluorome-
thyl)piperidine (21): Pd/C (10% wt, 56 mg, 0.052 mmol) was added to a
solution of 20 (28 mg, 0.105 mmol) in EtOH (2.6 mL). The reaction mix-
ture was stirred in a hydrogen atmosphere (1 atm) for 2 h, filtered, and
concentrated under reduced pressure. The crude mixture was purified by
column chromatography on silica gel to afford 21 (24 mg, 85%) as a col-
orless oil. Rf =0.27 (hexane/EtOAc, 1:1); [a]25D = +16.6 (c=1.2 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.13–1.22 (m, 1H), 1.25 (t, J=
7.1 Hz, 3H), 1.45–1.68 (m, 4H), 1.73–1.78 (m, 1H), 2.29–2.47 (m, 3H),
3.05–3.13 (m, 1H), 3.75 (d, J=12.6 Hz, 1H), 3.95 (d, J=12.6 Hz, 1H),
4.15 ppm (q, J=7.1 Hz, 2H); 13C NMR (75.5 MHz, CDCl3): d=14.1,
19.7, 24.0 (q, 3JCF =2.0 Hz), 30.6, 41.1, 47.0, 58.6, 59.7 (q, 2JCF =24.2 Hz),
1H), 7.28–7.46 ppm (m, 5H); 13C NMR (300 MHz, CDCl3): d=27.3, 47.7,
2
53.2 (q, 5JCF =4.1 Hz), 60.2 (q, 5JCF =1.3 Hz), 60.3, 62.3, 65.0 (q, JCF
=
23.4 Hz), 123.7 (q, 4JCF =2.6 Hz), 125.7 (q, 1JCF =290.3 Hz), 128.2 (q,
6JCF =1.3 Hz), 128.2, 128.8, 130.5, 138.4 ppm; 19F NMR (282.4 MHz,
CDCl3): d=À72.7 ppm (s, 3F); HRMS (EI): m/z calcd for C16H19F3N4O2:
357.1538 [M+H+]; found: 357.1533.
(À)-(2S,6S)-6-(Acetoxymethyl)-2-(hydroxymethyl)-1-[(R)-2-hydroxy-1-
phenylethyl]-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridine (26): General
procedure A and 24 (116 mg, 0.32 mmol) were employed with stirring for
3 h to obtain 26 (96 mg, 82%) as a colorless oil. Rf =0.29 (hexane/
EtOAc, 1:1); [a]25D =À21.8 (c=0.6 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=1.95 (s, 3H), 2.17 (ddd, J=16.7, 6.9, 1.3 Hz, 1H), 2.31–2.42
(m, 1H), 3.00 (d, J=10.5 Hz, 1H), 3.48 (br, 2H), 3.58 (d, J=12.0 Hz,
1H), 3.68 (dd, J=11.2, 3.7 Hz, 1H), 3.70–3.76 (m, 1H), 3.84 (td, J=10.6,
1.0 Hz, 1H), 4.19 (d, J=12.0 Hz, 1H), 4.25 (t, J=10.8, 1H), 4.52 (dd, J=
10.4, 3.6 Hz, 1H), 5.69 (dd, J=10.2, 2.8 Hz, 1H), 6.17–6.26 (m, 1H),
7.28–7.38 ppm (m, 5H); 13C NMR (75.5 MHz, CDCl3): d=20.9, 27.1,
1
60.8, 127.0 (q, JCF =284.6 Hz), 172.4 ppm; 19F NMR (282.4 MHz, CDCl3):
d=À80.1 ppm (s, 3F); HRMS (EI): m/z calcd for C11H19F3NO3: 270.1317
[M+H+]; found: 270.1316.
(+)-(2S,6S)-6-(Ethoxycarbonylmethyl)-2-(methoxycarbonyl)-2-(trifluoro-
methyl)piperidine (22): General procedure C and 21 (65 mg, 0.241 mmol)
were employed to obtain 22 (40 mg, 56%) as a colorless oil. Rf =0.30
(hexane/EtOAc, 5:1); [a]25D = +0.9 (c=0.8 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.16 (qd, J=12.1, 3.5 Hz, 1H), 1.27 (t, J=7.1 Hz,
3H), 1.28–1.40 (m, 1H), 1.55–1.62 (m, 1H), 1.66 (td, J=12.8, 4.1 Hz,
1H), 1.75–1.83 (m, 1H), 2.30–2.38 (m, 1H), 2.40 (d, J=6.4 Hz, 2H),
2.90–3.00 (m, 1H), 3.14 (br, 1H), 3.84 (s, 3H), 4.16 ppm (q, J=7.1 Hz,
5
2
46.4, 60.1, 60.6, 62.3, 64.8 (q, JCF =4.1 Hz)„ 65.0 (q, JCF =23.6 Hz), 123.8,
125.6 (q, 1JCF =290.0 Hz), 128.1, 128.2, 128.6, 130.7, 138.6, 170.4 ppm;
19F NMR (282.4 MHz, CDCl3): d=À73.2 ppm (s, 3F); HRMS (FAB): m/z
calcd for C18H22F3NO4 [M]+: 373.1501; found: 373.1503.
2H); 13C NMR (75.5 MHz, CDCl3): d=14.2, 20.6, 25.7 (q, 3JCF =1.6 Hz),
1
30.5, 41.5, 49.4, 53.1, 60.6, 66.7 (q, 2JCF =26.7 Hz), 124.2 (q, JCF
=
283.8 Hz), 169.5, 171.7 ppm; 19F NMR (282.4 MHz, CDCl3): d=
À78.4 ppm (s, 3F); HRMS (EI): m/z calcd for C12H19F3NO4: 298.1266
[M+H+]; found: 298.1262.
(+)-(2S,6S)-6-(tert-Butoxycarbonylaminomethyl)-2-(hydroxymethyl)-2-
(trifluoromethyl)piperidine (27): General procedure B and 25 (69 mg,
0.193 mmol) in the presence of Boc2O (1.5 equiv) were employed with
stirring for 6 h to obtain 27 (46 mg, 76%) as a colorless oil. Rf =0.18
(hexane/EtOAc, 3:1); [a]25D = +17.8 (c=1.2 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.09 (qd, J=12.5, 4.0 Hz, 1H), 1.42 (s, 9H), 1.44–
1.54 (m, 2H), 1.57–1.66 (m, 2H), 1.66–1.80 (m, 1H), 2.38 (br, 1H), 2.82–
2.93 (m, 1H), 2.98–3.17 (m, 2H), 3.70 (d, J=12.5 Hz, 1H), 3.86 (d, J=
12.5 Hz, 1H), 5.04 ppm (br, 1H); 13C NMR (75.5 MHz, CDCl3): d=19.3,
24.2 (q, 3JCF =1.9 Hz), 28.2, 28.3, 46.5, 49.5, 58.2, 59.5 (q, 2JCF =23.9 Hz),
(À)-(4R,6S,9aS)-6-(Azidomethyl)-4-phenyl-9a-(trifluoromethyl)-3,4,6,7-
tetrahydropyridoACHTUNGTRENNUNG[2,1-c]ACHTUNGTRENNUNG[1,4]oxazin-1ACHTNGURTEN(NUGN 9aH)-one (23): NaN3 (50 mg,
0.771 mmol) was added to a solution of 13 (169 mg, 0.385 mmol) in DMF
(1.9 mL). The reaction mixture was stirred at 658C for 4 h, concentrated
under reduced pressure, and purified by column chromatography on
silica gel to afford 23 (131 mg, 97%) as a white solid. Rf =0.27 (hexane/
1
EtOAc, 15:1); m.p. 47–498C; [a]25D =À137.2 (c=1.5 in CHCl3); H NMR
(300 MHz, CDCl3): d=1.98–2.26 (m, 2H), 3.07 (qd, J=6.7, 4.4 Hz, 1H),
3.22 (dd, J=12.4, 6.4 Hz, 1H), 3.34 (dd, J=12.4, 6.4 Hz, 1H), 4.37–4.45
1
79.6, 127.0 (q, JCF =282.6 Hz), 156.5 ppm; 19F NMR (282.4 MHz, CDCl3):
3760
www.chemeurj.org
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 3753 – 3764

Preparation of Optically Pure Quaternary Piperidines
FULL PAPER
d=À80.4 ppm (s, 3F); HRMS (FAB): m/z calcd for C13H24F3N2O3:
313.1739 [M+H+]; found: 313.1738.
fied by column chromatography on silica gel to afford 32 (39 mg, 93%)
as a white solid. Rf =0.24 (hexane/EtOAc, 5:1); m.p. 48–508C; [a]25
=
D
À81.5 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=1.68–1.76 (m,
1H), 1.92–2.00 (m, 1H), 2.00 (s, 3H), 2.02 (s, 3H), 2.19 (s, 3H), 3.24–3.33
(m, 1H), 3.97–4.05 (m, 1H), 4.31 (dt, J=12.1, 1.1 Hz, 1H), 4.38 (dd, J=
11.2, 4.2 Hz, 1H), 4.58 (d, J=4.2 Hz, 1H), 4.86 (dd, J=12.1, 4.5 Hz, 1H),
5.37–5.46 (m, 1H), 5.99 (dd, J=2.6, 0.9 Hz, 1H), 7.41–7.43 (m, 3H),
7.49–7.58 ppm (m, 2H); 13C NMR (75.5 MHz, CDCl3): d=20.7, 20.8,
20.8, 24.5, 53.4, 57.2, 63.8, (c, 5JCF =5.9 Hz), 64.8 (q, 3JCF =3.4 Hz), 66.7
(q, 4JCF =1.0 Hz), 69.9 (q, 2JCF =27.2 Hz), 70.0 (q, 5JCF =3.5 Hz), 123.6 (q,
1JCF =295.4 Hz), 126.9, 128.5, 128.9, 140.7, 163.3 (q, 3JCF =2.1 Hz), 168.6,
169.9, 170.5 ppm; 19F NMR (282.4 MHz, CDCl3): d=À67.4 ppm (s, 3F);
HRMS (FAB): m/z calcd for C22H24F3NO8Na: 510.1352 [M+Na+];
found: 510.1347.
(+)-(2S,6S)-6-(Acetoxymethyl)-2-(hydroxymethyl)-2-(trifluoromethyl)pi-
peridine (28): General procedure B and 26 (91 mg, 0.24 mmol) were em-
ployed with stirring for 6 h to obtain 28 (56 mg, 90%) as a white solid.
Rf =0.25 (hexane/EtOAc, 1:1); m.p. 57–598C; [a]25D = +32.8 (c=0.4 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.14 (qd, J=12.3, 4.1 Hz, 1H),
1.41–1.70 (m, 4H), 1.75–1.85 (m, 1H), 1.99 (br, 1H), 2.07 (s, 3H), 2.33
(br, 1H), 2.94–3.05 (m, 1H), 3.76 (d, J=12.5 Hz, 1H), 3.81–3.87 (m, 1H),
3.85 (dd, J=10.9, 7.9 Hz, 1H), 4.12 ppm (dd, J=10.9, 4.0 Hz, 1H);
13C NMR (75.5 MHz, CDCl3): d=19.1, 20.8, 24.2 (q, 3JCF =2.0 Hz), 27.1,
48.9, 58.5, 59.3 (q, 2JCF =24.0 Hz), 68.6, 127.1 (q, 1JCF =282.6 Hz),
170.9 ppm; 19F NMR (282.4 MHz, CDCl3): d=À80.5 ppm (s, 3F); HRMS
(FAB): m/z calcd C10H17F3NO3: 256.1161 [M+H+]; found: 256.1164.
(À)-(2S,6S)-2,6-Bis(hydroxymethyl)-6-(trifluoromethyl)-1,2,3,6-tetrahy-
dropyridine (33): A solution of 26 (33 mg, 0.088 mmol) in HCl (1.25m in
MeOH, 0.71 mL, 0.88 mmol) was heated under microwave irradiation at
1008C for 10 min. Saturated aqueous NaHCO3 was added to the reaction
mixture, the aqueous layer was extracted with EtOAc (3ꢇ), and the com-
bined organic layers were dried over Na2SO4. The filtrates were concen-
trated and purified by column chromatography on silica gel to afford 33
(15 mg, 80%) as a white solid. Rf =0.26 (hexane/EtOAc, 1:2); m.p. 74–
(+)-(2S,6S)-6-(tert-Butoxycarbonylaminomethyl)-2-(methoxycarbonyl)-2-
(trifluoromethyl)piperidine (29): General procedure C and 27 (25 mg,
0.08 mmol) were employed to obtain 29 (14 mg, 51%) as a white solid.
Rf =0.21 (hexane/EtOAc, 5:1); m.p. 52–548C; [a]25D = +6.9 (c=0.3 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.06–1.36 (m, 2H), 1.45 (s,
9H), 1.51–1.61 (m, 1H), 1.66 (dd, J=13.0, 4.0 Hz, 1H), 1.75–1.87 (m,
1H), 2.11 (br, 1H), 2.34 (dtd, J=12.9, 3.5, 1.7 Hz, 1H), 2.64–2.84 (m,
1H), 3.00–3.22 (m, 2H), 3.81 (s, 3H), 4.81 ppm (br, 1H); 13C NMR
(75.5 MHz, CDCl3): d=20.4, 25.9, 27.6, 28.3, 46.2, 52.0, 53.2, 66.7 (q,
2JCF =26.5 Hz), 79.4, 124.2 (q, 1JCF =282.6 Hz), 156.1, 169.5 ppm;
19F NMR (282.4 MHz, CDCl3): d=À78.3 ppm (s, 3F); HRMS (FAB): m/z
calcd for C14H23F3N2O4: 341.1688 [M+H+]; found: 341.1695.
1
768C; [a]25D =À50.5 (c=1.1 in CHCl3); H NMR (300 MHz, CDCl3): d=
1.85–1.90 (m, 2H), 3.02–3.10 (m, 1H), 3.23 (br, 3H), 3.46 (dd, J=10.7,
8.2 Hz, 1H), 3.62–3.67 (m, 2H), 3.77 (d, J=12.4 Hz, 1H), 5.44 (ddd, J=
10.2, 2.4, 1.7 Hz, 1H), 6.04 ppm (ddd, J=10.2, 5.0, 3.1 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): d=27.0, 48.9, 61.6 (q, 2JCF =25.1 Hz), 61.6, 65.8,
121.1 (q, 4JCF =1.9 Hz), 125.9 (q, 1JCF =284.5 Hz), 131.2 ppm; 19F NMR
(282.4 MHz, CDCl3): d=À77.0 ppm (s, 3F); HRMS (EI): m/z calcd for
C8H13F3NO2: 212.0898 [M+H+]; found: 212.0896.
(+)-(2S,6S)-6-(Acetoxymethyl)-2-(methoxycarbonyl)-2-(trifluoromethyl)-
piperidine (30): General procedure C and 28 (41 mg, 0.505 mmol) were
employed to obtain 30 (21 mg, 47%) as a colorless oil. Rf =0.26 (hexane/
EtOAc, 4:1); [a]25D = +7.1 (c=0.2 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=1.04–1.38 (m, 2H), 1.52–1.62 (m, 1H), 1.69 (td, J=13.0,
4.2 Hz, 1H), 1.77–1.89 (m, 1H), 2.10 (s, 3H), 2.32–2.42 (m, 1H), 2.76 (br,
1H), 2.79–2.91 (m, 1H), 3.77 (dd, J=10.9, 8.7 Hz, 1H), 3.83 (s, 3H),
4.17 ppm (dd, J=10.9, 3.7 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=
20.2, 20.8, 26.0 (q, 3JCF =1.6 Hz), 26.6, 51.3, 53.2, 66.3 (q, 2JCF =26.4 Hz),
68.4, 124.1 (q, 1JCF =282.0 Hz), 169.5, 170.8 ppm; 19F NMR (282.4 MHz,
CDCl3): d=À78.8 ppm (s, 3F); HRMS (EI): m/z calcd for C11H17F3NO4:
284.1110 [M+H+]; found: 284.1111.
(À)-(2S,6S)-2,6-Bis(acetoxymethyl)-6-(trifluoromethyl)-1,2,3,6-tetrahy-
dropyridine (34): Ac2O (0.01 mL, 0.106 mmol), pyridine (0.085 mL,
0.106 mmol), and DMAP (0.5 mg, 0.003 mmol) were added to a solution
of 33 (7.5 mg, 0.035 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was
stirred at room temperature for 6 h. Saturated aqueous NH4Cl was added
was added to the reaction mixture, the aqueous layer was extracted with
EtOAc, and the combined organic layers were dried over Na2SO4, fil-
tered, and concentrated under reduced pressure. The product was puri-
fied by column chromatography on silica gel to afford 34 (10 mg, 95%)
as a colorless oil. Rf =0.52 (hexane/EtOAc, 2:1); [a]25D =À56.1 (c=1.9 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.80–2.00 (m, 3H), 2.03 (s,
3H), 2.05 (s, 3H), 3.12–3.21 (m, 1H), 3.78 (dd, J=10.9, 8.6 Hz, 1H), 4.17
(d, J=12.1 Hz, 1H), 4.19 (dd, J=10.9, 3.5 Hz, 1H), 4.30 (dq, J=12.1,
1.6 Hz, 1H), 5.50 (ddd, J=10.2, 2.8, 1.3 Hz, 1H), 6.10 ppm (ddd, J=10.1,
5.7, 2.3 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=20.6, 20.7, 27.4, 46.8,
(À)-(4R,6S,8R,9S,9aS)-6-(Acetoxymethyl)-8,9-dihydroxy-4-phenyl-9a-
(trifluoromethyl)hexahydropyrido
G
G
(31):
NMO (43 mg, 0.362 mmol) and OsO4 (2.5% wt in 2-methylpropanol;
0.284 mL, 0.018 mmol) were added to solution of 24 (67 mg,
a
0.181 mmol) in acetone/H2O (8:1, 1.8 mL). The reaction mixture was
stirred for 48 h at room temperature. The reaction was quenched with
some drops of 10% aqueous NaHSO3, filtered through a short pad of
silica with EtOAc as the eluent, and concentrated under reduced pres-
sure. The crude reaction mixture was purified by column chromatography
on silica gel to afford 31 (65 mg, 89%) as a white solid. Rf =0.20
(hexane/EtOAc, 2:1); m.p. 51–538C; [a]25D =À153.0 (c=1.5 in CHCl3);
1H NMR (300 MHz, CDCl3): d=1.74 (dd, J=12.9, 4.8 Hz, 1H), 1.84–1.95
(m, 1H), 2.01 (s, 3H), 2.64 (d, J=10.4 Hz, 1H), 3.14–3.25 (m, 1H), 3.57
(d, J=4.5 Hz, 1H), 3.98 (td, J=10.1, 1.1 Hz, 1H), 4.11–4.24 (m, 1H),
4.24–4.34 (m, 2H), 4.59 (m, 2H), 4.90 (dd, J=13.0, 4.8 Hz, 1H), 7.27–
7.39 (m, 3H), 7.50–7.56 ppm (m, 2H); 13C NMR (75.5 MHz, CDCl3): d=
20.8, 27.4, 53.8, 57.4, 63.3 (q, 3JCF =3.5 Hz), 63.9 (q, 5JCF =5.4 Hz), 68.2,
70.6 (q, 5JCF =3.7 Hz), 71.3 (q, 2JCF =25.6 Hz), 124.2 (q, 1JCF =293.9 Hz),
126.8, 128.3, 128.9, 140.8, 166.1 (q, 3JCF =2.2 Hz), 170.7 ppm; 19F NMR
(282.4 MHz, CDCl3): d=À67.8 ppm (s, 3F); HRMS (FAB): m/z calcd for
C18H21F3NO6: 404.1321 [M+H+]; found: 404.1324.
2
1
60.2 (q, JCF =26.7 Hz), 62.5, 67.6, 120.5 (q, 4JCF =1.7 Hz), 125.2 (q, JCF
=
283.3 Hz), 131.5, 170.2, 170.6 ppm; 19F NMR (282.4 MHz, CDCl3): d=
À78.0 ppm (s, 3F); HRMS (EI): m/z calcd for C12H17F3NO4: 296.1110
[M+H+]; 296.1117.
(À)-(2R,3S,4R,6S)-3,4-Bis
ACHTUNGTREN(NGNU acetoxy)-2,6-bis(acetoxymethyl)-2-(trifluoro-
methyl)piperidine (36): NMO (21 mg, 0.176 mmol) and OsO4 (2.5% wt
in 2-methylpropanol, 0.11 mL, 0.009 mmol) was added to a solution of 34
(26 mg, 0.088 mmol) in acetone/H2O (8:1,1.3 mL). The reaction mixture
was stirred for 48 h at room temperature and then quenched with some
drops of 10% aqueous NaHSO3, filtered through a short pad of silica
with EtOAc, and concentrated under reduced pressure. Ac2O (0.033 mL,
0.352 mmol) and DMAP (1 mg, 0.009 mmol) were added to the residue
dissolved in CH2Cl2 (1.5 mL) and pyridine (0.028 mL, 0.352 mmol). The
reaction mixture was stirred for 24 h at room temperature. Saturated
aqueous NH4Cl was added to the reaction mixture, the aqueous layer
was extracted with EtOAc (3ꢇ), and the combined organic layers were
dried over Na2SO4. The filtrates were concentrated and purified by
column chromatography on silica gel to afford 44 (26 mg, 71%) as a col-
orless oil. Rf =0.34 (hexane/EtOAc, 2:1); [a]25D =À60.8 (c=0.9 in
(À)-(4R,6S,8R,9S,9aS)-6-(Acetoxymethyl)-8,9-(diacetoxy)-4-phenyl-9a-
(trifluoromethyl)hexahydropyridoACHTUNGTNER[NNUG 2,1-c]AHCTUNRTGEG[NNUN 1,4]oxazin-1ACTHNUGTREN(NUGN 6H)-one (32): 4-
Dimethylaminopyridine (DMAP; 11 mg, 0.086 mmol), pyridine
(0.035 mL, 0.430 mmol), and Ac2O (0.041 mL, 0.430 mmol) were added
to a solution of 31 (35 mg, 0.086 mmol) in CH2Cl2 (1.8 mL). The reaction
mixture was stirred at room temperature for 16 h and quenched with sa-
turated aqueous NH4Cl. The aqueous layer was extracted with EtOAc
(3ꢇ) and the combined organic layers were dried over Na2SO4. The fil-
trates were concentrated under reduced pressure concentrated and puri-
1
CHCl3); H NMR (300 MHz, CDCl3): d=1.55 (ddd, J=14.1, 11.9, 3.0 Hz,
1H), 1.75 (ddd, J=14.2, 3.4, 2.6 Hz, 1H), 1.96 (s, 3H), 2.03 (s, 3H), 2.07
(s, 3H), 2.08 (s, 3H), 3.22–3.31 (m, 1H), 3.73 (dd, J=11.0, 8.4 Hz, 1H),
4.15 (dd, J=11.0, 3.4 Hz, 1H), 4.29 (d, J=12.8 Hz, 1H), 5.12 (dq, J=
Chem. Eur. J. 2012, 18, 3753 – 3764
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3761

S. Fustero, J. L. AceÇa et al.
12.7, 2.1 Hz, 1H), 5.27 (d, J=3.9 Hz, 1H), 5.41 ppm (q, J=3.5 Hz, 1H);
CH2Cl2/MeOH (2:1, 4.3 mL) at 08C. The reaction mixture was vigorously
stirred for 1 h at 08C, H2O (4.3 mL) was added, and the temperature was
allowed to warm to room temperature. After 4 h of additional stirring,
the reaction mixture was filtered through celite with CH2Cl2 and H2O as
the eluents. The organic solvents were removed under reduced pressure,
the aqueous residue was washed with CH2Cl2, and the mixture concen-
trated under reduced pressure. The product was purified by DOWEX
50WX8-100 to afford 40 (50 mg, 60%) as a white solid. M.p. 269–2718C;
[a]25D =À8.7 (c=1.1 in MeOH); 1H NMR (300 MHz, MeOD): d=0.97
(d, J=6.3 Hz, 6H), 1.33–1.48 (m, 1H), 1.48–1.60 (m, 1H), 1.60–1.73 (m,
2H), 1.74–1.92 (m, 3H), 2.07 (q, J=6.9 Hz, 2H), 4.95 (d, J=10.2 Hz,
1H), 5.02 (dq, J=17.2, 1.9 Hz, 1H), 5.80 ppm (ddt, J=17.0, 10.4, 6.9 Hz,
1H); 13C NMR (75 MHz, MeOD): d=23.3, 23.8,25.0, 25.2, 34.8, 38.7,
46.5, 65.5, 115.5, 139.2, 175.0 ppm; HRMS (EI): m/z calcd for C11H22NO2:
200.1651 [M+H+]; found 200.1645.
13C NMR (75.5 MHz, CDCl3): d=20.4, 20.6, 20.7, 21.0, 31.1, 44.1, 58.3,
1
61.5 (q, 2JCF =24.5 Hz), 66.8, 67.3, 68.1 (q, 3JCF =2.2 Hz), 125.1 (q, JCF
=
286.4 Hz), 168.8, 169.6, 170.2, 170.4 ppm; 19F NMR (282.4 MHz, CDCl3):
d=À76.4 ppm (s, 3F); HRMS (EI): m/z calcd for C16H23F3NO8: 414.1376
[M+H+]; found: 414.1370.
(À)-(3S,5R)-3-Methyl-3-(pent-4-enyl)-5-phenylmorpholin-2-one
(37):
BF3·OEt2 (0.21 mL, 1.64 mmol) was added to a solution of 1[13] (200 mg,
0.82 mmol) in toluene (8.2 mL) at À788C. After stirring for 2 h, MeMgBr
(3m in Et2O, 0.55 mL, 1.64 mmol) was added dropwise to the reaction
mixture over 15 min. The reaction mixture was stirred at À788C for 4 h,
and then saturated aqueous NH4Cl was added. The aqueous layer was ex-
tracted with EtOAc and the combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The product
was purified by column chromatography on silica gel to afford 37
(137 mg, 65%) as a white solid. Rf =0.16 (hexane/EtOAc, 15:1); m.p. 67–
Methyl
(+)-(R)-2-(tert-butoxycarbonylamino)-2-methylhept-6-enoate
1
698C; [a]25D =À12.0 (c=0.9 in CHCl3); H NMR (300 MHz, CDCl3): d=
(41): Boc2O (3.27 g, 14.98 mmol) and NaOH (10% aq., 5 mL) were
added to a solution of 39 (785 mg, 4.99 mmol) in THF/H2O (2:1, 50 mL).
The reaction mixture was stirred at room temperature for 12 h, and the
organic solvents were removed under reduced pressure. The aqueous
phase was washed with EtOAc and acidified with citric acid (10% aq.)
until pH 3 was reached. The aqueous layer was extracted with EtOAc
(3ꢇ), and the combined organic layers were dried over Na2SO4 and con-
centrated under reduced pressure. TMSCHN2 (2m in hexane, 3.7 mL,
7.49 mmol) was added dropwise to the residue dissolved in PhMe/MeOH
(2.5:1, 50 mL) at 08C. The reaction mixture was stirred at 08C for 12 h
and quenched with some drops of AcOH. The organic solvents were re-
moved under reduced pressure, and the crude mixture was purified by
column chromatography on silica gel to afford 41 (880 mg, 65%) as a col-
orless oil. Rf =0.40 (hexane/EtOAc, 8:1); [a]25D = +6.3 (c=1.0 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.14–1.27 (m, 1H), 1.29–1.39
(m, 1H), 1.41 (s, 9H), 1.50 (s, 3H), 1.74 (ddd, J=13.4, 12.0, 4.8 Hz, 1H),
1.93–2.09 (m, 3H), 3.71 (s, 3H), 4.93 (d, J=9.2 Hz, 1H), 4.97 (dq, J=
16.9, 1.7 Hz, 1H), 5.21 (br, 1H), 5.73 ppm (ddt, J=16.9, 10.2, 6.6 Hz,
1H); 13C NMR (75 MHz, CDCl3): d=23.2, 23.3, 28.3, 33.4, 36.6, 52.4,
59.5, 79.4, 114.9, 138.1, 154.3, 175.0 ppm; HRMS (EI): m/z calcd for
C14H26NO4: 272.1862 [M+H+]; found 272.1856.
1.38–1.52 (m, 2H), 1.52–1.61 (m, 1H), 1.54 (s, 3H), 1.80–1.93 (m, 1H),
2.01 (dd, J=11.9, 3.2 Hz, 1H), 2.06–2.16 (m, 2H), 4.23 (t, J=10.6 Hz,
1H), 4.31 (dd, J=10.4, 3.2 Hz, 1H), 4.38 (dd, J=10.5, 3.2 Hz, 1H), 4.98
(d, J=10.2 Hz, 1H), 5.04 (dq, J=17.6, 1.8 Hz, 1H), 5.83 (ddt, J=16.9,
10.2, 6.6 Hz, 1H), 7.32–7.48 ppm (m, 5H); 13C NMR (75.5 MHz, CDCl3):
d=23.5, 27.3, 33.7, 42.0, 53.2, 60.9, 75.4, 114.8, 127.1, 128.6, 128.8, 138.0,
138.4, 173.2 ppm; HRMS (EI): m/z calcd for C16H22NO2: 260.1651 [M+
H+]; found 260.1645.
(À)-(3R,5R)-3-Isobutyl-3-(pent-4-enyl)-5-phenylmorpholin-2-one (38):
BF3·OEt2 (0.21 mL, 1.64 mmol) was added to a solution of 1[13] (200 mg,
0.82 mmol) in THF (8.2 mL) at À788C. After stirring for 2 h, iBuMgBr
(2m in THF, 0.82 mL, 1.64 mmol) was added dropwise to the reaction
mixture over 15 min. The reaction mixture was stirred at À788C for 4 h,
and then saturated aqueous NH4Cl was added. The aqueous layer was ex-
tracted with EtOAc and the combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The product
was purified by column chromatography on silica gel to afford 38
(119 mg, 48%) as a colorless oil. Rf =0.20 (hexane/EtOAc, 10:1); [a]25
=
D
À2.1 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=0.98 (d, J=
6.5 Hz, 3H), 1.00 (d, J=6.4 Hz, 3H), 1.41–1.67 (m, 4H), 1.81–1.94 (m,
3H), 1.98–2.16 (m, 3H), 4.24 (t, J=10.5 Hz, 1H), 4.31 (dd, J=10.4,
3.3 Hz, 1H), 4.39 (dd, J=10.5, 3.3 Hz, 1H), 4.98 (d, J=10.2 Hz, 1H),
5.04 (dq, J=17.3, 2.0 Hz, 1H), 5.83 (ddt, J=17.0, 10.6, 6.8 Hz, 1H), 7.30–
7.47 ppm (m, 5H); 13C NMR (75.5 MHz, CDCl3): d=23.7, 24.1,24.2, 25.1,
33.8, 41.4, 48.8, 53.6, 63.6, 75.0, 114.8, 127.2, 128.6, 128.8, 138.2, 138.4,
173.2 ppm; HRMS (EI): m/z calcd for C19H28NO2: 302.2120 [M+H+];
found. 302.2115.
Methyl
(+)-(S)-2-(tert-Butoxycarbonylamino)-2-isobutylhept-6-enoate
(42): Boc2O (177 mg, 0.81 mmol) and NaOH (10% aq., 0.27 mL) were
added to a solution of 40 (54 mg, 0.27 mmol) in THF/H2O (2:1, 2.7 mL).
The reaction mixture was stirred at room temperature for 12 h, and the
organic solvents were removed under reduced pressure. The aqueous
phase was washed with EtOAc and acidified with citric acid (10% aq.)
until pH 3 was reached. The aqueous layer was extracted with EtOAc
(3ꢇ), and the combined organic layers were dried over Na2SO4 and con-
centrated under reduced pressure. TMSCHN2 (2m in hexane, 0.21 mL,
0.41 mmol) was added dropwise to the residue dissolved in PhMe/MeOH
(2.5:1, 2.7 mL) at 08C. The reaction mixture was stirred at 08C for 12 h
and quenched with some drops of AcOH. The organic solvents were re-
moved under reduced pressure and the crude mixture was purified by
column chromatography on silica gel to afford 42 (60 mg, 70%) as a col-
orless oil. Rf =0.45 (hexane/EtOAc, 10:1); [a]25D = +2.7 (c=1.1 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.76 (d, J=6.4 Hz, 3H), 0.89
(d, J=6.5 Hz, 3H), 0.93–1.11 (m, 1H), 1.29–1.40 (m, 1H), 1.43 (s, 9H),
1.49–1.73 (m, 4H), 2.00 (q, J=6.9 Hz, 2H), 2.27–2.42 (m, 1H), 3.73 (s,
3H), 4.92 (d, J=10.1 Hz, 1H), 4.97 (dq, J=17.2, 1.6 Hz, 1H), 5.65 (br,
1H), 5.73 ppm (ddt, J=16.9, 10.2, 6.6 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3): d=22.8, 23.2, 23.8, 24.6, 28.4, 33.3, 35.9, 44.0, 52.4, 63.3, 78.9,
114.7, 138.3, 153.6, 175.3 ppm; HRMS (EI): m/z calcd for C17H32NO4:
314.2331 [M+H+]; found 314.2326.
(+)-(S)-2-Amino-2-methylhept-6-enoic acid (39): LiOH·H2O (582 mg,
13.88 mmol) was added to a solution of 37 (1.8 g, 6.94 mmol) in THF/
H2O (5:1, 69 mL). The reaction mixture was stirred for 3 h and the or-
ganic solvents were removed under reduced pressure. The aqueous phase
was washed with Et2O and concentrated under reduced pressure. Pb-
ACHTUNGTRENNUNG(OAc)4 (4.62 g, 10.41 mmol) was added to the residue dissolved in
CH2Cl2/MeOH (2:1, 69 mL) at 08C. The reaction mixture was vigorously
stirred for 1 h at 08C, H2O (69 mL) was added, and the temperature was
allowed to warm to room temperature. After 4 h of additional stirring,
the reaction mixture was filtered through celite with CH2Cl2 and H2O as
the eluents. The organic solvents were removed under reduced pressure,
the aqueous residue was washed with CH2Cl2, and the mixture concen-
trated under reduced pressure. The product was purified by DOWEX
50WX8-100 to afford 39 (900 mg, 82%) as a white solid, the NMR spec-
troscopic data of which matched those previously reported.[26a] M.p. 300–
3018C; [a]25D = +12.0 (c=1.0 in MeOH) (lit. data: m.p.>2008C
(decomp.); [a]25D = +10.8 (c=0.83 in MeOH));[26a] HRMS (EI): m/z
calcd for C8H16NO2: 158.1181 [M+H+]; found 158.1176.
1-Ethyl 8-methyl (+)-(S,E)-7-(tert-butoxycarbonylamino)-7-methyloct-2-
enedioate (43): The Grubbs second-generation catalyst (64 mg,
10 mol%) and ethyl acrylate (0.16 mL, 1.51 mmol) were added to a solu-
tion of 41 (205 mg, 0.755 mmol) in CH2Cl2 (3.8 mL). The reaction mix-
ture was heated under reflux for 3 h, allowed to cool to room tempera-
ture, and concentrated under reduced pressure. The product was purified
by column chromatography on silica gel to afford 43 (243 mg, 93%) as a
colorless oil. Rf =0.45 (hexane/EtOAc, 4:1); [a]25D = +7.1 (c=1.1 in
(À)-(R)-2-Amino-2-isobutylhept-6-enoic acid (40): LiOH·H2O (36 mg,
0.86 mmol) was added to a solution of 38 (130 mg, 0.43 mmol) in THF/
H2O (5:1, 4.3 mL). The reaction mixture was stirred for 3 h and the or-
ganic solvents were removed under reduced pressure. The aqueous phase
was washed with Et2O and concentrated under reduced pressure. Pb-
ACHTUNGTRENNUNG(OAc)4 (286 mg, 0.645 mmol) was added to the residue dissolved in
3762
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ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 3753 – 3764

Preparation of Optically Pure Quaternary Piperidines
FULL PAPER
CHCl3); 1H NMR (300 MHz, CDCl3): d=1.20–1.30 (m, 1H), 1.21 (t, J=
7.1 Hz, 3H), 1.32–1.42 (m, 1H), 1.36 (s, 9H), 1.45 (s, 3H), 1.75 (ddd, J=
13.5, 12.0, 4.8 Hz, 1H), 1.93–2.07 (m, 1H), 2.12 (q, J=7.0 Hz, 2H), 3.68
(s, 3H), 4.11 (q, J=7.0, 2H), 5.25 (br, 1H), 5.74 (dt, J=15.6, 1.4, 1H)
6.84 ppm (dt, J=15.6, 6.8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): d=
14.1, 22.4, 23.3, 28.2, 31.7, 36.2, 52.4, 59.3, 60.0, 79.4, 121.6, 148.1, 154.1,
166.4, 174.7 ppm; HRMS (EI): m/z calcd for C17H30NO6: 344.2073 [M+
H+]; found 344.2068.
Acknowledgements
We would like to thank MICINN of Spain (CTQ2010-19774) and Gener-
alitat Valenciana (PROMETEO/2010/061 and ACOMP/2011/052) for
their financial support. L.A. and N.M. thank the Universidad de Valencia
for predoctoral fellowships, and J.L.A. thanks the MICINN for a Ramꢀn
y Cajal research contract.
1-Ethyl 8-methyl (+)-(R,E)-7-(tert-butoxycarbonylamino)-7-isobutyloct-
2-enedioate (44): The Grubbs second-generation catalyst (16 mg,
10 mol%) and ethyl acrylate (0.04 mL, 0.38 mmol) were added to a solu-
tion of 42 (60 mg, 0.19 mmol) in CH2Cl2 (1.0 mL). The reaction mixture
was heated under reflux for 3 h, allowed to cool to room temperature,
and concentrated under reduced pressure. The product was purified by
column chromatography on silica gel to afford 44 (70 mg, 95%) as a col-
orless oil. Rf =0.40 (hexane/EtOAc, 5:1); [a]25D = +3.0 (c=0.9 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=0.75 (d, J=6.4 Hz, 3H), 0.88
(d, J=6.6 Hz, 3H), 0.99–1.17 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.42 (s,
9H), 1.46–1.54 (m, 1H), 1.54–1.59 (m, 1H), 1.59–1.65 (m, 1H), 1.65–1.75
(m, 1H), 2.07–2.23 (m, 2H), 2.23–2.42 (m, 2H), 3.74 (s, 3H), 4.16 (q, J=
7.1 Hz, 2H), 5.65 (br, 1H), 5.77 (dt, J=15.7, 1.6 Hz, 1H), 6.87 ppm (dt,
J=15.7, 6.8, Hz, 1H); 13C NMR (75 -MHz, CDCl3): d=14.2, 22.4, 22.8,
23.7, 24.5, 28.3, 31.7, 35.8, 44.0, 52.5, 60.1, 63.2, 79.0, 121.5, 148.4, 153.6,
166.6, 175.0 ppm; HRMS (EI): m/z calcd for C20H36NO6: 386.2543 [M+
H+]; found 386.2537.
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(+)-(2S,6S)-6-(Ethoxycarbonylmethyl)-2-(methoxycarbonyl)-2-methylpi-
peridine (45): TFA (0.27 mL, 3.55 mmol) was added to a solution of 43
(243 mg, 0.71 mmol) in CH2Cl2 (7.1 mL). The reaction mixture was
stirred overnight at room temperature. The solvents were evaporated
under reduced pressure, the residue was dissolved in CH2Cl2 (7.1 mL),
and Et3N (0.30 mL, 2.13 mmol) was added to the residue. The reaction
mixture was heated under microwave irradiation at 1008C for 50 min.
The organic solvents were removed under reduced pressure, and the
crude mixture was purified by column chromatography on silica gel to
afford 45 (96 mg, 56%) and the (2S,6R) diastereoisomer epi-45 (24 mg,
14%) as colorless oils. 45: Rf =0.29 (hexane/EtOAc, 1:1); [a]25 +7.1
D
(c=1.1, CHCl3); 1H NMR (300 MHz, CDCl3): d=1.08 (qd, J=11.7,
3.4 Hz, 1H), 1.19–1.28 (m, 1H), 1.23 (s, 3H), 1.24 (t, J=7.0 Hz, 3H),
1.27–1.40 (m, 1H), 1.55 (dd, J=13.4, 1.9 Hz, 1H), 1.60–1.70 (m, 1H),
2.16 (d, J=10.6 Hz, 1H), 2.30–2.36 (m, 2H), 2.68 (br, 1H), 2.87–2.98 (m,
1H), 3.70 (s, 3H), 4.12 ppm (q, J=7.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3): d=14.2, 22.0, 28.6, 31.2, 33.7, 41.7, 50.2, 51.9, 60.2, 60.3, 171.9,
176.9 ppm; HRMS (EI): m/z calcd for C12H22NO4: 244.1549 [M+H+];
found 244.1543.
(+)-(2R,6S)-6-(Ethoxycarbonylmethyl)-2-isobutyl-2-(methoxycarbonyl)-
piperidine (46): TFA (0.07 mL, 0.90 mmol) was added to a solution of 44
(70 mg, 0.18 mmol) in CH2Cl2 (1.8 mL). The reaction mixture was stirred
overnight at room temperature. The solvents were evaporated under re-
duced pressure, the residue was dissolved in CH2Cl2 (1.8 mL), and Et3N
(0.07 mL, 0.54 mmol) was added to the residue. The reaction mixture was
heated under microwave irradiation at 1008C for 50 min. The organic sol-
vents were removed under reduced pressure, and the crude mixture was
purified by column chromatography on silica gel to afford 46 (27 mg,
52%) and the (2S,6R) diastereoisomer epi-46 (7 mg, 14%) as colorless
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D
1H NMR (300 MHz, CDCl3): d=0.85 (d, J=6.6 Hz, 3H), 0.87 (d, J=
6.6 Hz, 3H), 1.10 (qd, J=12.1, 3.7 Hz, 1H), 1.20–1.37 (m, 2H), 1.26 (t,
J=7.1 Hz, 3H), 1.47–1.61 (m, 3H), 1.61–1.75 (m, 2H), 2.16–2.23 (m,
1H), 2.32–2.36 (m, 2H), 2.93–3.05 (m, 1H), 3.71 (s, 3H), 4.14 ppm (q, J=
7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=14.2, 21.9, 23.6, 24.4, 24.4,
31.6, 33.3, 41.9, 49.8, 51.2, 51.6, 60.4, 63.1, 172.1, 176.4 ppm; HRMS (EI):
m/z calcd for C15H28NO4: 286.2018 [M+H+]; found 286.2013.
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[28] The conditions tested included a change of catalyst (Grubbs second
generation or Grubbs–Hoveyda second generation), solvent, the use
of additives (i.e., TiACTHNUTRGNENUG(O-iPr)4, BF3·OEt2), or microwave heating;
methyl vinyl ketone was also employed instead of ethyl acrylate
with similar results.
[22] The removal of the phenylglycinol moiety did not occur when relat-
ed non-fluorinated compounds were subjected to these conditions;
for a similar reaction, see ref. [8c].
Received: July 28, 2011
Published online: February 14, 2012
3764
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Chem. Eur. J. 2012, 18, 3753 – 3764