Totally selective synthesis of enantiopure (3S,5S)- and (3R,5R)-4-amino-3, 5-dihydroxypiperidines from aminodiepoxides derived from serine

Article abstract of DOI:10.1021/jo801058c

(Chemical Equation Presented) The transformation of enantiopure (2R,4R)- and (2S,4S)-N,N-dibenzyl-1,2:4,5-diepoxypentan-3-amine, 1 and 2, into the corresponding enantiopure (3S,5S)- and (3R,5R)-3,5-dihydroxy-3-aminopiperidines, 3 and 4 respectively, is described. The opening of the two epoxide rings with a range of amines takes place with total regioselectivity and high yields, in the presence of LiClO₄. A mechanism to explain this transformation is proposed.

Full text of DOI:10.1021/jo801058c

drolysis. Thus, polyhydroxylated piperidines2 have demonstrated
their utility in the treatment of carbohydrate-mediated diseases.
In recent years, much attention has been focused toward the
development of the efficient synthesis of different polyhydroxy-
lated piperidines due to their potential therapeutic applications
and the need to discover efficient routes for the synthesis of
biologically active analogues. The main synthetic strategy
described in the literature to obtain polyhydroxylated piperidines
utilizes carbohydrates as starting materials and, in general,
requires a large number of steps. Thus, the development of new
methods for the synthesis of enantiopure 1-azasugars from
alternative starting compounds is of considerable interest.6 In
addition, no synthesis of both enantiomers of polyhydroxylated
piperidines has been reported.
Totally Selective Synthesis of Enantiopure
(3S,5S)- and (3R,5R)-4-Amino-3,
5-dihydroxypiperidines from Aminodiepoxides
Derived from Serine
Jose´ M. Concello´n,*,† Ignacio A. Rivero,*,‡
Humberto Rodr´ıguez-Solla,† Carmen Concello´n,†
Estibaly Espan˜a,‡ Santiago Garc´ıa-Granda,† and M. R. D´ıaz†
Departamento de Qu´ımica Orga´nica e Inorga´nica, and
Qu´ımica F´ısica y Anal´ıtica, Facultad de Qu´ımica,
UniVersidad de OViedo, Julia´n ClaVer´ıa 8, 33071 OViedo,
Spain, and Centro de Graduados e InVestigacio´n del
Instituto Tecnolo´gico de Tijuana, BouleVard Industrial s/n,
Mesa de Otay, Tijuana, B. C., Me´xico 22000
(2) For a recent review, see: (a) Pearson, M. S. M.; Mathe´-Allainmat, M.;
Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159–2191. (b) Asano, N.
Glycobiology 2003, 13, 93R–104R. (c) Asano, N. Curr. Top. Med. Chem. 2003,
3, 471–484. (d) Compain, P.; Martin, O. R. Curr. Top. Med. Chem. 2003, 3,
541–560. (e) Nash, R. J.; Watson, A. A.; Asano, N. In Alkaloids Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Elsevier, Oxford, UK, 1996; Vol.
11, pp 345-376. (f) Elbein, A. D.; Molyneux, R. J. In ComprehensiVe Natural
Products; Barton, D., ; Nakanishi, K., Eds.; Elsevier: New York, 1999; Vol. 3,
pp 129-160.
jmcg@unioVi.es
ReceiVed May 16, 2008
(3) (a) Jespersen, T. M.; Dong, W.; Sierks, M. R.; Skrydstrup, T.; Lundt, I.;
Bols, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 1778–1779. (b) Ichikawa, M.;
Igarashi, Y.; Ichikawa, Y. Tetrahedron Lett. 1995, 36, 1767–1770. (c) Ichikawa,
Y.; Igarashi, Y. Tetrahedron Lett. 1995, 36, 4585–4586. (d) Hansen, A.; Tagmose,
T. M.; Bols, M. Chem. Commun. 1996, 2649, 2650. (e) Nishimura, Y.; Satoh,
T.; Kudo, T.; Kondo, S.; Takeuchi, T. Bioorg. Med. Chem. 1996, 4, 91–96. (f)
Igarashi, Y.; Ichikawa, M.; Ichikawa, Y. Tetrahedron Lett. 1996, 37, 2707–
2708. (g) Igarashi, Y.; Ichikawa, M.; Ichikawa, Y. Bioorg. Med. Chem. Lett.
1996, 6, 553–558. (h) Bols, M.; Hazell, R. G.; Thomsen, I. B. Chem.-Eur. J.
1997, 3, 940–947. (i) Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am.
Chem. Soc. 1998, 120, 3007–3018. (j) Nishimura, Y.; Shitara, E.; Adachi, H.;
Toyoshima, M.; Nakajima, M.; Okami, Y.; Takeuchi, T. J. Org. Chem. 2000,
65, 2–11. (k) Shitara, E.; Nishimura, Y.; Kojima, F.; Takeuchi, T. Bioorg. Med.
Chem. 2000, 8, 343–352. (l) Søhoel, H.; Liang, X.; Bols, M. J. Chem. Soc.,
Perkin Trans. 1 2001, 1584–1585. (m) Jakobsen, P.; Lundbeck, J. M.; Kristiansen,
M.; Breinholt, J.; Demuth, H.; Pawlas, J.; Candela, M. P. T.; Andersen, B.;
Westergaard, N.; Lundgren, K.; Asano, N. Bioorg. Med. Chem. 2001, 9, 733–
744. (n) Liu, H.; Liang, X.; Søhoel, H. H.; Bu¨low, A.; Bols, M. J. Am. Chem.
Soc. 2001, 123, 5116–5117.
The transformation of enantiopure (2R,4R)- and (2S,4S)-N,N-
dibenzyl-1,2:4,5-diepoxypentan-3-amine, 1 and 2, into the
corresponding enantiopure (3S,5S)- and (3R,5R)-3,5-dihy-
droxy-3-aminopiperidines, 3 and 4 respectively, is described.
The opening of the two epoxide rings with a range of amines
takes place with total regioselectivity and high yields, in the
presence of LiClO4. A mechanism to explain this transfor-
mation is proposed.
(4) (a) Bols, M. Acc. Chem. Res. 1998, 31, 1–8. (b) Iminosugars as
Glycosidase Inhibitors. Nojirimicin and Beyond; Stu¨tz, A. E., Ed.; Wiley-VCH:
Weinheim, Germany, 1999. (c) Somsak, L.; Nagy, V.; Hadady, Z.; Docsa, T.;
Gergely, P. Curr. Pharm. Des. 2003, 9, 1177–1189. (d) Greimel, P.; Spreitz, J.;
Stutz, A. E.; Wrodnigg, T. M. Curr. Top. Med. Chem. 2003, 3, 513–523. (e)
Nishimura, Y. Curr. Top. Med. Chem. 2003, 3, 575–591. (f) Butters, T. D.;
Dwek, R. A.; Platt, F. M. Glycobiology 2005, 15, 43R.
(5) For selected recent approaches, see: (a) Wang, R.-W.; Qing, F.-L. Org.
Lett. 2005, 7, 2189–2192. (b) Segraves, N. L.; Crews, P. J. Nat. Prod. 2005, 68,
118–121. (c) Goodenough, K. M.; Raubo, P.; Harrity, J. P. A. Org. Lett. 2005,
7, 2993–2996. (d) Mart´ın, R.; Murruzzu, C.; Perica´s, M. A.; Riera, A. J. Org.
Chem. 2005, 70, 2325–2328. (e) Lemire, A.; Charette, A. B. Org. Lett. 2005, 7,
2747. (f) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966–
8967. (g) Thomassigny, C.; Barroso, M. T.; Greck, C. Lett. Org. Chem. 2005,
2, 316–318. (h) McDonnell, C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V. J.
Org. Chem. 2004, 69, 3565–3568. (i) Takahata, H.; Banba, Y.; Sasatani, M.;
Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60, 8199–8205. (j)
Adelbrecht, J. C.; Craig, D.; Dymock, B. W.; Thorimbert, S. Synlett 2002, 467,
470.
Glycosidases inhibitors are a pharmacologically important
class of compounds, and consequently, an important number
of glycosidase inhibitors have been developed.1 Among these,
polyhydroxylated piperidines,5 which can be regarded as 1-aza-
sugars having a nitrogen atom at the anomeric position, have
been the subject of intense research. The inhibitory activity of
1-azasugars, also called iminosugars, is due to their ability to
mimic the transition state for the enzymatic glycosidase hy-
(6) (a) Kazmaier, U.; Schneider, C. Tetrahedron Lett. 1998, 39, 817–818.
(b) Kim, Y. J.; Ichikawa, M.; Ichikawa, Y. J. Org. Chem. 2000, 65, 2599–2602.
(c) Mehta, G.; Mohal, N. Tetrahedron Lett. 2000, 41, 5747–5751. (d) Liang,
X.; Lohse, A.; Bols, M. J. Org. Chem. 2000, 65, 7432–7437. (e) Pandey, G.;
Kapur, M. Tetrahedron Lett. 2000, 41, 8821–8824. (f) Zhao, G.; Deo, U. C.;
Ganem, B. Org. Lett. 2001, 3, 201–203. (g) Pandey, G.; Kapur, M. Synthesis
2001, 1263, 1267. (h) Andersch, J.; Bols, M. Chem.-Eur. J. 2001, 7, 3744–
3747. (i) Comins, D. L.; Fulp, A. B. Tetrahedron Lett. 2001, 42, 6839–6841. (j)
Best, W. M.; MacDonald, J. M.; Skelton, B. W.; Stick, R. V.; Tilbrook, D. M. G.;
White, A. H. Can. J. Chem. 2002, 80, 857–865. (k) Guanti, G.; Riva, R.
Tetrahedron Lett. 2003, 44, 357–360. (l) Pandey, G.; Kapur, M.; Khan, M. I.;
Gaikwad, S. M. Org. Biomol. Chem. 2003, 1, 3321–3326.
† Universidad de Oviedo.
‡ Instituto Tecnolo´gico de Tijuana.
(1) (a) Cai, G.; Salonikidis Petrus, S.; Fei, J.; Schwarz, W.; Schu¨le-in, R.;
Reutter, W.; Fan, H. FEBS J. 2005, 272, 1625–1638. (b) Karaveg, K.;
Siriwardena, A.; Tempel, W.; Liu, Z.-J.; Glushka, J.; Wang, B.-C.; Moremen,
K. W. J. Biol. Chem. 2005, 280, 16197–16207. (c) Zechel, D. L.; Withers, S. G.
Acc. Chem. Res. 2000, 33, 11–18. (d) Ganem, B. Acc. Chem. Res. 1996, 29,
340–347.
6048 J. Org. Chem. 2008, 73, 6048–6051
10.1021/jo801058c CCC: $40.75 2008 American Chemical Society
Published on Web 07/04/2008

TABLE 1. Synthesis of (3S,5S)-3,5-Dihydroxy-3-aminopiperidine 3
SCHEME 1. Synthesis of (3S,5S)-3,5-Dihydroxy-3-
aminopiperidine 3
entry
3
R
Yield(%)a
1
2
3
4
3a
3b
3c
3d
allyl
Pr
Cyclohexyl
Bn
90
94
93
92
a Yield after column chromatography based on the starting amino
epoxide 1.
Moreover, the synthesis of enantiopure organic compounds
with C2 symmetry or pseudo-C2 symmetry has also received
much attention due to their important synthetic applications.
These compounds are used as chiral ligands7 and to prepare
chiral catalysts,8 and the core unit of pseudopeptide HIV
protease inhibitors and other bioactive compounds9 present this
symmetry. Consequently, the polyhydroxylated piperidines with
pseudo-C2 symmetry present a double interest: as 1-azasugar
compounds and as building blocks.
SCHEME 2. Synthesis of (3 R,5 R)-3,5-Dihydroxy-3-
aminopiperidine 4
Previously, we have described an efficient synthesis of the
pseudo-C2 symmetric (2R,4R)- and (2S,4S)-N,N-dibenzyl-1,2:
4,5-diepoxypentan-3-amine, 1 and 2, in enantiomerically pure
form.10 Both aminodiepoxides were prepared from the same
the natural R-aminoacid, L-serine.
SCHEME 3. Proposed Mechanism
Herein, we describe a synthetic application of these amino-
diepoxides 1 and 2 to obtain the pseudo-C2 symmetric (3S,5S)-
and (3R,5R)-3,5-dihydroxy-3-aminopiperidines in enantiopure
form, 3 and 4, respectively.
Our initial studies were performed starting from (2R,4R)-N,N-
dibenzyl-1,2:4,5-diepoxypentan-3-amine, 1. Thus, the treatment
of a solution of the aminodiepoxide 1 in acetonitrile, with a
range of amines in the presence of LiClO4 at room temperature,
afforded the corresponding (3S,5S)-3,5-dihydroxy-3-aminopi-
peridines 3 in moderate or high yield (Scheme 1 and Table 1).11
1
The selectivity of the reaction was determined by H NMR
This transformation seems to be general, and the reaction
could be carried out with different aliphatic (linear and cyclic)
and unsaturated amines. Here, no differences were observed
during the course, or the outcome of the reaction, when allyl,
n-propyl, benzyl or cyclohexylamine were used, under the same
reaction conditions. As shown in Table 1, the different (3S,5S)-
4-amine-3,5-dihydroxypiperidines 3 were obtained in similar
yields.
spectroscopy (300 MHz) of the crude mixture of products,
showing the presence of a single isomer 3. Thus, has been shown
that the ring opening of epoxide 1 with amines took place with
total regioselectivity.
Synthetic methods that allow the synthesis of two pure
enantiomers are very useful since in many cases, the biological
or pharmaceutical properties of both enantiomers can be very
different. Indeed, it has been described that one enantiomer
shows therapeutic properties while the other can be toxic or
inactive.12 For this reason, and in order to extend the scope of
this synthesis, we performed the reaction on (2S,4S)-N,N-
dibenzyl-1,2:4,5-diepoxypentan-3-amine 2, instead of amino-
diepoxide 1 with allylamine and benzylamine, under the same
reaction conditions (Scheme 2).
(7) (a) Whitesell, J. K. Chem. ReV. 1989, 89, 1581–1590. (b) Konradi, A. W.;
Pedersen, S. F. J. Org. Chem. 1992, 57, 28–32. (c) Yu, Q.; Baroni, T. E.; Liable-
Sands, L.; Rheingold, A. L.; Borovik, A. S. Tetrahedron Lett. 1998, 39, 6831–
6834, and references cited therein. (d) Stranne, R.; Vasse, J.-L.; Moberg, C.
Org. Lett. 2001, 3, 2525–2528.
(8) (a) Sugimura, T.; Inoue, S.; Tai, A. Tetrahedron Lett. 1998, 39, 6487–
6490. (b) Cserepi-Szucs, S.; Bakos, J. J. Chem. Soc. Chem. Commun. 1997,
635, 636. (c) Schenk, W. A.; Stubbe, M.; Hagel, M. J. Organomet. Chem. 1998,
560, 257–263. (d) Marinetti, A.; Kruger, V.; Buzin, F. X. Tetrahedron Lett.
1997, 38, 2947–2950.
As was expected, no important differences were observed in
comparison to the transformation from 1 and the corresponding
(3S,5S)-3,5-dihydroxy-3-aminopiperidine 4a,d were obtained in
high yields (similar to the obtained in the synthesis of 3) and
(9) (a) Menozzi, C.; Dalko, P. I.; Cossy, J. Chem. Commun. 2006, 4638–
4640. (b) Parker, K. A.; Katsoulid, I. A. Org. Lett. 2004, 6, 1413–1416. (c)
Morgan, B. P.; Swick, A. G.; Hargrove, D. M.; LaFlamme, J. A.; Moynihan,
M. S.; Carroll, R. S.; Martin, K. A.; Lee, E.; Decosta, D.; Bordner, J. J. Chem.
Med. 2002, 45, 2417–2424. (d) Kempf, D. J.; Sham, H. L. Curr. Pharm. Des.
1996, 2, 225–246. (e) Kempf, D. J.; Codacovi, L. M.; Wang, X. C.; Kohlbrenner,
W. E.; Wideburg, N. E.; Saldivar, A.; Vasavanonda, S.; March, K. C.; Bryant,
P.; Sham, H. L.; Green, B. E.; Betebenner, D. A.; Erickson, J. J.; Norbeck, D. W.
J. Med. Chem. 1993, 36, 320–330. (f) Erickson, J. J.; Neidhart, D. J.; Van Drie,
J.; Kempf, D. J.; Wang, X. C.; Norbeck, D. W.; Pattner, J. J.; Rittenhouse, J. W.;
Turon, M.; Wideburg, N. E.; Kohlbrenner, W. E.; Simmer, R.; Helfrich, R.;
Paul, D. A.; Knigge, M. Science 1990, 249, 527–533.
1
with total selectivity (300 MHz H NMR spectroscopy of the
crude reaction mixture).
The mechanism proposed to explain the transformation of 1
into 3 is depicted in Scheme 3. The ring opening of the oxirane
by the amine would be favored by the presence of LiClO4, as
has been previously reported.13 Thus, one of the oxirane rings
would be opened by the amine at the less hindered position,14
affording the amino alcohol 5. The amine function in intermedi-
(10) Concello´n, J. M.; Riego, E.; Rodr´ıguez-Solla, H.; Plut´ın, A. M. J. Org.
Chem. 2001, 66, 8661–8665.
(11) The (3S,5S)-relative configuration of compound 3, employing as starting
material (2R,4R)-N,N-dibenzyl-1,2:4,5-diepoxypentan-3-amine 1, is explained
because the priority of the substituents (by application of the Cahn-Ingold-
Prelog priority rules) have changed during the course of the reaction.
(12) Ariens, E. J. Med. Res. ReV. 1996, 6, 451–466.
(13) Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990, 31, 4661–
4664.
J. Org. Chem. Vol. 73, No. 15, 2008 6049

In conclusion we have described a new and short synthesis
of both enantiomers (3S,5S)- and (3R,5R)-3,5-dihydroxy-3-
aminopiperidines 3 or 4 in enantiopure form, by double ring
opening reaction of epoxides of (2R,4R)- and (2S,4S)-N,N-
dibenzyl-1,2:4,5-diepoxypentan-3-amine, 1 or 2 with a range
of amines at room temperature in the presence of LiClO4. This
reported method is simple, and the starting aminodiepoxides 1
or 2 are readily available from serine. The opening of the
epoxide ring takes place with total regioselectivity.
FIGURE 1. Conformational equilibrium of piperidine 3d.
ate 5 participates in a nucleophilic attack to the second oxirane
ring at the less hindered position, affording the piperidine ring.
A similar mechanism could explain the transformation of
aminodiepoxides 2 into the enantiomers 4.
Experimental Section
The variation of symmetry at the C-3 carbon of 1 along the
transformation of 1 into 3, shown is Scheme 3, presents a
theoretical interest: the C-3 carbon of the aminodiepoxide 1 is
not a stereogenic center since both oxirane rings in 1 are
chemically equivalents. Conversely, the C-3 carbon in inter-
mediate 5, generated after the reaction of the aminodiepoxide
with the amine (NH2 R), is a stereogenic center. As a
consequence of the chemical equivalence of both oxirane rings,
the amine could equally attack both oxirane rings to give
intermediate 5 as mixture of epimers in a 1/1 ratio. An
intramolecular attack by the amine group (NHR) to the other
oxirane ring afforded the piperidine 3, in which the C-4 carbon
(formerly the C-3 carbon in compound 1) is not a stereogenic
center due the symmetry of the obtained piperidine (the two
substituents at the C-4 carbon of compound 3 are the same).
The structure of compounds 3 and 4, as depicted in Schemes
1, 2, and 3, was established based on IR, 1H, 13C NMR spectra
including DEPT, HMBC, HSQC, and NOESY experiments on
the 4-amino-3,5-dihydroxypiperidine 3d.
An HMBC NMR experiment on 3d showed correlation
between methylene hydrogens of C-2, and C-6 (see Schemes 1
and 2 for the numbering protocol) and the benzylic protons from
the cyclic nitrogen. Similarly, a correlation was observed
between the methylene hydrogens at C-6 and the methylene
and methine hydrogens at C-2 and C-5, respectively. Correlation
between methine protons at C-3 and C-5 was also observed.
Moreover, NOESY experiments showed correlation between
geminal hydrogens of the C-2 and C-6 methylenes. This
correlation is observed in six-member cyclic molecules due to
a conformational equilibrium that produces an exchange of the
environment of methylene protons (Figure 1, I and II). Hence,
all these data were consistent with the assigned structures for
compounds 3 and 4 (Schemes 1 and 2).
The configurational assignments of piperidines 3 were
established by 1H NMR coupling constant analysis and NOESY
experiments on 3d (Figure 1). The H-4 signal shows J ) 10.3,
2.0 Hz which is in accordance with a trans relative configuration
between H-4 and H-3, and cis for H-4 and H-5. Moreover, the
NOE interaction of H-4 with H-5, H-2, and H-6, and the absence
of NOE interactions between H-4 and H-3, would also support
the configuration of compounds 3 and 4. This stereochemical
assignment is also in agreement with the proposed ring-opening
mechanism.
This proposed structure and the absolute configurational
assignment of compounds 3 or 4 was unambiguously confirmed
by the single-crystal X-ray analysis of 3c.15 The structure and
absolute configuration of the other compounds 3a,b,d and 4a,d,
as depicted in Schemes 1 and 2, was assigned by analogy.
General Procedure. To a stirred solution of the corresponding
aminodiepoxide 1 or 2 (2 mmol) in dry acetonitrile (8 mL) was
added LiClO4 (2 mmol) at room temperature. After stirring for 5
min, the corresponding amine (3 mmol) was added dropwise at
the same temperature, and the mixture was stirred at room
temperature for 48 h. After this time, the reaction was quenched
with water (10 mL) and extracted with EtOAc (3 × 10 mL). The
organic layers were combined, dried over Na2SO4, filtered, and
concentrated in vacuum. Flash column chromatography on silica
gel (hexane/EtOAc 10/1) provided pure compounds 3 or 4.
(3S,5S)- and (3R,5R)-enantiomers showed identical spectroscopi-
cal data except [R]20 which were indicative.
D
1-Allyl-4-dibenzylamino-3,5-dihydroxypiperidine. (3S,5S)-3a
[R]20D) +90.9 (c 1.00, CHCl3); (3R,5R)-4a [R]20D) -91.0 (c 1.00,
CHCl3); Colorless solid; Mp 101 °C; 1H NMR (300 MHz, CDCl3)
δ 7.45-7.15 (m, 10 H), 5.91-5.71 (m, 1 H), 5.25-5.10 (m, 2 H),
4.35-4.28 (m, 1H), 4.25-4.10 (m, 1H), 3.95 (AB syst., J ) 13.9
Hz, 2 × 2H), 3.38 (br s, 2H), 3.31-3.20 (m, 1H), 3.10 (d, J ) 6.3
Hz, 2H), 3.01 (dt, J ) 12.0, 3.2 Hz, 1H), 2.32 (dd, J ) 10.7, 2.0
Hz, 1H), 2.13 (apparent d, J ) 11.4 Hz, 1 H), 1.85 (apparent t, J
) 10.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 139.6 (2 × C),
133.7 (CH), 128.7 (2 × CH), 128.4 (2 × CH), 127.0 (2 × CH),
118.8 (CH2), 64.7 (CH), 64.3 (CH), 62.4 (CH), 60.4 (CH2), 59.6
(CH2), 58.5 (CH2), 54.4 (2 × CH2); MS (70 eV, EI) m/z (%) 352
[M+, <1], 261 (23), 91 (100); HRMS (70 eV) calcd for
[C22H28N2O2 - CH2Ph] 261.1597, found 261.1598; IR (KBr): 3445,
2922, 2815, 1639 cm-1; Rf ) 0.25 (hexane/EtOAc 10:1)
4-Dibenzylamino-3,5-dihydroxy-1-propylpiperidine. (3S,5S)-
3b [R]20D) +52.8 (c 0.68, CHCl3); Pale-yellow solid; Mp 70 °C;
1H NMR (CDCl3, 200 MHz) δ 7.23-7.13 (m, 10H), 4.19-4.14
(m, 1H), 4.02-3.97 (m, 1H), 3.81 (AB syst., J ) 13.8 Hz, 2 ×
2H), 3.17-3.06 (m, 1H), 2.98 (br s, 2H), 2.79 (d, J ) 11.4 Hz,
1H), 2.22 (t, J ) 7.2 Hz, 2H), 2.18 (d, J ) 10.5 Hz, 1H), 1.96 (d,
J ) 12.5 Hz, 1H), 1.66 (t, J ) 9.9 Hz, 1H), 1.38-1.22 (m, 2H),
0.77 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3, 50 MHz) δ 139.7 (2
× C), 128.7 (4 × CH), 128.4 (4 × CH), 127.0 (2 × CH), 64.8
(CH), 64.3 (CH), 62.5 (CH), 60.0 (CH2), 59.1 (CH2), 58.6 (CH2),
54.4 (2 × CH2), 19.7 (CH2), 11.5 (CH3); MS (70 eV, EI) m/z (%)
354 [M+, <1], 263 (22), 91 (100); HRMS (70 eV) calcd for
[C22H30N2O2 - CH2Ph] 263.1754, found 263.1756; IR (KBr) 3426,
2933, 1642, 1455, 1375 cm-1; Rf ) 0.35 (hexane/EtOAc 3:1)
4-Dibenzylamino-1-cyclohexyl-3,5-dihydroxypiperidine. (3S,5S)-
3c [R]20D) +61.3 (c 0.70, CHCl3); Yellow solid; Mp 65 °C; H
1
NMR (CDCl3, 200 MHz) δ 7.31-7.06 (m, 10H), 4.20-4.11 (m,
1H), 3.99-3.90 (m, 1H), 3.84 (AB syst., J ) 14.0 Hz, 2 × 2H),
3.04 (dd, J ) 10.3, 4.4 Hz, 1H), 2.95 (br s, 2H), 2.77 (d, J ) 11.3
Hz, 1H), 2.30-2.19 (m, 1H), 2.17 (apparent t, J ) 12.2 Hz, 1H),
1.91 (apparent t, J ) 8.8 Hz, 1H), 1.66-1.60 (m, 4H), 1.51 (d, J
) 12.3 Hz, 1H), 1.20-0.91 (m, 6H);13C NMR (CDCl3, 50 MHz)
δ 139.8 (2 × C), 128.7 (4 × CH), 128.4 (4 × CH), 127.0 (2 ×
CH), 65.3 (CH), 64.0 (CH), 63.4 (CH), 63.2 (CH), 56.2 (CH2),
(15) CCDC 687287 contains the supplementary crystallographic data for
compound 3c. These data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html (or the Cambridge Data Center 12 Union Road
Cambridge CB2 1EZ UK fax (+44)1223-336-033 or deposit@ccdc.cam.ac.uk).
(14) (a) Concello´n, J. M.; Sua´rez, J. R.; del Solar, V. J. Org. Chem. 2005,
70, 7447–7450. (b) Concello´n, J. M.; Cuervo, H.; Ferna´ndez-Fano, R. Tetra-
hedron 2001, 57, 8983–8987.
6050 J. Org. Chem. Vol. 73, No. 15, 2008

55.0 (CH2), 54.4 (2 × CH2), 29.0 (CH2), 28.8 (CH2), 26.0 (CH2),
25.7 (2 × CH2); MS (70 eV, EI) m/z (%) 394 [M+, <1], 303 (15),
91 (100); HRMS (70 eV) calcd for [C25H34N2O2 - CH2Ph]
303.2067, found 303.2071; IR (KBr) 3430, 2924, 1455 cm-1; Rf
) 0.26 (hexane/EtOAc 10:1)
(70 eV) calcd for [C26H30N2O2 - CH2Ph] 311.1754, found
311.1749; IR (KBr): 3418, 3022, 2916, 2810, 1489, 1451 cm-1; Rf
) 0.40 (hexane/EtOAc 3:1)
Acknowledgment. We thank the Ministerio de Educacio´n y
Ciencia (CTQ2007-61132, and MAT2006-01997) for financial
support. J.M.C. thanks his wife Carmen Ferna´ndez-Flo´rez for
her time. H.R.S. thanks Ministerio de Educacio´n y Ciencia for
a Ramo´n y Cajal Contract (Fondo Social Europeo). We thank
Euan C. Goddard (University of Oxford) for his revision of the
English.
1-Benzyl-4-dibenzylamino-3,5-dihydroxypiperidine. (3S,5S)-
3d [R]20D) +45.5 (c 0.22, CHCl3); (3R,5R)-4d [R]20D) -44.3 (c
0.20, CHCl3); Yelow solid; Mp 105 °C; 1H RMN (300 MHz,
CDCl3) δ 7.35-7.00 (m, 15H), 4.20-4.11 (m, 1 H), 4.05-3.92
(m, 1H), 3.69 (AB syst., J ) 13.8 Hz, 2 × 2H), 3.45 (AB syst., J
) 12.1 Hz, 2H), 3.08 (ddd, J ) 10.4, 5.1, 2.4 Hz, 1H), 2.96 (br s,
2H), 2.81 (dt, J ) 11.6, 2.9 Hz, 1H), 2.19 (dd, J ) 10.4, 2.0, Hz,
1H), 2.00 (dd, J ) 11.6, 1.1, Hz, 1H), 1.69 (apparent t, J ) 10.1
Hz, 1H); 13C RMN (75 MHz, CDCl3) δ 139.7 (2 × C), 137.4 (C),
128.9 (2 × CH), 128.7 (4 × CH), 128.4 (4 × CH), 128.3 (2 ×
CH), 127.4 (2 × CH), 127.0 (2 × CH), 65.0 (CH), 64.5 (CH),
62.7 (CH), 61.8 (CH2), 59.9 (CH2), 58.6 (CH2), 54.4 (2 × CH2);
MS (70 eV, EI) m/z (%) 402 [M+, <1], 311 (10), 91 (100); HRMS
1
Supporting Information Available: Copies of H and 13C
NMR spectra for compounds 3, and crystallographic data (CIF)
of 3c. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801058C
J. Org. Chem. Vol. 73, No. 15, 2008 6051