Highly stereoselective cycloadditions of Danishefsky's diene to (-)-8-phenylmenthyl and (+)-8-phenylneomenthyl glyoxylate N-phenylethylimines

Article abstract of DOI:10.1016/j.tet.2013.02.027

Enantiopure 4-oxo-pipecolic acid derivatives were obtained by double asymmetric induction aza-Diels-Alder reactions between chiral glyoxylate N-phenylethylimines and Danishefsky's diene mediated by zinc iodide. The key to success was the use of iminoacetates possessing two chiral auxiliaries, N-(S)- or N-(R)-1-phenylethyl and (-)-8-phenylmenthyl or (+)-8-phenylneomenthyl. Adducts were formed in good yields (78-81%), with complete regioselectivity and high diastereoselectivity (87-96%). The absolute configuration of the adducts formed was unequivocally assigned through NMR, specific optical rotation and X-ray data of appropriated derivatives. These cycloadducts can serve as precursors for bioactive piperidinic azasugars and pipecolic acid derivatives.

Full text of DOI:10.1016/j.tet.2013.02.027

Tetrahedron 69 (2013) 2909e2919
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly stereoselective cycloadditions of Danishefsky’s diene to
(ꢀ)-8-phenylmenthyl and (þ)-8-phenylneomenthyl glyoxylate
N-phenylethylimines
Xerardo García-Mera a, Maria J. Alves b, Albertino Goth c, Maria Luísa do Vale c,
c
,
*
ꢀ
Jose E. Rodríguez-Borges
a
ꢀ
Departamento de Química Organica, Facultade de Farmacia, Universidade de Santiago de Compostela, E-15782 Santiago de Compostela, Spain
b Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
ˇ
c CIQ-Departamento de Química e Bioquímica, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiopure 4-oxo-pipecolic acid derivatives were obtained by double asymmetric induction aza-Diel-
seAlder reactions between chiral glyoxylate N-phenylethylimines and Danishefsky’s diene mediated by
zinc iodide. The key to success was the use of iminoacetates possessing two chiral auxiliaries, N-(S)- or N-
(R)-1-phenylethyl and (ꢀ)-8-phenylmenthyl or (þ)-8-phenylneomenthyl. Adducts were formed in good
yields (78e81%), with complete regioselectivity and high diastereoselectivity (87e96%). The absolute
configuration of the adducts formed was unequivocally assigned through NMR, specific optical rotation
and X-ray data of appropriated derivatives. These cycloadducts can serve as precursors for bioactive
piperidinic azasugars and pipecolic acid derivatives.
Received 21 December 2012
Received in revised form 30 January 2013
Accepted 7 February 2013
Available online 13 February 2013
Keywords:
Asymmetric synthesis
Cycloadditions
Aza-DielseAlder reaction
Danishefsky’s diene
Chiral auxiliaries
Ó 2013 Elsevier Ltd. All rights reserved.
Pipecolic acid derivatives
1. Introduction
pharmacologically active compounds.5 The significant biological
activity of these compounds has resulted in the development of
The importance of cycloadditions in organic chemistry stems
mainly from their great versatility and high stereochemical and
regiochemical control in the construction of cyclic frameworks.1
Within cycloadditions, the aza-DielseAlder reaction is one of the
most efficient methods available for the formation of nitrogen
heterocycles, allowing for the synthesis of a wide range of chiral
piperidinic derivatives with regio-, diastereo- and enantioselecti-
vities.2,3 The imines used as aza-dienophiles generally require ac-
tivation by an electron-withdrawing group and a Lewis acid. The
electronic nature of the substituents at the diene/dienophile pair is
known to influence the reaction pathways and determine either
a concerted mechanism2,3 (synchronous or asynchronous2h,seu) or
a stepwise one.4
many synthetic approaches for their preparation (Scheme 1).
The cycloadducts obtained in these reactions contain a piper-
idinic functionalized ring system that may undergo further trans-
formations6,7 to yield chiral nonnatural amino alcohols and
a-amino
acids (piperidinic derivatives) as well as pipecolic acid derivatives.
The former compounds have shown useful activity as glycosidase
inhibitors8 with application as antiviral,9 included potential non-
nucleosidic inhibitors of HIV replication,10 antineoplastic11 and an-
tidiabetic agents.9a,12 The pipecolic acid derivatives are useful as
synthetic intermediates in the preparation of potential therapeutic
agents such as N-methyl-D
-aspartate (NMDA) receptor agonists,5bed
anti-HIV agents,5eeg antibiotics,5g,h antineoplastic agents,5iek pro-
tein tyrosine phosphatase modulators,5l thrombin inhibitors,5l,m
anaesthetics5n and immunosuppressive agents.5o,p Because of this
potential, in the last two decades several catalytic asymmetric
methods for producing asymmetric induction in the construction of
nitrogen heterocycles have been developed, with the use of chiral
Lewis acids to promote asymmetric induction being the most com-
monly used strategy. However, this methodology suffers from low
reproducibility and in most cases the chiral Lewis acids are toxic and
expensive.
In the case of the aza-DielseAlder reaction between Dani-
shefsky’s diene and iminoacetates, the products obtained, 4-oxo-
1,2,3,4-tetrahydropyridine-2-carboxylates,3f can be used as pre-
cursors of a large variety of nonproteinogenic a-amino acids and of
pipecolic acid and its derivatives, which are components of many
* Corresponding author. E-mail address: jrborges@fc.up.pt (J.E. Rodríguez-Borges).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.027

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X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
Scheme 1. 4-Oxo-1,2,3,4-tetrahydropyridine-2-carboxylates (aza-DielseAlder cycloadducts) as precursors of a large variety of compounds.
Concerning the imino-DielseAlder reaction, L. Stella and co-
workers investigated the cycloaddition of methyl (S)-N-(1-
phenylethyl)-
-iminoacetate with Danishefsky’s diene.3f Cyclic
with excess Danishefsky’s diene (2 equiv) at rt yielding the corre-
sponding adducts (3a,4a/3b,4b) (Scheme 2).
The reaction was monitored by TLC (aliquots treated with
NaHCO3), and the total consumption of the imine was observed
after 3 days. The results of the aza-DielseAlder reactions are pre-
sented in Table 1.
As can be seen (Table 1), reaction of the glyoxylates with Dan-
ishefsky’s diene gave, in each case, rise to a mixture of the two
possible isomers (epimers) in good yields (z80%). In each case,
a high diastereomeric excess was observed and the major adduct
was isolated from the mixture either by recrystallization or by
column chromatography.
The absolute configurations of adducts 3a (2S) and 4b (2R) were
unequivocally determined from crystallographic data of X-ray dif-
fraction (Fig. 1).16,17
a
a
-
amino-esters were formed with complete regioselectivity but with
low diastereoselectivity (24% de at rt). The diastereomers were not
separated and the absolute configuration of the stereoisomers was
not determined. However, the cycloaddition occurred in good yield
(85%) when using ZnI2 as Lewis acid and THF as solvent. The
authors postulated the in situ formation of a square-planar
zinceimine complex to explain the cycloaddition mechanism.3f,g
More recently, we described the highly diastereoselective cy-
cloaddition between cyclopentadiene and protonated glyoxylate
imines possessing two chiral auxiliaries, N-(S)- or N-(R)-1-
phenylethyl and 8-phenylmenthyl or 8-phenylneomenthyl, to af-
ford optically pure 3-functionalized 2-azabicyclo [2.2.1]hept-5-
enes.2t These reactions showed to be highly accelerated in the
presence of a Lewis acid, due to the formation of an iminium cation
complex that rapidly undergoes cycloaddition under mild condi-
tions to give products with high stereoselectivity.2,3
For the determination of the absolute configuration of the other
adducts, the transformations outlined in Scheme 2 were per-
formed. Treatment of the enantiopure cycloadducts (3a, 4a, 3b, 4b)
with L-Selectride afforded the corresponding enantiopure 4-oxo-2-
Considering the results obtained by Stella and ourselves, we
decided to explore the enantioselective synthesis of 4-oxo-1,2,3,4-
tetrahydropyridine-2-carboxylates, performing an aza-DielseAlder
reaction between Danishefsky’s diene and chiral phenyl-
ethylimines, formed from the corresponding (R)- or (S)-phenyl-
ethylamine and the glyoxylates of chiral alcohols. The presence of
two chiral auxiliaries in the imine was expected to promote
asymmetric induction with no need for chiral Lewis acids, resulting
in an effective and inexpensive enantioselective synthesis of
piperidinic derivatives, including pipecolic acid derivatives.
Hence we describe herein the most efficient asymmetric syn-
thesis of the adducts formed in the cycloaddition of Danishefsky’s
diene and N-(S)- or N-(R)-1-phenylethylimines of (ꢀ)-8-phenyl-
menthyl or (þ)-8-phenylneomenthyl glyoxylates. The assignment
of the absolute configuration of all the adducts formed was ach-
ieved through NMR, specific optical rotation and X-ray data of the
appropriate derivatives.
pipecolates (4-piperidones) [(ꢀ)-5a,(ꢀ)-6a, (þ)-5b, (þ)-6b], which
2iek,t
by reaction with LiAlH4
afforded the enantiopure aminodiols
[(ꢀ)-7, (ꢀ)-8, (þ)-7, (þ)-8, respectively]. The absolute configura-
tions of adducts 4a (2S) and 3b (2R) were determined by compar-
ison of NMR spectroscopic data (1H and 13C) and specific rotation
data of the corresponding aminodiol derivatives, (þ)-7 (from 3b)
and (ꢀ)-8 (from 4a), respectively, with the values obtained for their
enantiomers (configuration confirmed by X-ray), (ꢀ)-7 (from 3a)
and (þ)-8 (from 4b), respectively.
2.1. Regio and stereoselectivity of reductions
T.J. Donohoe and co-workers18 have described the regioselective
conjugate addition of hydride to dihydropyridones using L-Selec-
tride to obtain the corresponding 4-piperidones. Following this
same methodology, translated by a Michael-type attack of the hy-
dride to the olefinic bond of the a,b-unsaturated system, we ob-
tained the enantiopure 4-piperidones [(ꢀ)-5a, 71%; (ꢀ)-6a, 70%/
(þ)-5b, 73%; (þ)-6b, 76%] from the corresponding cycloadducts (3a,
4a, 3b, 4b, respectively).
2. Results and discussion
(ꢀ)-8-Phenylmenthol (HOPM,1a)13 and (þ)-8-phenylneomenthol
(HOPNM, 1b)14 were obtained from (þ)-(R)-pulegone. Conversion of
the alcohols into the corresponding glyoxylates (2a and 2b) was
achieved by reaction with acryloyl chloride in the presence of Et3N
and DMAP, followed by treatmentof the resulting acrylates with OsO4
and NaIO4.2i,t,15 Treatment of the glyoxylate (2a or 2b) with equimolar
amounts of 1-phenylethylamine (R-PEA or S-PEA) and ZnI2 in THF
generated the corresponding iminium complex, which reacted in situ
Applying a methodology developed in our research group, the
piperidones (5a, 6a, 5b and 6b) were then transformed, by treat-
ment with LiAlH4,2iek,t into the corresponding enantiopure ami-
nodiols [(ꢀ)-7, 70%, (ꢀ)-8, 72%; (þ)-7, 71%; (þ)-8, 73%, respectively],
while allowing quantitative recovery of the corresponding chiral
auxiliaries (1a or 1b).13,14 The high diastereoselectivity observed in
this reduction step, under thermodynamic and kinetic control, can
be explained by assuming that the LiAlH4 prefers the axial attack at

X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
2911
Scheme 2. Synthesis of pipecolic acid derivatives. Reagents and conditions: (a) (1) acryloyl chloride, DCM, Et3N, DMAP, 0 ꢁC; (2) OsO4, NaIO4, dioxane/H2O; (b) (1) R-PEA or S-PEA,
ZnI2, Danishefsky’s diene (2 equiv), THF, rt, 3 days; (c) (1) L-Selectride, THF; 0 ꢁC; (2) H2O2, NaOH; (d) (1) LiAlH4, rt, THF, 12 h; (2) H2O.
the ring carbonyl (C4), on the face opposite the bulky ester group at
the C2 position (equatorial), generating only the corresponding
pseudoequatorial alkoxide.19 The reductive cleavage of the ester
group occurs later because it is less reactive (less electrophilic) than
the ketone carbonyl group. Reduction of the intermediate aldehyde
occurs in situ yielding, after final treatment by oxidative pro-
tonation and extraction, the cis-aminodiol with recovery of the
observed when using N-arylimines as dienophiles, where,
depending on the diene used, either a Mannich-like or an inverse-
electron-demand aza-DielseAlder mechanism seems to operate.3i,4
In the present case, and in analogy to what Stella refers,3f the cyclic
silylenolether intermediates could not be isolated, and their hy-
drolysis followed by a retro-Michael elimination of the methoxy
group gives rise to the final tetrahydropyridin-4-ones isolated. No
products other than these cycloadducts were observed.
chiral alcohol R OH (chiral auxiliary).
*
In the case of combinations of PM/S-PEA (Scheme 3) and PM/R-
PEA (Scheme 5) the exo or endo attack of diene would be on the Si
face of the imino-cationic Zn-complex providing the corresponding
cycloadducts with 2S configuration (3a and 4a, respectively).
Moreover, combinations of PNM/S-PEA (Scheme 4) and PNM/R-PEA
(Scheme 5) favour diene attack on the Re face providing the cor-
responding adducts with 2R configuration (4b and 3b, respectively).
Taking into account, simultaneously, polar effects (hydrogen
bonding) and repulsive interactions in the different conformations,
the geometries 9a, 9b, 10a and 10b are those which best explain the
obtention of the major adducts (3a, 4b, 4a and 3b, respectively). The
high selectivity observed in these cases may be explained consid-
ering that:
2.2. Diastereoselectivity of aza-DielseAlder reaction
In an attempt to explain the diastereoselectivity observed we
present in Schemes 3e5 models for the approach of diene and
dienophile. After formation of the phenylethylimine, from the
corresponding primary amine and the glyoxylates of PM and PNM,
the Lewis acid (ZnI2) promotes the formation of a plane square
imino-cationic-Zn intermediate complex (activated dienophile)3fei
with S-cis conformation, which allows the concerted attack of the
diene to form the intermediate adducts. Attack of Danishefsky’s
diene results in the formation of a cyclic intermediate, which upon
desilylation and elimination of the methoxy group yields mainly
one of the two possible diastereoisomers of the final adduct (de
74e92%).
In order to account for the high diastereoselectivity observed,
and based on previous DFT studies on cycloadditions of the imines
with CPD, performed in our research group,2h,s,u an asynchronous
concerted mechanism is proposed. In fact, most studies on re-
actions of Danishefsky’s diene with imines refer a concerted [4þ2]
cyclic transition state, giving rise to the corresponding cyclic ad-
ducts with good to high diastereoselectivities, depending on sol-
vent, catalyst, Lewis acid and temperature.3 Exceptions are
* S-cis conformation of the imine caused by metal complexation
with Zn and establishment of hydrogen bonding interactions
between the carboxylate group and the hydrogen atoms of the
imine and of carbon C10 (menthol ring), favour diene approach on
the Si face in the case of the 8-phenylmenthol group (PM), and on
the Re face in the case of the 8-phenylneomenthol group (PNM).
* The relative position of the two phenyl groups on each in-
termediate complex should be such as to minimize non-
favourable interactions: (a) for PM/S-PEA (9a) and PNM/R-PEA

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X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
Table 1
Results for the aza-DielseAlder reaction between Danishefsky’s diene and in situ generated N-phenylethyliminoacetates of (ꢀ)-8-phenylmenthol and (þ)-8-
phenylneomenthol in the presence of ZnI2 (rt, THF, 3 days)
Entry
Glyoxylate
Phenylethylamine
Adducts (de)a/yieldb (%)
Major adductdyield (%)
1
96:4 (92%)/(80)
2
88:12 (76%)/(78)
3
94:6 (88%)/(81)
4
87:13 (74%)/(79)
cAfter recrystallization.
dAfter preparative chromatographic purification.
a
Determined by 1H NMR analysis.
After chromatographic purification.
b
(10b) the most stable conformation has the two phenyl groups
(8-Ph and PhNMe) on opposite sites as to minimize steric hin-
drance and repulsion. Consequently, the phenyl group of PEA and
the imine function have a coplanar arrangement, and the methyl
group of PEA (PhNMe) and 8-Ph are on the same side of the
complex, thus accounting for the high diastereoselectivity ob-
served, (96:4) and (94:6), respectively; (b) in the case of the
complexes PNM/S-PEA (9b) and PM/R-PEA (10a), the two phenyl
groups (8-Ph and PhNMe) are closer together, possibly due to
more favourable secondary interactions. Although the approach
of the diene is mainly from one of the faces, steric hindrance
promotes the formation of minor conformational intermediates
(9b0 and 10a0) in which the methyl group blocks the approach of
the diene from that same face and therefore a slight reduction of
the diastereoselectivity (87:13 and 88:12, respectively) is ob-
served; (c) for all intermediates the 8-phenyl group causes
greater steric hindrance on one of the faces of the dienophile (PM
blocks the Re face and PNM blocks the Si face).
3. Conclusions
The results obtained illustrate the utility of (ꢀ)-8-phenylmenthol
and (þ)-8-phenylneomenthol as easily recoverable stereo control-
ling auxiliaries, affording optically pure 4-oxo-pipecolic acid

X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
2913
Fig. 1. X-ray single crystal structures of compounds (ꢀ)-3a16 and (þ)-4b.17
Scheme 3. Model for the approach of diene and iminium complex of corresponding 8-phenylmenthyl (S)-N-(1-phenylethyl)-
a
-iminoacetate to afford the major adduct (ꢀ)-3a (2S).
derivatives from aza-DielseAlder reaction between Danishefsky’s
diene and chiral phenylethylimines, formed from the corresponding
(R)- or (S)-phenylethylamine and the glyoxylates of these alcohols.
For the combination of the auxiliaries 8-phenylmenthyl/N-(S)-phe-
nylethyl and 8-phenylmenthyl/N-(R)-phenylethyl, the major prod-
ucts were diastereomers (ꢀ)-(2S)-3a (75%, 92% de) and (ꢀ)-(2S)-4a
(68%, 76% de), respectively. When 8-phenylneomenthyl/N-(R)-phe-
nylethyl and 8-phenylneomenthyl/N-(S)-phenylethyl were used in
combination, the reaction yielded as major adducts (þ)-(2R)-3b
(75%, 88% de) and (þ)-(2R)-4b (66%, 74% de), respectively. The results
obtained point to the occurrence of a sole mechanism, involving
a cyclic [4þ2] transition state, which may be concerted, asynchro-
nous, as the only products observed were the aza-DielseAlder
cycloadducts. We have unambiguously the absolute configuration of
all adducts assigned, using NMR, specific optical rotation and X-ray
data of the appropriated derivatives, 4-oxo-pipecolates [5a (71%), 6a
(70%), 5b (73%) and 6b (76%)] and 2-hydromethyl-piperidin-4-ols
[(ꢀ)-7 (70%), (ꢀ)-8 (72%), (þ)-7 (71%), (þ)-8 (73%)].

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X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
Scheme 4. Model for the approach of diene and iminium complex of corresponding 8-phenylneomenthyl (S)-N-(1-phenylethyl)-a-iminoacetate to afford the major adduct
(þ)-4b (2R).
4. Experimental
doublets (d), triplets (t), doublets of doublets (dd), doublets of
triplets (dt), quartets (q) and multiplets (m). Optical rotations were
4.1. General methods
measured on a conventional thermostated polarimeter using a so-
t
dium lamp and are reported as follows: [
a]
(c in g per 100 mL,
D
All reactions were carried out under anhydrous conditions.
Solvents were dried according to standard procedures and distilled
prior to use. All reagents were commercially available and used
without further purification, unless otherwise stated. Flash column
solvent). X-ray diffraction data were collected in a diffractometer
apparatus and the structures were designed by Mercury, PLATON
and/or ORTEP programs. Elemental analyses were obtained on
a microanalyser apparatus. Mass spectra (low and high resolution)
were recorded on Hewlett-Packard HP5988A or Autospec spec-
trometers. ESI-MS analyses were performed on a liquid 35 chro-
matography Finnigan Surveyor equipment, coupled to a mass
detector Finnigan LQC DECA XP MX with an API and an ESI
interface.
ꢁ
chromatography was performed on silica gel (60 A, 230e240 mesh)
and analytical thin-layer chromatography (TLC) on pre-coated silica
gel 60 F254 plates using iodine vapour and/or UV light (254 nm) for
visualization. Preparative chromatography was performed on glass
plates (20 cmꢂ20 cm) with 200e400 mesh silica gel 60 ACC.
Melting points were determined on an electrothermal melting
point apparatus and are uncorrected. Infrared spectra were recor-
ded on an FT/IR spectrophotometer and main bands are given in
cmꢀ1. The 1H NMR (400 MHz) and 13C NMR (75.47 MHz) spectra
were recorded using CDCl3 as solvent and are reported in parts per
Chiral alcohols (1a and 1b) and chiral glyoxylates (2a and 2b)
were obtained according to the literature procedure.2i,t,15
4.2. General procedure for aza-DielseAlder reaction
million (ppm) downfield from TMS (chemical shifts (
Hz). Multiplicities are recorded as broad peaks (br), singlets (s),
d
) in ppm, J in
4.2.1. (ꢀ)-(1R,2S,5R)-8-Phenylmenthyl (2S)-4-oxo-1-[(1S)-1-phenyle-
thyl]-1,2,3,4-tetrahydropyridine-2-carboxylate (3a). To a solution of

X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
2915
Scheme 5. Model for the approach of diene and iminium complex of corresponding 8-phenylmenthyl (R)-N-(1-phenylethyl)-a-iminoacetate or 8-phenylneomenthyl (R)-N-(1-
phenylethyl)-a-iminoacetate to afford the major adducts (ꢀ)-4a (2S) and (þ)-3b (2R), respectively.
(ꢀ)-8-phenylmenthyl glyoxylate (2a) (2.00 g, 6.52 mmol, 1.2 equiv)
cycloadducts (epimers) (2S/2R) in a ratio of 96:4. Purification by
slow recrystallization of the mixture with hexane/Et2O afforded
pure major adduct (3a) (75%).
in dried THF (60 mL) under an argon atmosphere and at 0 ꢁC were
ꢁ
added molecular sieves 4 A (2 g, previously dried under vacuum)
and a solution of (S)-1-phenylethylamine (0.676 g, 0.72 mL,
5.58 mmol, 1.0 equiv) in dried THF (20 mL). After stirring for 30 min,
ZnI2 (2.08 g, 6.52 mmol, 1.0 equiv) was added and the solution was
stirred for 1 h at rt. Then, Danishefsky’s diene (1.5 mL, 1.2 g,
6.7 mmol,1.2 equiv) was added and the reaction mixture was stirred
for another 24 h. An additional portion of diene (1.5 mL, 1.2 g,
6.7 mmol) was added and the mixture was allowed to react for
another 48 h. The reaction was quenched with saturated aqueous
NaHCO3 solution (40 mL) and solid NaHCO3 (4 g) and EtOAc (50 mL)
were added. The two layers were separated and the aqueous layer
was extracted with EtOAc (2ꢂ50 mL). The pooled organic layers
were washed with brine (60 mL) and dried (Na2SO4). Removal of the
solvent under reduced pressure yielded an orange oil (3.15 g), which
was purified by column chromatography (silica gel) using hexane/
EtOAc 1:2 as eluent. Fractions of Rf 0.6 afforded a white cream solid
(2.06 g, 80.2%) identified (NMR) as a mixture of two diastereomeric
4.2.1.1. Compound (3a). White solid. Mp¼109e111 ꢁC. Rf¼0.63
25
(hexane/EtOAc 1:2). [
d
a
]
ꢀ18.5 (c 1, CHCl3). 1H NMR (CDCl3):
D
¼0.88 (d, 3H, J 6.4 Hz, 50-Me), 0.90e1.03 (m, 2H, H40aþH60a),1,15 (s,
3H, 80-Me), 1.16e1.20 (m, 1H, H30a), 1.23 (s, 3H, 80-Me), 1.38e1.55
(m,1H, H50),1,63 (d, 3H, J 6.8 Hz, CH3CHPh),1.68e1.75 (m,1H, H40b),
1.76e1.86 (m, 1H, H60b), 1.87e1.95 (m, 1H, H30b), 1.99 (dt, 1H, J 16.8,
2.0 Hz, H3anti), 2.09 (td, 1H, J 11.0, 3.6 Hz, H20), 2.26 (dd, 1H, J 16.8,
7.2 Hz, H3syn), 3.02 (dt, 1H, J 7.2, 1.6 Hz, H2), 4.49 (q, 1H, J 6.8 Hz,
CH3CHPh), 4.77 (td, 1H, J 10.8, 4.4 Hz, H10), 4.97 (dd, 1H, J 7.6, 1.1 Hz,
H5), 6.77 (t, 1H, J 7.4 Hz, H4Ph), 6.91 (t, 2H, J 7.8 Hz, H3PhþH5Ph), 7.14
(dd, 2H, J 8.6, 1.0 Hz, H2PhþH6Ph), 7.20e7.33 (m, 2H, Ph), 7.39 (dd,
1H, J 7.6, 1.2 Hz, H6), 7.41e7.50 (m, 3H, Ph). 13C NMR (CDCl3): 21.6
(CH3CHPh), 21.7 (50-Me), 22.0 (80-Me), 26.1 (C30), 30.2 (80-Me), 31.3
(C50), 34.4 (C40), 37.5 (C30), 39.2 (C80), 41.0 (C60), 49.9 (C20), 58.8 (C2),
62.3 (CH3CHPh), 76.4 (C10), 98.6 (C5), 124.8 (CH, Ph), 124.9 (CH, Ph),

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X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
126.1 (CH, Ph), 127.8 (CH, Ph), 128.2 (CH, Ph), 129.2 (CH, Ph), 142.8
8.11, N 3.05. Found: C 78.39, H 8.09, N 3.06. HRMS (EI) calcd for
C30H37NO3 459.2773, found 459.2780.
0
(C1PheCH), 149.0 (C6), 152.2 (C1Ph-8 ), 169.5 (COO), 189.0 (CO). IR
(KBr): 1758, 1691 cmꢀ1. Anal. Calcd for C30H37NO3: C 78.40, H 8.11, N
3.05. Found: C 78.38, H 8.15, N 3.03. HRMS (EI) calcd for C30H37NO3
459.2773, found 459.2769. Suitable crystals of 3a were obtained
from hexane/Et2O and the structure was confirmed by the X-ray
crystallographic analysis.16
4.2.4. (þ)-(1S,2S,5R)-8-Phenylneomenthyl (2R)-4-oxo-1-[(1R)-1-phe-
nylethyl]-1,2,3,4-tetrahydropyridine-2-carboxylate (3b). Following
the same procedure as above, using (R)-1-phenylethylamine (0.75 g,
0.80 mL, 6.19 mmol) and (ꢀ)-8-phenylneomenthyl glyoxylate (2b)
(2.22 g, 7.24 mmol). Flash chromatography of the crude product
(EtOAc/hexane 2:1) afforded a yellow oil (2.31 g 81.2%) identified
(NMR) as a mixture of two diastereomeric cycloadducts (epimers)
(2R/2S) in a ratio of 94:6. Purification by preparative chromatogra-
phy using EtOAc/hexane 2:1 as eluent afforded pure major adduct
(3b) (75%).
4.2.2. (þ)-(1S,2S,5R)-8-Phenylneomenthyl (2R)-4-oxo-1-[(1S)-1-phe-
nylethyl]-1,2,3,4-tetrahydropyridine-2-carboxylate (4b). Following the
same procedure as above, using (S)-1-phenylethylamine (0.749 g,
0.80 mL, 6.18 mmol) and (þ)-8-phenylneomenthyl glyoxylate
(2b) (2.21 g, 7.22 mmol). Flash chromatography of the crude pro-
duct (hexane/EtOAc 1:2) afforded a white solid (2.24 g, 79.0%)
identified (NMR) as a mixture of two diastereomeric cycloadducts
(epimers) (2R/2S) in a ratio of 87:13. Purification by slow re-
crystallization of the mixture with hexane/Et2O afforded pure major
adduct (4b) (66%).
4.2.4.1. Compound (3b). Yellow oil. Rf¼0.64 (hexane/AcOEt 1:2).
25
[a
]
þ73.0 (c 1, CHCl3). 1H NMR (CDCl3): 1H NMR (CDCl3):
¼0.81
d
D
(d, 3H, J 6.8 Hz, 50-Me), 0.86e0.96 (m, 1H, H40a), 0.97e1.05 (m, 1H,
H60a), 1.25 (s, 3H, 80-Me), 1.26 (s, 3H, 80-Me), 1.52e1.62 (m, 4H,
H30aþH30bþH20þH50), 1.65 (d, 3H, J 6.8 Hz, CH3CHPh), 1.73e1.87 (m.
2H, H40bþH60b), 2.54 (ddd, 1H, J 16.8, 2.8, 1.2 Hz, H3anti), 2.64 (dd,
1H, J 16.8, 6.8 Hz, H3syn), 3.70 (ddd, 1H, J 7.2, 2.8, 1.2 Hz, H2), 4.56 (q,
1H, J 6.8 Hz, CH3CHPh), 5.01 (s, 1H, H10), 5.05 (dd, 1H, J 8.0, 0.8 Hz,
H5), 7.02e7.13 (m, 1H, H1Ph), 7.18e7.65 (m, 11H, PhþH6). 13C NMR
(CDCl3): 22.6 (CH3CHPh), 23.0 (50-Me), 23.5 (C30), 27.7 (80-Me), 27.8
(80-Me), 28.3 (C50), 36.3 (C40), 38.6 (C3), 40.8 (C80), 40.9 (C60), 52.4
(C20), 60.4 (C2), 63.6 (CHCH3Ph), 74.8 (C10), 99.6 (C5),126.7 (CH, Ph),
127.1 (CH, Ph), 127.1 (CH, Ph), 129.0 (CH, Ph), 129.9 (CH, Ph), 130.3
4.2.2.1. Compound (4b). White solid. Mp¼164e165 ꢁC. Rf¼0.63
25
(hexane/EtOAc 1:2). [
d
a
]
þ52.1 (c 1, CHCl3). 1H NMR (CDCl3):
D
¼0.80 (d, 3H, J 6.4 Hz, 50-Me), 0.82e0.93 (m, 1H, H40a), 0.94e1.03
(m, 1H, H60a), 1,30 (s, 3H, 80-Me), 1.33 (s, 3H, 80-Me), 1.52e1.61 (m,
4H, H50þH20þH30aþH30b), 1.63 (d, 3H, J 7.2 Hz, CH3CHPh), 1.68e1.86
(m, 2H, H40bþH60b), 2.65 (dd, 1H, J 16.8, 2.8 Hz, H3anti), 2.70 (dd, 1H,
J 16.8, 6.8 Hz, H3syn), 4.04 (ddd, 1H, J 6.8, 2.8, 0.8 Hz, H2), 4.69 (q,1H,
J 7.2 Hz, CH3CHPh), 4.90 (d, 1H, J 7.6 Hz, H5), 5.03 (s, 1H, H10), 6.94
(d, 1H, J 7.6 Hz, H6), 7.12e7.14 (m, 1H, Ph), 7.15e7.46 (m, 9H, Ph). 13C
NMR (CDCl3): 19.7 (CH3CHPh), 22.9 (50-Me), 23.4 (C30), 27.4 (80-Me),
27.6 (C50), 28.3 (80-Me), 36.1 (C40), 39.3 (C3), 40.7 (C60), 40.8 (C80),
52.2 (C20), 58.2 (C2), 62.9 (CH3CHPh), 74.7 (C10), 100.1 (C5), 126.6
(CH, Ph), 127.0 (CH, Ph), 128.4 (CH, Ph), 128.9 (CH, Ph), 129.4 (CH,
0
(CH, Ph), 143.4 (C1PheCH), 149.8 (C1Ph-8 ), 150.1 (C6), 170.3 (COO),
190.1 (CO). IR (NaCl): 1758, 1690 cmꢀ1. Anal. Calcd for C30H37NO3: C
78.40, H 8.11, N 3.05. Found: C 78.38, H 8.13, N 307. MS (ESI) calcd
for C30H37NO3 (Mþ1) 460.28, found 460.47; dimmer 919.20;
246.00; 142.04; 96.07.
0
Ph), 130.0 (CH, Ph), 140.8 (C1PheCH), 149.9 (C1Ph-8 ), 153.0 (C-6),
170.3 (COO), 189.8 (CO). IR (KBr): 1758, 1691 cmꢀ1. Anal. Calcd for
C30H37NO3: C 78.40, H 8.11, N 3.05. Found: C 78.39, H 8.10, N 3.00.
HRMS (EI) calcd for C30H37NO3 459.2773, found 459.2770. Suitable
crystals of 4b were obtained from hexane/Et2O and the structure
was confirmed by the X-ray crystallographic analysis.17
4.3. General procedure for reduction of cycloadducts with
L-Selectride
4.3.1. (ꢀ)-(1R,2S,5R)-8-Phenylmenthyl (2S)-4-oxo-1-[(1S)-1-
phenylethyl]-piperidine-2-carboxylate (5a). To
a solution of 3a
4.2.3. (ꢀ)-(1R,2S,5R)-8-Phenylmenthyl (2S)-4-oxo-1-[(1R)-1-phenyle-
thyl]-1,2,3,4-tetrahydropyridine-2-carboxylate (4a). Following the
same procedure as above, using (R)-1-phenylethylamine (0.722 g,
0.77 mL, 5.96 mmol) and (ꢀ)-8-phenylmenthyl glyoxylate (2a)
(2.13 g, 6.96 mmol). Flash chromatography of the crude product
(EtOAc/hexane 2:1) afforded a yellow oil (2.14 g, 78.1%) identified
(NMR) as a mixture of two diastereomeric cycloadducts (epimers)
(2S/2R) in a ratio of 88:12. Purification by preparative chromatog-
raphy using EtOAc/hexane 2:1 as eluent afforded pure major adduct
(4a) (68%).
(1.012 g, 2.20 mmol) in dry THF (11 mL) was added, dropwise and
under an argon atmosphere, a solution of L-Selectride 1 M (5.5 mL,
5.5 mmol) at 0 ꢁC. The reaction mixture was stirred for 2 h at 0 ꢁC,
and then a solution of NaOH 1 M (5.6 mL, 5.6 mmol) and H2O2 30%
(2.3 mL, ca. 20 mmol) was added dropwise at 0 ꢁC. Brine (50 mL)
was added and the resulting mixture was extracted with EtOAc
(3ꢂ60 mL). The pooled organic layers were washed with more brine
(60 mL) and dried with Na2SO4. Removal of the solvent in a rotary
evaporator left a yellow oil (1.21 g) that when chromatographed on
silica gel with hexane/EtOAc 1:2 as eluent afforded a pale yellow oil
(0.725 g, 71.3%) identified (NMR) as the piperidine 5a.
4.2.3.1. Compound (4a). Yellow oil. Rf¼0.65 (hexane/EtOAc 1:2).
25
[
a]
25 ꢀ15.3 (c 1, CHCl3). 1H NMR (CDCl3):
d
¼0.78 (d, 3H, J 6.4 Hz, 50-
4.3.1.1. Compound (5a). Rf¼0.62 (hexane/EtOAc 1:2).
[a]
D
D
Me), 0.80e0.94 (m, 2H, H40aþH60a), 1.01e1.10 (m, 1H, H30a), 1.14 (s,
3H, 80-Me), 1.25 (s, 3H, 80-Me), 1.34e1.37 (m, 1H, H50), 1.36 (d, 3H, J
7.2 Hz, CH3CHPh), 1.55e1.64 (m, 1H, H40b), 1.67e1.75 (m, 2H,
H30bþH60b), 1.99e2.08 (m, 1H, H20), 2.46 (dd, 1H, J 16.8, 6.8 Hz,
H3anti), 2.64 (dd, 1H, J 16.8, 2.4 Hz, H3syn), 3.35 (ddd, 1H, J 6.8, 2.8,
0.8 Hz, H2), 4.05 (q,1H, J 7.2 Hz, CH3CHPh), 4.73 (dd,1H, J 7.6, 0.8 Hz,
H5), 4.88 (td, 1H, J 10.8, 4.4 Hz, H10), 6.59 (dd, 1H, J 7.6, 0.8 Hz, H6),
7.03e7.16 (m, 1H, C1Ph), 7.09e7.36 (m, 9H, Ph). 13C NMR (CDCl3):
19.96 (CH3CHPh), 22.6 (50-Me), 23.1 (80-Me), 27.0 (C30), 31.2 (80-Me),
32.2 (C50), 35.3 (C40), 39.0 (C3), 40.2 (C80), 41.9 (C60), 50.7 (C20), 57.5
(C2), 62.9 (CH3CHPh), 77.2 (C10), 99.8 (C5), 125.8 (CH, Ph), 126.1 (CH,
Ph), 128.6 (CH, Ph), 128.9 (CH, Ph), 129.3 (CH, Ph), 129.9 (CH, Ph),
ꢀ54.9 (c 1, CHCl3). 1H NMR (CDCl3):
d
¼0.79 (d, 3H, J 6.4 Hz, 50-Me),
0.79e0.94 (m, 2H, H40aþH60a), 0.95 (s, 3H, 80-Me), 1.03 (s, 3H, 80-
Me), 1.05e1.15 (m, 1H, H30a), 1.18e1.24 (m, 1H, H50), 1.25 (d, 3H, J
6.4 Hz, CHCH3Ph), 1.31e1.50 (m, 3H, H40bþH30bþH60b), 1.51e1.65
(m, 2H, H3antiþH5anti), 1.75e1.90 (m, 3H, H3synþH5synþH20),
2.83e3.01 (m, 2H, H6antiþH6synþH2), 4.16 (q, 1H,
J 6.4 Hz,
CHCH3Ph), 4.56 (td, 1H, J 10.8, 4.0, 1.2 Hz, H10), 6.80e6.90 (m, 4H,
Ph), 6.21e6.30 (m, 6H, Ph). 13C NMR (CDCl3): 22.2 (CH3CHPh), 23.1
(50-Me), 24.6 (80-Me), 26.8 (C30), 28.4 (80-Me), 31.6 (C50), 35.0 (C40),
35.7 (C5), 37.4 (C60), 39.6 (C80), 41.8 (C3), 42.2 (C6), 50.8 (C20), 58.2
(C2), 60.5 (CH3CHPh), 75.1 (C10),125.0 (CH, Ph),125.3 (CH, Ph),127.4
(CH, Ph), 127.7 (CH, Ph), 128.1 (CH, Ph), 128.9 (CH, Ph), 146.1
0
0
140.7 (C1PheCH), 152.7 (C6), 153.4 (C1Ph-8 ), 170.5 (COO), 189.96 (CO).
(C1PheCH), 152.3 (C1Ph-8 ), 171.9 (COO), 202.5 (CO). IR (NaCl): 1727,
IR (NaCl): 1758, 1690 cmꢀ1. Anal. Calcd for C30H37NO3: C 78.40, H
1693 cmꢀ1. Anal. Calcd for C30H39NO3: C 78.05, H 8.52, N 3.03.

X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
2917
Found: C 78.08, H 8.56, N 3.06. MS (ESI) calcd for C30H39NO3 (Mþ1)
(CH3CHPh), 22.3 (50-Me), 22.5 (C30), 26.6 (80-Me), 26.8 (80-Me), 27.1
(C50), 35.5 (C40), 40.1 (C80), 40.5 (C5), 40.9 (C60), 43.2 (C3), 43.3 (C6),
51.5 (C20), 60.2 (C2), 60.5 (CH3CHPh), 72.5 (C10), 125.9 (CH, Ph),
126.2 (CH, Ph), 127.5 (CH, Ph), 127.6 (CH, Ph), 128.2 (CH, Ph), 128.9
(C1, Ph), 144.6 (C1, Ph), 149.6 (CH, Ph), 170.8 (COO), 207.7 (CO). IR
(NaCl): 1727, 1691 cmꢀ1. Anal. Calcd for C30H39NO3: C 78.05, H 8.52,
N 3.03. Found: C 78.03, H 8.50, N 3.01. MS (ESI) calcd for C30H39NO3
(Mþ1) 462.30, found 462.32.
462.30, found 462.34.
4.3.2. (þ)-(1S,2S,5R)-8-Phenylneomenthyl (2R)-4-oxo-1-[(1S)-1-
phenylethyl]-piperidine-2-carboxylate (6b). Following the same
procedure as above, using adduct 4b (1.032 g, 2.24 mmol). Flash
chromatography of the crude product (hexane/EtOAc 1:2) afforded
a pale yellow oil (0.79 g, 76.1%) identified (NMR) as the piperidine 6b.
4.3.2.1. Compound (6b). Rf¼0.63 (hexane/AcOEt 1:2). [
a
]
25 þ63.6
4.4. General procedure for reduction of piperidin-4-ones with
LiAlH4
D
(c 1, CHCl3). 1H NMR (CDCl3):
d
¼0.82 (d, 3H, J 6.4 Hz, 50-Me),
0.83e0.96 (m, 1H, H40a), 1.01 (ddd, 1H, J 14.4 Hz, 12.0, 2.4 Hz, H60a),
1.09 (s, 3H, 80-Me), 1.18 (s, 1H, 80-Me), 1.37 (d, 3H, J 6.8 Hz, CHCH3Ph),
1.42e1.70 (m, 7H, H30aþH30bþH50þH40bþH60bþH20þH5anti),
1.85e1.93 (m, 1H, H3anti), 1.94e2.02 (m, 1H, H5syn), 2.10e2.18 (m, 1H,
H3syn), 3.03e3.09 (m, 1H, H6anti), 3.15 (td, 1H, J 12.0, 2.8 Hz, H6syn),
3.46 (t, 1H, J 4.4 Hz H2), 4.21 (q, 1H, J 6.8 Hz, CHCH3Ph), 5.03 (s, 1H,
H10), 7.15e7.39 (m, 10H, Ph). 13C NMR (CDCl3): 22.5 (PhCHCH3), 22.6
(50-Me), 22.8 (C30), 26.2 (80-Me), 26.7 (80-Me), 27.5 (C50), 30.0 (C40),
35.6 (C5), 37.9 (C60), 40.2 (C80), 40.3 (C3), 41.9 (C6), 51.3 (C20), 58.7
(C2), 60.6 (PhCHCH3), 71.5 (C10), 125.9 (CH, Ph), 126.3 (CH, Ph), 127.4
(CH, Ph), 128.2 (CH, Ph), 128.3 (CH, Ph), 128.9 (CH, Ph), 145.5 (C1Ph),
0
4.4.1. (ꢀ)-(2S,4R)-2-(Hydroxymethyl)-1-[(1S)-1-phenylethyl]-pipe-
piridin-4-ol [(ꢀ)-7]. A solution of 5a (0.507 g, 1.10 mmol) in dry THF
(25 mL) was added dropwise under argon to a suspension of LiAlH4
(ca. 6 equiv; 0.25 g, 6.59 mmol) in dry THF (10 mL) at 0 ꢁC. The
reaction mixture was stirred for 16 h at rt, and then EtOAc (2 mL),
H2O (2 mL) and NaOH 15% (2 mL) were added dropwise at 0 ꢁC.
More H2O (20 mL) was added, the resulting mixture was extracted
with AcOEt (3ꢂ20 mL) and the pooled organic layers were washed
with brine (100 mL) and dried with Na2SO4. Removal of the solvent
in a rotary evaporator left a yellow oil (0.55 g) that when chro-
matographed on silica gel with hexane/EtOAc 3:1 as eluent affor-
ded the chiral auxiliary, (ꢀ)-8-phenylmenthol (Rf 0.4; 0.23 g,
91%),20 and compound (ꢀ)-7 (Rf 0.51; 0.181 g, 70.2%), as a pale oil,
using MeOH/EtOAc 1:10 as eluent.
150.0 (C18 -Ph), 172.1 (COO), 208.6 (CO). IR (NaCl): 1727, 1692 cmꢀ1
.
Anal. Calcd for C30H39NO3: C 78.05, H 8.52, N 3.03. Found: C 78.07, H
8.55, N 3.05. MS (ESI) calcd for C30H39NO3 (Mþ1) 462.30, found
462.35.
25
4.3.3. (ꢀ)-(1R,2S,5R)-8-Phenylmenthyl (2S)-4-oxo-1-[(1R)-1-
phenylethyl]-piperidine-2-carboxylate (6a). Following the same
procedure as above, using adduct 4a (1.007 g, 2.19 mmol). Flash
chromatography of the crude product (hexane/EtOAc 1:2) afforded
a pale yellow oil (0.71 g, 70.3%) identified (NMR) as the piperidine 6a.
4.4.1.1. Compound [(ꢀ)-7]. Rf¼0.51 (MeOH/AcOEt 1:10). [
a]
D
ꢀ35.51 (c 1, CHCl3). 1H NMR (CDCl3):
d
¼1.47 (d, 3H, J 6.8 Hz,
CH3CHPh), 1.58 (br s, 2H, 2ꢂOH), 2.13e2.27 (m, 2H, H3antiþH5anti),
2.50 (dddd, 1H, J 14.8, 6.8, 5.6,1.2 Hz, H5syn), 2.62 (ddd,1H, J 15.6, 6.4,
0.8 Hz, H3syn), 3.08 (ddd,1H, J 17.6,10.0, 4.0 Hz, H6anti), 3.23e3.35 (m,
2H, H6synþH2), 3.36e3.52 (m, 3H, CH2eOHþH4), 4.17 (q,1H, J 6.8 Hz,
25
4.3.3.1. Compound (6a). Rf¼0.64 (hexane/AcOEt 1:2).
[a
]
CHCH3Ph), 7.24e7.40 (m, 5H, Ph). 13C NMR (CDCl3):
d
¼19.5
D
ꢀ69.8 (c 1, CHCl3). 1H NMR (CDCl3):
d
¼0.90 (d, 3H, J 6.4 Hz, 50-Me),
(CH3CHPh), 39.2 (C5), 40.9 (C3), 42.6 (C6), 58.2 (C2þC4), 58.5
(CH3CHPh), 61.8 (CH2O), 127.5 (C3PhþC5Ph), 128.0 (C4Ph), 129.1
(C2PhþC6Ph),144.1 (C1Ph). IR (NaCl): 3479, 3400 cmꢀ1. Anal. Calcd for
C14H21NO2: C 71.46, H 8.99, N 5.95. Found: C 71.43, H 8.95, N 5.92. MS
(ESI) calcd for (C14H21NO2) (Mþ1) 236.16, found 236.13.
0.92e1.08 (m, 2H, H40aþH60a), 1.08e1.22 (m, 1H, H30a), 1.23 (s, 3H,
80-Me), 1.34 (s, 3H, 80-Me), 1.39 (d, 3H, J 6.4 Hz, CH3CHPh), 1.42e1.58
(m, 1H, H50), 1.65e1.84 (m, 3H, H40bþH30bþH60b), 2.03e2.19 (m, 3H,
H20þH5antiþH3anti), 2.25e2.42 (m, 2H, H3synþH5syn), 2.77e2.89 (m,
2H, H6antiþH6syn), 2.36 (dd, 1H, J 15.0, 6.7 Hz, H2), 4.16 (q, 1H, J
6.4 Hz, CHCH3Ph), 4.90 (td, 1H, J 10.8, 4.4 Hz, H10), 7.12e7.47 (m,
10H, Ph). 13C NMR (CDCl3): 21.7 (CH3CHPh), 22.1 (50-Me), 24.1 (80-
Me), 26.8 (C30), 28.9 (80-Me), 31.6 (C50), 34.7 (C40), 39.9 (C80), 40.8
(C5), 42.0 (C60), 43.2 (C3), 45.2 (C6), 50.3 (C20), 58.4 (C2), 60.9
(CH3CHPh), 75.7 (C10), 125.4 (CH, Ph), 125.6 (CH, Ph), 127.2 (CH, Ph),
127.4 (CH, Ph), 128.3 (CH, Ph), 128.8 (CH, Ph), 146.1 (C1PheCH), 152.2
4.4.2. (þ)-(2R,4S)-2-(Hydroxymethyl)-1-[(1S)-1-phenylethyl]-pipe-
piridin-4-ol [(þ)-8]. Following the same procedure as above, using
piperidin-4-one 6b (0.523 g, 1.13 mmol). Flash chromatography of
the crude product (hexane/EtOAc 3:1) afforded the chiral auxiliary,
(þ)-8-phenylneomenthol (Rf 0.60; 0.26 g, 99%),20 in the early
fractions and compound (þ)-8 (0.195 g, 73.1%, Rf 0.50), as a pale
yellow oil, using MeOH/EtOAc 1:10 as eluent.
(C1Ph-8 ), 170.9 (COO), 208.4 (CO). IR (NaCl): 1727, 1690 cmꢀ1. Anal.
0
Calcd for C30H39NO3: C 78.05, H 8.52, N 3.03. Found: C 78.07, H 8.55,
N 3.01. MS (ESI) calcd for C30H39NO3 (Mþ1) 462.30, found 462.36.
25
4.4.2.1. Compound [(þ)-8]. Rf¼0.50 (MeOH/EtOAc 1:10). [
a]
D
þ23.62 (c 1, CHCl3). 1H NMR (CDCl3):
¼1.18 (br s, 2H, 2ꢂOH), 1.41
d
4.3.4. (þ)-(1S,2S,5R)-8-Phenylneomenthyl (2R)-4-oxo-1-[(1R)-1-
phenylethyl]-piperidine-2-carboxylate (5b). Following the same
procedure as above, using adduct 3b (1.027 g, 2.23 mmol). Flash
chromatography of the crude product (hexane/EtOAc 1:2) affor-
ded a pale yellow oil (0.754 g, 73.1%) identified (NMR) as the
piperidine 5b.
(d, 3H, J 6.4 Hz, CH3CHPh), 1.99e2.17 (m, 1H, H5anti), 2.13 (dt, 1H, J
14.8, 2.0 Hz, H3anti), 2.41 (dddd, 1H, J 14.8, 10.8, 6.0, 0.8 Hz, H5syn),
2.55 (ddd, 1H, J 14.8, 6.4, 0.8 Hz, H3syn), 2.79e2.89 (m, 1H, H6anti),
2.96 (ddd, 1H, J 14.4, 10.8, 4.0 Hz, H6syn), 3.34e3.45 (m, 2H,
H2þOCHaHb), 3.53 (dd, 1H, J 10.8, 5.2 Hz, OCHaHb), 3.59e3.62 (m,
1H, H4), 4.09 (q, 1H, J 6.4 Hz, CHCH3Ph), 7.18e7.30 (m, 5H, Ph). 13
C
NMR (CDCl3):
d
¼22.0 (Me), 38.6 (C5), 40.8 (C3), 43.4 (C6), 57.4 (C4),
25
4.3.4.1. Compound (5b). Rf¼0.64 (hexane/AcOEt 1:2).
[a
]
58.9 (CHMe), 61.6 (C2), 61.6 (CH2O), 127.5 (C3PhþC5Ph), 128.0 (C4Ph),
129.1 (C2PhþC6Ph). IR (NaCl): 3480, 3401 cmꢀ1. Anal. Calcd for
C14H21NO2: C 71.46, H 8.99, N 5.95. Found: C 71.44, H 8.98, N 5.97.
MS (ESI) calcd for (C14H19NO2) (Mþ1) 236.16, found 236.20.
D
þ79.8 (c 1, CHCl3). 1H NMR (CDCl3):
d
¼0.85 (d, 3H, J 6.8 Hz, 50-Me),
0.86e1.09 (m, 2H, H40aþH60a), 1.23 (s, 3H, 80-Me), 1.27 (s, 3H, 80-
Me), 1.46 (d, 3H,
J 6.4 Hz, CH3CHPh), 1.47e1.59 (m, 4H,
H30aþH30bþH50þH20), 1.73e1.81 (m, 1H, H40b), 1.76 (dt, 1H, J 14.4,
2.0 Hz, H60b), 2.34e2.49 (m, 2H, H5antiþH3anti), 2.50e2.66 (m, 2H,
H5synþH3syn), 3.15e3.32 (m, 2H, H6antiþH6syn), 3.72 (dd, 1H, J 6.0,
2.2 Hz, H2), 4.27 (q, 1H, J 6.4 Hz, CH3CHPh), 5.14 (s, 1H, H10),
7.11e7.19 (m, 1H, Ph), 7.22e7.47 (m, 9H, Ph). 13C NMR (CDCl3): 22.26
4.4.3. (ꢀ)-(2S,4R)-2-(Hydroxymethyl)-1-[(1R)-1-phenylethyl]-pipe-
piridin-4-ol [(ꢀ)-8]. Following the same procedure as above, using
piperidin-4-one 6a (0.533 g, 1.16 mmol). Flash chromatography of
the crude product (hexane/EtOAc 3:1) afforded the chiral auxiliary,

2918
X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
(ꢀ)-8-phenylmenthol (Rf 0.4; 0.27 g, 98.6%),20 in the early fractions
and compound (ꢀ)-8 (0.196 g, 72.3%, Rf 0.50), as a pale yellow oil,
using MeOH/EtOAc 1:10 as eluent.
(n) Szymanski, S.; Chapuis, C.; Jurczak, J. Tetrahedron: Asymmetry 2001, 12, 1939;
(o) Bailey, P. D.; Londesbrough, D. J.; Hancox, T. C.; Heffernan, J. D.; Holmes, A. B.
J. Chem. Soc., Chem. Commun. 1994, 2543; (p) Bailey, P. D.; Wilson, R. D.; Brown,
G. R. J. Chem. Soc., Perkin Trans. 1 1991, 1337; (q) Bailey, P. D.; Brown, G. R.;
Korber, F.; Reed, A.; Wilson, R. D. Tetrahedron: Asymmetry 1991, 12, 1263; (r) Lau,
J. F.; Hansen, T. K.; Kilburn, J. P.; Frydenvang, K.; Holsworth, D. D.; Ge, Y.; Uyeda,
R. T.; Judge, L. M.; Andersen, H. S. Tetrahedron 2002, 58, 7339; (s) Teixeira, F.;
Rodríguez-Borges, J. E.; Melo, A.; Cordeiro, M. Chem. Phys. Lett. 2009, 477, 60; (t)
García-Mera, X.; Rodríguez-Borges, J. E.; Vale, M. L.; Alves, M. J. Tetrahedron
2011, 67, 7162; (u) Miranda, M. S.; Rodríguez-Borges, J. E.; Esteves da Silva, J. C.
G.; Garcia-Mera, X. J. Phys. Org. Chem. 2012, 25, 515; (v) Barluenga, J.; Aznar, F.;
Valdes, C.; Cabal, M. P. J. Org. Chem. 1993, 58, 3391.
25
4.4.3.1. Compound [(ꢀ)-8]. Rf¼0.50 (MeOH/EtOAc 1:10). [
a]
D
ꢀ23.63 (c 1, CHCl3). 1H NMR (CDCl3):
¼1.41 (d, 3H, J 6.4 Hz,
d
CH3CHPh), 1.52 (br s, 2H, 2ꢂOH), 1.99e2.17 (m, 1H, H5anti), 2.13 (dt,
1H, J 14.8, 2.0 Hz, H3anti), 2.41 (dddd, 1H, J 14.8, 10.8, 6.0, 0.8 Hz,
H5syn), 2.55 (ddd, 1H, J 14.8, 6.4, 0.8 Hz, H3syn), 2.79e2.89 (m, 1H,
H6anti), 2.96 (ddd, 1H, J 14.4, 10.8, 4.0 Hz, H6syn), 3.34e3.45 (m, 2H,
H2þOCHaHb), 3.53 (dd, 1H, J 10.8, 5.2 Hz, OCHaHb), 3.59e3.62 (m,
1H, H4), 4.09 (q, 1H, J 6.4 Hz, CHCH3Ph), 7.18e7.30 (m, 5H, Ph). The
NMR (1H, 13C) spectra were identical with those of compound (þ)-8
except deviations of hydroxylic protons. MS (ESI) calcd for
(C14H19NO2) (Mþ1) 236.16, found 236.19.
3. (a) Danishefsky, S.; Kitahara, T.; Yan, C. F.; Morris, J. J. Am. Chem. Soc. 1979, 101,
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6996; (b) Pegot, B.; Van Buu, O. N.; Gori, D.; Vo-Thanh, G. Beilstein J. Org. Chem.
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K.; Yamamoto, H. Tetrahedron 1993, 49, 1749; (f) Abraham, H.; Theus, E.; Stella,
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9594; (l) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int. Ed. 1998, 37,
979; (m) Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int.
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4.4.4. (þ)-(2R,4S)-2-(Hydroxymethyl)-1-[(1R)-1-phenylethyl]-pipe-
piridin-4-ol [(þ)-7]. Following the same procedure as above, using
the piperidin-4-one 5b (0.541 g, 1.17 mmol). Flash chromatography
of the crude product (hexane/EtOAc 3:1) afforded the chiral aux-
iliary, (þ)-8-phenylneomenthol (Rf 0.60; 0.27 g, 98%),20 in the early
fractions and compound (þ)-7 (0.196 g, 71.2%, Rf 0.50), as a pale
yellow oil, using MeOH/EtOAc 1:10 as eluent.
4. (a) Jorgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558; (b) Badorrey, R.;
ꢀ
Cativiela, C.; Díaz-de-Villegas, M. D.; Galvez, J. A. Tetrahedron 1999, 55, 7601; (c)
Waldmann, H. Synlett 1995, 133; (d) Hermitage, S.; Howard, J. A. K.; Jay, D. A.;
Pritchard, R. G.; Probert, M. R.; Whiting, A. Org. Biomol. Chem. 2004, 2, 2451; (e)
25
4.4.4.1. Compound [(þ)-7]. Rf¼0.50 (MeOH/AcOEt 1:10). [
a]
D
ꢀ
Domingo, L. R.; Oliva, M.; Andres, J. J. Org. Chem. 2001, 66, 6151; (f) Yuan, Y.; Li,
þ35.50 (c 1, CHCl3). 1H NMR (CDCl3):
¼1.47 (d, 3H, J 6.8 Hz,
d
X.; Ding, K. Org. Lett. 2002, 4, 3309.
5. (a) Cant, A. A.; Sutherland, A. Synthesis 2012, 44, 1935; (b) Ornstein, P. L.;
Schoepp, D. D.; Arnold, M. B.; Leander, J. D.; Lodge, J. D.; Paschal, J. W.; Elzey, T. J.
Med. Chem. 1991, 34, 90; (c) Pellicciari, R.; Marinizzi, M.; Natalini, B.;
Constantino, G.; Lankin, D. C.; Snyder, J. P.; Monahan, J. B. Il Farmaco 1997, 52,
477; (d) Ornstein, P. L.; Arnold, M. B.; Lunn, W. H. W.; Heinz, L. J.; Leander, J. D.;
Lodge, J. D.; Schoepp, D. D. Bioorg. Med. Chem. Lett. 1998, 8, 389; (e) Beaulieu, P.
CH3CHPh), 2.13e2.27 (m, 2H, H3antiþH5anti), 2.50 (dddd, 1H, J 14.8,
6.8, 5.6, 1.2 Hz, H5syn), 2.62 (ddd, 1H, J 15.6, 6.4, 0.8 Hz, H3syn), 3.08
(ddd, 1H, J 17.6, 10.0, 4.0 Hz, H6anti), 3.23e3.35 (m, 2H, H6synþH2),
3.36e3.52 (m, 3H, CH2eOHþH4), 4.17 (q, 1H, J 6.8 Hz, CHCH3Ph),
4.71 (br s, 2H, 2ꢂOH), 7.24e7.40 (m, 5H, Ph). The NMR (1H, 13C)
spectra were identical with those of compound (ꢀ)-7 except de-
viations of hydroxylic protons. MS (ESI) calcd for (C14H19NO2)
(Mþ1) 236.16, found 236.23.
ˇ
ꢀ
L.; Lavallee, P.; Abraham, A.; Anderson, P. C.; Boucher, C.; Bousquet, Y.; Duceppe,
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I. Tetrahedron 1997, 53, 15671; (g) Lamarre, D.; Croteau, G.; Bourgon, L.;
Thibeault, D.; Wardrop, E.; Clouette, C.; Vaillancourt, M.; Cohen, E.; Pargellis, C.;
Yoakin, C.; Anderson, P. C. Antimicrob. Agents Chemother. 1997, 41, 965; (h) Reed,
Acknowledgements
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~
Thanks are due to Fundac¸ ao para a Cienciˇ a e Tecnologia (FCT) for
financial support given to Faculdade de Ciencias do Porto (project
PTDC/QUI/67407/2006) and for financial support through the re-
equipment program REDE/1517/RMN/2005.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.02.027.
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41, 8957; (b) Crilley, M. M. L.; Larsen, D. S.; Stoodley, R. J.; Tome, F. Tetrahedron
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ꢀ
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Tetrahedron: Asymmetry 2000, 41, 4805.

X. García-Mera et al. / Tetrahedron 69 (2013) 2909e2919
2919
~
ꢀ
14. (a) Caamano, O.; Fernandez, F.; García-Mera, X.; Rodríguez-Borges, J. E. Tetra-
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tallics 1988, 7, 883.
CCDC 815905. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
18. (a) Donohoe, T. J.; Connolly, M. J.; Walton, L. Org. Lett. 2009, 11, 5562; (b)
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Biomol. Chem. 2006, 4, 1071.
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Chem. 1986, 51, 551; (b) Whitesell, J. K.; Bhattacharya, A.; Buchanan, C. M.; Chen,
H.-H.; Deyo, D.; James, D.; Liu, C.-L.; Minton, M. A. Tetrahedron 1986, 42, 2993.
16. The crystallographic data for the structure (ꢀ)-3a have been deposited at the
Cambridge Crystallographic Data Center as supplementary publication number
CCDC 817519. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
19. Camozzato, A. C.; Tenius, B. S. M.; de Oliveira, E. R.; Viegas, C., Jr.; Victor, M. M.;
da Silveira, L. G. Quím. Nova 2008, 31, 793 and references therein.
25
20. The recovered alcohols were identified as (ꢀ)-8-phenylmenthol [[
a
]
ꢀ25.2
D
23
(c 0.5, CHCl3)] and (þ)-8-phenylneomenthol [[
a
]
þ34.0 (c 1.0, CHCl3)] by
D
17. The crystallographic data for the structure (þ)-4b have been deposited at the
comparison of its spectroscopic and specific rotation data with those reported
Cambridge Crystallographic Data Center as supplementary publication number
in the literature.13,14