Asymmetric homologation of ketones. A new entry to orthogonally protected (2R,4R)-piperidine-2,4-dicarboxylic acid

Article abstract of DOI:10.1021/jo801515k

(Chemical Equation Presented) A new conformationally constrained analogue of glutamic acid has been synthesized efficiently in seven steps from a chiral 2-alkyl-4-piperidone. The synthesis is based on (a) the unprecedented asymmetric one-carbon homologation of the ketone controlled by the size of the N-substituent and (b) the appropriate manipulation of substituents at positions 2 and 4 of the piperidine ring, a step that involves two independent oxidation processes.

Full text of DOI:10.1021/jo801515k

Glutamic acid is the principal excitatory neurotransmitter in
the mammalian central nervous system and is involved in a
variety of essential physiological functions, including neuronal
plasticity and development, memory, and learning. This amino
acid is also implicated in the pathogenesis of several acute,
chronic, and neurodegenerative disorders such as cerebral
ischemia, hypoxia, epilepsy, amyotrophic lateral sclerosis, and
Parkinson’s and Alzheimer’s diseases.3 In this context, the
design and synthesis of conformationally constrained glutamic
acid analogues is currently an active area of research4 directed
toward the development of potentially novel therapeutics to
prevent or treat these diseases.5
Asymmetric Homologation of Ketones. A New
Entry to Orthogonally Protected
(2R,4R)-Piperidine-2,4-dicarboxylic Acid
Pablo Etayo, Ramo´n Badorrey, Mar´ıa D. D´ıaz-de-Villegas,*
and Jose´ A. Ga´lvez*
Departamento de Qu´ımica Orga´nica, Instituto de Ciencia de
Materiales de Arago´n, Instituto UniVersitario de Cata´lisis
Homoge´nea, UniVersidad de Zaragoza-CSIC,
E-50009 Zaragoza, Spain
Piperidine-2,4-dicarboxylic acid is a conformationally con-
strained glutamic acid analogue. This amino acid and its close
derivatives have shown high affinity for TFN-R-converting
enzyme (TACE), matrix metalloprotease (MMP), tachykinin,
and N-methyl-D-aspartic acid (NMDA) subtype amino acid
receptors.6 The inhibition of these targets is important in the
treatment of artherosclerotic lesions, inflammatory diseases, pain,
asthma, and Alzheimer’s disease.
loladiaz@unizar.es, jagl@unizar.es
ReceiVed July 10, 2008
It is known that each stereoisomer of a biologically active
compound usually displays a different effect on a specific
receptor. Piperidine-2,4-dicarboxylic acid has four stereoisomers:
a pair of cis-enantiomers and a pair of trans-enantiomers.
Racemic trans-piperidine-2,4-dicarboxylic acid is reported6a to
(2) See, for example: (a) Glenn, M. P.; Fairlie, D. P. Mini-ReV. Med. Chem.
2002, 2, 433–445. (b) Rajesh, S.; Ami, E.; Kotake, T.; Kimura, T.; Hayashi, Y.;
Kiso, Y. Bioorg. Med. Chem. Lett. 2002, 12, 3615–3617. (c) Swamy, K. M. K.;
Lin, M. J.; Sun, C. M. Mini-ReV. Med. Chem. 2003, 3, 621–631. (d) Kee, S.;
Jois, S. D. S. Curr. Pharm. Des. 2003, 9, 1209–1224. (e) Andronati, S. A.;
Karaseva, T. L.; Krysko, A. A. Curr. Med. Chem. 2004, 11, 1183–1211. (f)
Reissmann, S.; Imhof, D. Curr. Med. Chem. 2004, 11, 2823–2844.
(3) Parsons, C. G.; Danysz, W.; Quack, G. Drugs News Perspect. 1998, 11,
523–569.
(4) See, for example: (a) Pellicciari, R.; Marinozzi, M.; Camaioni, E.; Nunez,
M. D.; Costantino, G.; Gasparini, F.; Giorgi, G.; Macchiarulo, A.; Subramanian,
N. J. Org. Chem. 2002, 67, 5497–5507. (b) Conti, P.; De Amici, M.; Grazioso,
G.; Roda, G.; Stensbol, T. B.; Bräuner-Osborne, H.; Madsen, U.; Toma, L.; De
Micheli, C. Eur. J. Org. Chem. 2003, 4455–4461. (c) Bunch, L.; Liljefors, T.;
Greenwood, J. R.; Frydenvang, K.; Bra¨uner-Osborne, H.; Krogsgaard-Larsen,
P.; Madsen, U. J. Org. Chem. 2003, 68, 1489–1495. (d) Ohfune, Y.; Demura,
T.; Iwama, S.; Matsuda, H.; Namba, K.; Shimamoto, K.; Shinado, T. Tetrahedron
Lett. 2003, 44, 5431–5434. (e) Roda, G.; Conti, P.; De Amici, M.; He, J. T.;
Polavarapu, P. L.; De Micheli, C. Tetrahedron: Asymmetry 2004, 15, 3079–
3090. (f) Bräuner-Osborne, H.; Bunch, L.; Chopin, N.; Couty, F.; Evano, G.;
Jensen, A. A.; Kusk, M.; Nielsen, B.; Rabasso, N. Org. Biomol. Chem. 2005, 3,
3926–3936. (g) Oba, M.; Nishiyama, N.; Nishiyama, K. Tetrahedron 2005, 61,
8456–8464. (h) Conti, P.; Pinto, A.; Tamborini, L.; Gracioso, G.; De Sarro, G.;
Bräuner-Osborne, H.; Szabo, G.; Harsing, L. G.; De Micheli, C. ChemMedChem
2007, 2, 1639–1647. (i) Conti, P.; Caligiuri, A.; Pinto, A.; Roda, G.; Tamborini,
L.; Nielsen, B.; Madsen, U.; Frydenvan, K.; Colombo, A.; De Micheli, C. Eur.
J. Med. Chem. 2007, 42, 1056–1068. (j) Maison, W. Eur. J. Org. Chem. 2007,
2276–2284.
A new conformationally constrained analogue of glutamic
acid has been synthesized efficiently in seven steps from a
chiral 2-alkyl-4-piperidone. The synthesis is based on (a) the
unprecedented asymmetric one-carbon homologation of the
ketone controlled by the size of the N-substituent and (b)
the appropriate manipulation of substituents at positions 2
and 4 of the piperidine ring, a step that involves two
independent oxidation processes.
Conformationally constrained amino acids are useful struc-
tural components for pseudopeptides and peptidomimetics in
drug discovery, as the introduction of appropriate conformational
constraints provides a powerful strategy for improved drug
design.1 Replacement of a natural amino acid with a confor-
mationally constrained analogue in biologically active peptides
has often led to new compounds with improved properties and
has provided new insights in the elucidation of receptor-bound
ligand conformations.2
(5) (a) Bra¨uner-Osborne, H.; Egebjerg, J.; Nielsen, E.; Madsen, U.; Krogs-
gaard-Larsen, P. J. Med. Chem. 2000, 43, 2609–2645. (b) Kew, J. N. C.; Kemp,
J. A. Psychopharmacology 2005, 179, 4–29. (c) Swanson, C. J.; Bures, M.;
Johnson, M. P.; Linden, A. M.; Monn, J. A.; Schoepp, D. D. Nat. ReV. Drug
DiscoVery 2005, 4, 131–144.
(6) (a) Madsen, U.; Brehm, L.; Schaumburg, K.; Jorgensen, F. S.; Krogsgaard-
Larsen, P. J. Med. Chem. 1990, 33, 374–380. (b) MacCoss, M.; Mills, S. G.
PCT Int. Appl. WO 9522525 A1, 19950824. (c) Hamanaka, E. S.; Hayward,
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Appl. WO 9834918 A1, 19980813. (e) Bocan, T. M. A. PCT Int. Appl. WO
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T. J.; Danley, D. E.; Geoghegan, K. F.; Halim, N. S.; Hoth, L. R.; Kamath,
A. V.; Laird, E. R.; Lopresti-Morrow, L. L.; McClure, K. F.; Mitchell, P. G.;
Natarajan, V.; Noe, M. C.; Pandit, L. R.; Schulte, G. K.; Snow, S. L.; Sweeney,
F. J.; Tan, D. H.; Yu, C. H. Bioorg. Med. Chem. Lett. 2002, 12, 1387–1390.
(1) For reviews on this topic, see: (a) Giannis, A.; Kolter, T. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1244–1267. (b) Gante, J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1699–1720. (c) Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789–12854. (d) Gillespie, P.; Cicariello,
J.; Olson, G. L. Biopolymers (Peptide Sci.) 1997, 43, 191–217. (e) Gibson, S. E.;
Guillo, N.; Tozer, M. J. Tetrahedron 1999, 55, 585–615. (f) Methods in Organic
Chemistry: Synthesis of Peptides and Peptidomimetics; Goodman, M., Felix,
A., Moroder, L., Toniolo, C., Eds.; Houben-Weyl; Thieme: Stuttgart, 2003; Vol.
E22c. (g) Cowell, S. M.; Lee, Y. S.; Cain, J. P.; Hruby, V. J. Curr. Med. Chem.
2004, 11, 2785–2798. (h) Belvisi, L.; Colombo, L.; Manzoni, L.; Potenza, D.;
Scolastico, C. Synlett 2004, 1449–1471. (i) Cluzeau, J.; Lubell, W. D.
Biopolymers 2005, 80, 98–150. (j) Handbook of Biologically ActiVe Peptides;
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8594 J. Org. Chem. 2008, 73, 8594–8597
10.1021/jo801515k CCC: $40.75 2008 American Chemical Society
Published on Web 10/01/2008

SCHEME 1. Retrosynthetic Analysis
SCHEME 2. Synthesis of Methyl Ester 4
behave as an agonist at the NMDA receptor. On the other hand,
cis-piperidine-2,4-dicarboxylic acid has NMDA antagonist
profiles. As a consequence, the efficient independent synthesis
of any of the possible stereoisomers of piperidine-2,4-dicar-
boxylic acid represents a significant achievement due to the
important physiological properties associated with its three-
dimensional structure.
In spite of its biological relevance, only a few methods have
been reported for the preparation of racemic trans- or cis-
piperidine-2,4-dicarboxylic acid.7 In addition, two asymmetric
syntheses of enantiopure piperidine-2,4-dicarboxylic acid de-
rivatives of 2S configuration have been described.8
In the course of our work on the asymmetric synthesis of
polysubstituted piperidines from enantiopure (R)-2-[(S)-1,2-
dibenzyloxyethyl]-1-[(S)-1-phenylethyl]-4-piperidone (1),9 we
envisaged that this compound could be a useful starting material
for the preparation of piperidine-2,4-dicarboxylic acid deriva-
tives with the R absolute configuration at C2 (Scheme 1). The
proposed strategy involves the use of aldehyde 3, obtained by
asymmetric one-carbon homologation of 4-piperidone 1, as the
key intermediate. Appropriate transformation of the piperidine
ring substituents at C2 and C4 of aldehyde 3 would lead to the
desired glutamic acid analogue.
In this paper, we report full details of the asymmetric
synthesis of enantiomerically pure (2R,4R)-1-tert-butoxycarbo-
nyl-4-methoxycarbonylpiperidine-2-carboxylic acid (7) from
piperidone 1. Compound 1 is easily available on gram scale
from inexpensive D-mannitol.10
The addition of one carbon unit to a ketone to homologate it
to a new carbonyl derivative is an important transformation that
chemists have approached in different ways.11 It is known that
ketones and aldehydes react through a Wadsworth-Emmons
olefination using diethyl isocyanomethylphosphonate to give
R,ꢀ-unsaturated isocyanides.12 Acidic hydrolysis of these latter
compounds affords the corresponding homologated aldehydes.13
This strategy has proven to be appropriate to homologate
sterically hindered ketones, cyclic ketones, enolizable ketones,
and several aliphatic and aromatic aldehydes. Nevertheless, to
the best of our knowledge, an asymmetric version of this
synthetic methodology has yet to be reported.
Wadsworth-Emmons reaction of piperidone 1 with an excess
of diethyl isocyanomethylphosphonate (5.0 equiv) under the
reaction conditions described by Masamune and Roush14
afforded intermediate R,ꢀ-unsaturated isocyanide 2 as a ca. 50/
50 mixture of Z/E diastereoisomers,15 which was hydrolyzed
with HCl at room temperature in a two-phase system (diethyl
ether/water) to afford aldehyde 3 as a thermodynamically
unstable 25/75 mixture of cis and trans diastereoisomers.15 On
standing, the aldehyde of trans configuration slowly epimerized
to the cis isomer to reach a constant value of 76/24 in favor of
the cis-diastereoisomer after several days. Consequently, crude
aldehyde 3 was dissolved in acetone and immediately oxidized
with Jones’ reagent and subsequently esterified by treatment
with thionyl chloride/methanol to cleanly afford the correspond-
ing methyl ester 4 as a 25/75 mixture of cis/trans diastereoi-
somers.15 Configurationally stable methyl esters cis-4 and
trans-4 were easily isolated by column chromatography in 14%
and 44% yield, respectively, from starting 4-piperidone 1
(Scheme 2).
Conversion of trans-4 into the conveniently protected (2R,4R)-
piperidine-2,4-dicarboxylic acid derivative was performed as
follows (Scheme 3). Selective hydrogenolytic N-debenzylation
of trans-4 using Pd on carbon as the catalyst and in the presence
of Boc2O gave N-Boc derivative 5 in 74% yield. Subsequent
removal of the O-benzyl groups by extensive hydrogenolysis
using Pd(OH)2 on carbon as the catalyst afforded diol 6 in nearly
quantitative yield. This compound was immediately submitted
to oxidative cleavage by treatment with excess of sodium
periodate in the presence of a catalytic amount of anhydrous
ruthenium trichloride to give orthogonally protected (2R,4R)-
piperidine-2,4-dicarboxylic acid 7 in 59% yield. A parallel
synthetic scheme starting from cis-3 could not be completed as
diol of cis configuration suffered an immediate lactonization
process.
(7) (a) Mastafanova, L. I.; Turchin, K. F.; Yevstratova, M. I.; Sheinker, Y. N.;
Yakhontov, L. N. Khim. Geterotsikl. Soedin. 1985, 367–371. (b) Nazih, A.;
Schneider, M. R.; Mann, A. Synlett 1998, 1337–1338. (c) Nielsen, J.; Bols, M.;
Carstensen, E. V.; Willert, M. PCT Int. Appl. WO 9903832 A1, 19990128.
(8) (a) Hanessian, S.; Margarita, R. Tetrahedron Lett. 1998, 39, 5887–5890.
(b) Del Bosco, M.; Johnstone, A. N. C.; Bazza, G.; Lopatriello, S.; North, M.
Tetrahedron 1995, 51, 8545–8554.
(9) (a) Etayo, P.; Badorrey, R.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A. Chem.
Commun. 2006, 3420–3422. (b) Etayo, P.; Badorrey, R.; D´ıaz-de-Villegas, M. D.;
Ga´lvez, J. A. Synlett 2006, 2799–2803. (c) Etayo, P.; Badorrey, R.; D´ıaz-de-
Villegas, M. D.; Ga´lvez, J. A. J. Org. Chem. 2007, 72, 1005–1008. (d) Etayo,
P.; Badorrey, R.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A. Tetrahedron: Asymmetry
2007, 18, 2812–2819. (e) Etayo, P.; Badorrey, R.; D´ıaz-de-Villegas, M. D.;
Ga´lvez, J. A. Tetrahedron Lett. 2008, 49, 2251–2253.
Preferential formation of aldehyde 3 of trans configuration
in the homologation process indicated that hydrolysis of
isocyanide 2 had mainly occurred from the side of the piperidine
ring where the bulky 1,2-dibenzyloxyethyl substituent at C2 is
(10) Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A.
Tetrahedron 1999, 55, 7601–7612.
(11) Badham, N. F. Tetrahedron 2004, 60, 11–42.
(12) (a) Scho¨llkopf, U.; Scho¨der, R.; Stafforst, D. Liebigs Ann. Chem. 1974,
44–53. (b) Scho¨llkopf, U.; Stafforst, D.; Jentch, R. Liebigs Ann. Chem. 1977,
1167–1173.
(13) Moskal, J.; van Leusen, A. M. Recl. TraV. Chim. Pays-Bas 1987, 106,
137–141.
(14) Blanchette, M. A.; Choy, W.; Davis, J.; Essenfield, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
(15) Diastereomeric ratios were determined by 1H NMR analysis of crude
reaction mixtures. The E and Z or cis and trans configurations were unambigu-
ously assigned by 2D 1H-1H NOESY experiments.
J. Org. Chem. Vol. 73, No. 21, 2008 8595

TABLE 1. Homologation Process for Piperidones 1, 8, and 10
SCHEME 3. Synthesis of Orthogonally Protected
(2R,4R)-Piperidine-2,4-dicarboxylic Acid from Ester trans-4
entry
R
substrate
product
cis/trans
1
2
3
(S)-CH(CH3)Ph
H
CH3
1
8
10
3
11
12
25/75
86/14
72/28
SCHEME 5. Stereochemical Course of the Isocyanide
Hydrolysis
SCHEME 4. Synthesis of Piperidones 8 and 10
located. In an effort to rationalize this stereochemical course,
some additional investigations were carried out.
Piperidones 8 and 10, in which the bulky N-[(S)-1-phenyl-
ethyl] substituent has been replaced with much less sterically
demanding groups (hydrogen and methyl), were prepared as
follows. Compound 8 was obtained by N-debenzylation of 1
with molecular hydrogen in the presence of Pd(OH)2/C as the
catalyst (Scheme 4). Compound 10 was prepared through a
synthetic route similar to that previously described for piperidone
1. Treatment of (R)-2,3-di-O-benzyl-glyceraldehyde with me-
thylamine in the presence of anhydrous MgSO4 afforded crude
imine 9. This compound reacted with Danishefsky’s diene in
the presence of ZnI2 as a catalyst at low temperature and using
anhydrous acetonitrile as solvent to give a cyclic enaminone
(dr ) 93/7), which upon regioselective reduction with L-
Selectride at -78 °C, followed by purification by column
chromatography, afforded enantiomerically pure piperidone 10
(Scheme 4).
The homologation process was investigated next. Treatment
of piperidones 8 and 10 with an excess of diethyl isocyanom-
ethylphosphonate using DBU as a base, in the presence of LiCl,
and subsequent acidic hydrolysis gave aldehydes 11 and 12,
which were obtained, respectively, as 86/14 and 72/28 cis/trans
thermodynamically stable diastereomeric mixtures15 in which
the cis-diastereoisomer predominated (Table 1).
small group, such as hydrogen or methyl, cis-11 and cis-12,
respectively, are obtained in excess.
An attempt to rationalize the stereochemical course of the
formation of aldehydes 3, 11, and 12 by acidic hydrolysis of
the isocyanides 1, 8, and 10 is made below.
Acidic treatment of isocyanides A led to hydration of the
isonitrile group with concomitant protonation of the nitrogen
of the ring opposite to the C2 substituent to afford the
corresponding N-formylenamine B. Depending on the R sub-
stituent on the nitrogen, the conformational equilibrium would
be shifted to conformer B1 (small-sized substituents) or
conformer B2 [bulky (S)-1-phenylethyl group].
The initially formed N-formylenamine evolves to the corre-
sponding N-formylimine in which bulky substituents are situated
in an equatorial disposition through an enamine-imine tautomeric
equilibrium. Subsequent hydrolysis of the formylimino group
in 1,2,4-trisubstituted piperidinium salts C or D followed by
neutralization led to the preferential formation of the corre-
sponding aldehyde of cis or trans configuration (Scheme 5).
In conclusion, (2R,4R)-N-tert-butoxycarbonyl-4-methoxycar-
bonylpiperidine-2-carboxylic acid 7 has been obtained from
4-piperidone 1 in 19% overall yield. The route is a simple
procedure that is based on a novel diastereoselective one-carbon
These results indicate that the stereochemical course of the
homologation reaction of piperidones 1, 8, and 10 via an R,ꢀ-
unsaturated isocyanide depends on the size of the R substituent
on the nitrogen. When R is the bulky (S)-1-phenylethyl group,
trans-3 is obtained as the major product, whereas when R is a
8596 J. Org. Chem. Vol. 73, No. 21, 2008

J ) 3.3, J ) 2.3), 2.43 (1H, ddd, J ) 11.6, J ) 3.5, J ) 3.5), 2.69
(1H, ddd, J ) 11.2, J ) 4.1, J ) 2.3), 3.63 (1H, dd, J ) 10.6, J
) 7.6), 3.98 (1H, dd, J ) 10.6, J ) 0.9), 4.06-4.12 (1H, m), 4.08
(1H, q, J ) 6.9), 4.43 (1H, d, J ) 12.1), 4.54 (1H, d, J ) 12.1),
4.65 (1H, d, J ) 12.0), 4.79 (1H, d, J ) 12.0), 7.11-7.36 (15H,
m), 9.51 (1H, d, J ) 1.3); 13C NMR (100 MHz, CDCl3) δ 8.0,
25.7, 26.1, 44.2, 49.2, 53.8, 59.0, 71.1, 72.8, 73.6, 77.6, 126.5,
127.5, 127.5, 127.6, 127.6, 127.7, 128.0, 128.3, 128.4, 138.2, 138.8,
143.4, 203.7; HRMS (ESI+) calcd for C30H36NO3 (MH+) 458.2690,
found 458.2677.
homologation process of ketones via R,ꢀ-unsaturated isocya-
nides. The procedure described here constitutes (a) the first
asymmetric synthesis of a piperidine-2,4-dicarboxylic acid
derivative with 2R configuration and (b) the first example of
an asymmetric homologation of ketones of this type. This
synthesis, which avoids low reaction temperatures and difficult
purification procedures, highlights the utility of 4-piperidone 1
as a versatile chiral precursor for the stereoselective synthesis
of biologically active polysubstituted piperidines.
(2R,4R)-1-tert-Butoxycarbonyl-4-methoxycarbonylpiperidine-
2-carboxylic Acid (7).16 NaIO4 (428 mg, 2.0 mmol) was added to
a stirred solution of compound 6 (152 mg, 0.5 mmol) in CH3CN/
CCl4/H2O (2:2:3, 14 mL). After being vigorously stirred for 5 min,
the mixture was treated with anhydrous RuCl3 (5 mg, 0.025 mmol),
and stirring was continued for 3 h. The reaction mixture was diluted
with CH2Cl2 (10 mL) and water (10 mL). The aqueous phase was
extracted with CH2Cl2 (3 × 20 mL), and the combined organic
layers were dried over anhydrous MgSO4, filtered, and evaporated
in vacuo. Purification of the crude product by column chromatog-
raphy (eluent: EtOAc/hexanes 2:1) afforded 85 mg (59%) of
Experimental Section
Asymmetric Homologation of Piperidone 1. To a suspension of
anhydrous lithium chloride (424 mg, 10.0 mmol) in anhydrous Et2O
(10 mL) at room temperature under argon were added diethyl
isocyanomethylphosphonate (1.60 mL, 10.0 mmol) and DBU (1.64
mL, 11.0 mmol). The mixture was stirred for 10 min at room
temperature. A solution of compound 1 (886 mg, 2.0 mmol) in
anhydrous Et2O (30 mL) was added, and the resulting mixture was
stirred at room temperature for 24 h. The reaction was quenched
with 35 wt % hydrochloric acid in water (33 mL), and the biphasic
Et2O/H2O mixture was stirred at room temperature for 7 h. The
reaction mixture was cooled to 0 °C, neutralized with solid K2CO3,
and extracted with Et2O (3 × 50 mL). The combined organic
extracts were dried over anhydrous MgSO4, filtered, and evaporated
under reduced pressure to yield compound 3 as a 25/75 cis/trans
mixture of diastereoisomers. A solution of the obtained compound
in CHCl3 (50 mL) was stirred under reflux conditions for 7 d and
evaporated under reduced pressure to yield compound 3 as a 76/
24 cis/trans mixture of diastereoisomers.
compound 7 as a white solid: white solid; mp ) 102-104 °C; [R]25
D
) +17.2 (c 0.47, CHCl3); IR absorption (KBr) 3700-2250, 1734,
1
1717, 1699, 1257 cm-1; H NMR (500 MHz, CDCl3) δ 1.44 and
1.47 (s, 9H), 1.56 (dddd, 1H, J ) 13.0, J ) 13.0, J ) 12.5, J )
4.6), 1.76-1.89 (m, 1H), 1.93 and 1.99 (bd, 1H, J ) 13.0 and J )
13.0), 2.41 (bdd, 1H, J ) 13.0, J ) 13.0), 2.46 and 2.51 (bd, 1H,
J ) 13.1 and J ) 13.6), 2.92 and 3.02 (bdd, 1H, J ) 12.6, J )
12.6 and J ) 12.4, J ) 12.4), 3.69 (s, 3H), 4.02 and 4.13 (bd, 1H,
J ) 12.4 and J ) 12.6), 4.87 and 5.04 (bd, 1H, J ) 4.6 and J )
4.7), 8.33 (bs, 1H); 13C NMR (125 MHz, CDCl3) δ 27.4 and 27.5,
28.2 and 28.3, 28.6, 37.9 and 38.0, 40.2 and 41.1, 51.9, 52.8 and
53.8, 80.7 and 80.8, 155.1 and 155.8, 174.6, 176.4 and 176.7;
HRMS (ESI-) calcd for C13H20NO6 (M-H+) 286.1296, found
286.1293. Anal. Calcd for C13H21NO6: C, 54.35; H, 7.37; N, 4.88.
Found: C, 54.27; H, 7.68; N, 4.52.
(2R,4R)-2-[(S)-1,2-Dibenzyloxyethyl]-1-[(S)-1-phenylethyl]piperi-
dine-4-carbaldehyde (trans-3). From the 25/75 cis/trans mixture
obtained in the acidic hydrolysis of (E/Z)-2: IR absorptions (neat)
1
νmax 1724; H NMR (400 MHz, CDCl3) δ 1.13 (3H, d, J ) 6.6),
1.44 (1H, ddd, J ) 12.6, J ) 8.6, J ) 4.4), 1.47-1.54 (1H, m),
1.58-1.67 (1H, m), 2.11 (1H, ddd, J ) 11.8, J ) 7.7, J ) 4.4),
2.35 (1H, ddd, J ) 12.4, J ) 7.6, J ) 3.4), 2.45-2.52 (1H, m),
2.49-2.56 (1H, m), 2.89-2.95 (1H, m), 3.59 (1H, dd, J ) 10.6, J
) 6.4), 3.73 (1H, dd, J ) 10.6, J ) 2.5), 3.89-3.94 (1H, m), 3.95
(1H, q, J ) 6.6), 4.42 (1H, d, J ) 12.0), 4.49 (1H, d, J ) 12.0),
4.59 (1H, d, J ) 11.7), 4.72 (1H, d, J ) 11.7), 7.06-7.35 (15H,
m), 9.51 (1H, bs); 13C NMR (100 MHz, CDCl3) δ 7.9, 23.4, 24.6,
42.2, 45.1, 55.0, 57.1, 71.4, 72.7, 73.4, 78.5, 126.5, 127.3, 127.5,
127.6, 127.7, 127.8, 128.0, 128.2, 128.3, 138.2, 138.8, 145.3, 204.7;
HRMS (ESI+) calcd for C30H36NO3 (MH+) 458.2690, found
458.2695.
Acknowledgment. The financial support of the Government
of Arago´n (GA E-71) and the University of Zaragoza (CIE-05)
is acknowledged. P.E. was supported by a IUCH Fellowship.
Supporting Information Available: General statement de-
scribing materials and methods, additional experimental pro-
cedures, physical and spectral data (1H NMR, 13C NMR, and
IR) for all new compounds, and NOESY spectrum for com-
pound 7. This material is available free of charge via the Internet
at http://pubs.acs.org.
(2R,4S)-2-[(S)-1,2-Dibenzyloxyethyl]-1-[(S)-1-phenylethyl]piperi-
dine-4-carbaldehyde (cis-3). From the 76/24 cis/trans mixture
obtained in the epimerization of (cis/trans)-3: IR absorptions (neat)
JO801515K
(16) NMR data of compound 7 correspond to two conformers detected at
room temperature whose well-resolved signals at room temperature did not
collapse to a well-resolved spectrum even at 353 K in C6D6. In the NOESY
spectrum, duplicate signals clearly show exchange cross peaks.
ν
max 1724; 1H NMR (400 MHz, CDCl3) δ 1.11-1.22 (2H, m), 1.12
(3H, d, J ) 6.9), 1.59 (1H, bd, J ) 12.6), 1.99 (1H, ddd, J ) 11.6,
J ) 11.6, J ) 2.4), 2.03-2.13 (1H, m), 2.26 (1H, ddd, J ) 12.6,
J. Org. Chem. Vol. 73, No. 21, 2008 8597