Divergent asymmetric synthesis of 3,5-disubstituted piperidines

Article abstract of DOI:10.1021/jo0615091

A divergent synthesis of various 3,5-dioxygenated piperidines with interesting pharmacological properties is described. A mixture of the achiral cis- and racemic trans-3,5-piperidine diol could be efficiently obtained from N-benzylglycinate in five steps

Full text of DOI:10.1021/jo0615091

Divergent Asymmetric Synthesis of 3,5-Disubstituted Piperidines
Berit Olofsson, Krisztia´n Boga´r, Ann-Britt L. Fransson, and Jan-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm UniVersity,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
ReceiVed July 20, 2006
A divergent synthesis of various 3,5-dioxygenated piperidines with interesting pharmacological properties
is described. A mixture of the achiral cis- and racemic trans-3,5-piperidine diol could be efficiently
obtained from N-benzylglycinate in five steps by the use of chemoenzymatic methods. In the subsequent
enzyme- and Ru-catalyzed reaction, the rac/meso diol mixture was efficiently transformed to the cis-
(3R,5S)-diacetate with excellent diastereoselectivity and in high yield. Further transformations of the
cis-diacetate selectively delivered the cis-piperidine diol and the cis-(3R,5S)-hydroxy acetate. Alternatively,
the DYKAT could be stopped at the monoacetate stage to give the trans-(3R,5R)-hydroxy acetate.
Introduction
Substituted piperidines are common substructures in many
natural products and pharmacologically active compounds, and
novel methodologies for asymmetric synthesis of these targets
are therefore of considerable interest.1,2 Polyhydroxylated pip-
eridines, also called iminosugars, have recently received much
interest in the field of glycosidase inhibitors with applications
in the treatment of cancer and AIDS.3 More specifically, 3,5-
piperidine diols, which are 3-deoxy derivatives of iminosugars,
have been reported as substructures in compounds active in the
treatment of Alzheimer’s disease4 and schizophrenia.5,6 Fur-
thermore, protected 3,5-dihydroxypiperidines have recently been
employed as catalysts in asymmetric diethylzinc additions to
aldehydes.7
FIGURE 1. Ruthenium complexes used as epimerization catalysts.
In our recent dynamic kinetic asymmetric transformation
(DYKAT) of 1,3-cyclohexanediol,8 ruthenium catalysts 19 and
210 were employed to epimerize the hydroxyl groups of the diol
in the presence of an enzyme that preferentially acetylated (R)-
configured alcohols (Figure 1). The epimerization was found
to be facile, whereas the monoacylation selectivity was poor,
resulting in a mixture of (R)- and (S)-configured monoacetates.
High selectivity was, however, obtained in the second acylation,
giving the cis-diacetate in high yield. This compound could
subsequently be enantioselectively transformed into the cis-
monoacetate and the trans-diacetate.8
* To whom correspondence should be addressed. Phone: +46-(0)8-674 7178.
Fax: +46-(0)8-154908.
(1) Felpin, F.-X.; Lebreton, J. Eur. J. Org. Chem. 2003, 3693-3712.
(2) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun. 1998,
633-640.
(3) Ouchi, H.; Mihara, Y.; Takahata, H. J. Org. Chem. 2005, 70, 5207-
5214 and references therein.
(7) Roudeau, R.; Pardo, D. G.; Cossy, J. Tetrahedron 2006, 62, 2388-
2394.
(4) John, V.; Moon, J. B.; Pulley, S. R.; Rich, D. H.; Brown, D. L.;
Jagodzinska, B.; Jacobs, J. S. WO Patent 2003043987, 2002-US37037, 2003.
(5) Hoffmann, T.; Koblet, A.; Peters, J.-U.; Schnider, P.; Sleight, A.;
Stadler, H. U.S. Patent 2005/0090533, 2005.
(6) See also: Herbert, N. U.S. Patent 6828427 B1, 2004. Shepherd, R.
G.; White, A. C. GB Patent 2060617 A, 1981.
(8) Fransson, A.-B. L.; Xu, Y.; Leijondahl, K.; Ba¨ckvall, J.-E. J. Org.
Chem. 2006, 71, 6309-6316.
(9) Blum, Y.; Czarkie, D.; Rahamim, Y.; Shvo, Y. Organometallics 1985,
4, 1459-1461.
(10) Martin-Matute, B.; Edin, M.; Boga´r, K.; Kaynak, F. B.; Ba¨ckvall,
J.-E. J. Am. Chem. Soc. 2005, 127, 8817-8825.
10.1021/jo0615091 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/12/2006
8256
J. Org. Chem. 2006, 71, 8256-8260

Synthesis of 3,5-Disubstituted Piperidines
FIGURE 2. Target 3,5-oxygenated piperidines in the DYKAT of diol mixture 3.
SCHEME 1. Synthesis of Diol Mixture 3
SCHEME 2. DYKAT of Diol Mixture 3
We subsequently became interested in applying this chemistry
to piperidine diols. Starting from a cis:trans mixture of 3,5-diol
3, we envisioned an efficient, divergent synthesis of the oxygen-
substituted piperidines 3-5, several of which are novel com-
pounds (Figure 2). Herein we describe the results obtained with
this synthetic strategy.11
Results and Discussion
Our strategy toward the divergent synthesis of various 3,5-
disubstituted piperidines relies on a straightforward synthesis
of diol mixture 3. Reported syntheses of cis-3 derivatives are
lengthy and involve either the chiral pool12 or a chiral auxiliary,13
despite the fact that cis-3 is a meso compound. Also the
synthesis of trans-3 required the use of the chiral pool; a
protected (S,S)-enantiomer was obtained in 14 steps,14 whereas
an efficient ring expansion of a hydroxyprolinol derivative gave
the (R,R)-enantiomer.15,16
None of the reported syntheses of 3 met with our demands
on efficiency and simplicity, as we sought a short route
delivering both the cis- and trans-diols without tedious purifica-
tion steps. The synthetic strategy depicted in Scheme 1 was
thus designed to provide diols 3 as a cis:trans mixture by
reduction of the corresponding diketone.
SCHEME 3. Determination of Absolute Configuration
glycinate followed by Wacker oxidation but resulted in a lower
overall yield. Claisen condensation of 6 and trapping of the eno-
late with acetic anhydride afforded â-acetoxyenone 7 in a clean
reaction.18,19 As compound 7 was found to be unstable on silica,
the crude material was directly used in the following reaction.
To avoid having to isolate diketone 8, the best way to
transform compound 7 into diols 3 was to employ a coupled
deacetylation and reduction system in a sequential one-pot
reaction. Thus, vinyl acetate 7 was treated with the commercially
available enzyme Candida antarctica lipase B (CALB) in a
mixture of 2-propanol and toluene in order to transfer the acetyl
group from 7 to i-PrOH.
Commercially available N-benzylglycinate was reacted with
chloroacetone to yield compound 6.17 An alternative pathway
to 6, avoiding chloroacetone, involved allylation of the N-benzyl-
(11) A similar approach using KR was recently published on 3,4-
piperidine diols in moderate yields and selectivities, see: Solares, L. F.;
Lavandera, I.; Gotor-Ferna´ndez, B., R.; Gotor, V. Tetrahedron 2006, 62,
3284-3291.
(12) Bentley, N.; Dowdeswell, C. S.; Singh, G. Heterocycles 1995, 41,
2499-2506.
The deacetylation proceeded smoothly at room temperature,
after which the enzyme was filtered off to give diketone 8 in a
solution of toluene and i-PrOH. This mixture was directly
(13) John, V.; Moon, J.; Pulley, S. R.; Rich, D. H.; Brown, D. L.;
Jagodzinska, B. WO Patent 03/043987, 2003.
(14) Suhara, Y.; Kittaka, A.; Ono, K.; Kurihara, M.; Fujishima, T.;
Yoshida, A.; Takayama, H. Bioorg. Med. Chem. Lett. 2002, 12, 3533-
3536.
(15) Cossy, J.; Dumas, C.; Michel, P.; Pardo, D. G. Tetrahedron Lett.
1995, 36, 549-552.
(16) Cossy, J.; Dumas, C.; Pardo, D. G. Eur. J. Org. Chem. 1999, 1693-
1699.
(17) Schmeck, C.; Mueller-Gliemann, M.; Schmidt, G.; Brandes, A.;
Angerbauer, R.; Loegers, M.; Bremm, K.-D.; Bischoff, H.; Schmidt, D.;
Schuhmacher, J. DE Patent 19627431, 96-19627431, 1998.
(18) Shu, C.; Alcudia, A.; Yin, J.; Liebeskind, L. S. J. Am. Chem. Soc.
2001, 123, 12477-12487.
(19) The direct formation of diketone 8 from 7 by a Claisen condensation
is reported but was judged too low-yielding and impractical due to workup
and purification problems, see: Ziegler, F. E.; Bennett, G. B. J. Am. Chem.
Soc. 1973, 95, 7458-7464.
J. Org. Chem, Vol. 71, No. 21, 2006 8257

Olofsson et al.
SCHEME 4. Divergent Synthesis of Various 3,5-Disubstituted Piperidines
exposed to the transfer hydrogenation conditions we recently
developed for cyclic 1,3-diketones.20 Hence, Shvo catalyst 1
was added, and the reduction was smoothly accomplished at
elevated temperature, delivering diols 3 in 70% isolated yield
from glycinate 6. Alternatively, â-acetoxyenone 7 could be
transformed into diols 3 in one step with the Shvo catalyst and
a catalytic amount of DMAP as deacetylation agent, although
this procedure resulted in a lower yield of 3.
epimerization catalyst, this diastereomeric mixture was antici-
pated, and the ratio gives no information about the relative
acylation rates of trans-(3R,5R)-3 and cis-(3R,5S)-3. The
absolute configuration was proven by separation of the cis- and
trans-monoacetates 4 by column chromatography followed by
basic hydrolysis of the trans-monoacetate (Scheme 3). Com-
parison of the optical rotation of trans-diol 3 with literature data
confirmed the (3R,5R)-configuration.15,16
The second acylation step was much slower, but cis-diacetate
(3R,5S)-5 could be selectively obtained with PS-C at elevated
temperature in 94% crude yield and 97% ds; the diastereomers
could be separated to give pure cis-5 in 83% yield. Since the
different isomers of 4 are in fast equilibrium with one another
(Scheme 2), the preferential formation of cis-diacetate (3R,5S)-5
is consistent with a faster acylation of the cis-monoacetate
compared to the trans-monoacetate. A similar selectivity was
observed also in the previous investigation.8 Having succeeded
in selectively transforming diol mixture 3 into cis-diacetate 5,
we next looked into whether trans-diacetate (3R,5R)-5 could
be selectively formed under different reaction conditions.
Contrary to the 1,3-cyclohexanediol case, piperidine diol 3
was monoacetylated with high (R)-selectivity (vide supra). It
was therefore considered likely that trans-diacetate (3R,5R)-5
would be the major product in a DYKAT with CALB if only
the reactivity problems could be addressed. Unfortunately, the
acetylation selectivity dropped considerably upon increasing
temperature, which proved necessary in order to obtain diacetyl-
ation, and trans-5 could not be obtained in pure form.
Transformation of Diols 3 into Various Interesting 3,5-
Disubstituted Piperidines. The highly selective synthesis of
cis-diacetate (3R,5S)-5 was subsequently exploited in order to
efficiently transform the cis:trans-3 mixture into pure cis-3, a
compound previously reported only in lengthy syntheses.12,13
cis-Diacetate 5 was thus hydrolyzed in excellent yield to cis-3,
which subsequently was desymmetrized with high enantiose-
lectivity using PS-C, thus delivering monoacetate (3R,5S)-4 with
>99% ee in 91% yield over two steps (Scheme 4). Alternatively,
the highly enantioselective DYKAT of cis:trans-3 could be
stopped at the monoacetylation stage to obtain trans-monoac-
etate (3R,5R)-4 with excellent enantiomeric excess by separation
of the two monoacetate isomers.
Having succeeded in developing an efficient and high-yielding
synthesis of diols 3 that required only two purification steps,
we next looked into the transformation of diol mixture 3 into
enantiomerically and diastereomerically pure 3,5-dioxygenated
piperidines.
Investigation of DYKAT Conditions. The previously de-
veloped DYKAT system, which would be applied to diols 3,
consists of two parts working in tandem. The ruthenium catalyst
(1 or 2) epimerizes the hydroxy groups and gives an equilibrium
mixture of (R)- and (S)-configured alcohols. The enzyme
preferentially catalyzes the acetylation of alcohols with (R)-
configuration, thus shifting the equilibrium formed by the Ru
catalyst upon consumption of the (R)-isomer and transforming
all of the diol mixture into one single product.8
The possible products obtainable when this system is applied
to diol mixture 3 are shown in Scheme 2. Initial studies of the
epimerization of diols 3 with Ru catalysts 1 and 2 revealed that
the Shvo catalyst 1 resulted in large amounts of diketone 8,21
whereas catalyst 2 gave a fast epimerization at room temperature
and was thus employed in the remaining investigations.
The (CH2NBn) moiety was expected to be the large group
in the selectivity model described for lipases,22 and the (R)-
configured hydroxyl group was thus expected to be preferentially
acetylated with CALB and Pseudomonas cepacia lipase (PS-
C). Gratefully, monoacetylation of the diol mixture was highly
enantioselective and the reaction was complete within 3 h at
room temperature with both enzymes. As expected, the (R)-
hydroxyl group was selectively acetylated,23 resulting in a 3:2
mixture of (3R,5S)-4 and (3R,5R)-4. Due to the presence of
(20) Leijondahl, K.; Fransson, A.-B. L.; Ba¨ckvall, J.-E. J. Org. Chem.,
in press.
(21) The ketone is formed in the epimerization cycle and cannot be
rehydrogenated if hydrogen is lost from the catalyst, a feature previously
reported with the Shvo catalyst.
(22) Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J. Org. Chem. 1991, 56, 2656-2665.
(23) Calculated E values were >100 for both PS-C and CALB; PS-C
was faster and thus employed in the remaining reactions.
Conclusions
Diols 3 could be efficiently synthesized as a cis:trans mixture
in five steps from N-benzylglycinate. This mixture was selec-
8258 J. Org. Chem., Vol. 71, No. 21, 2006

Synthesis of 3,5-Disubstituted Piperidines
mg, 0.6 mmol) dissolved in toluene (2 mL). The mixture was stirred
for 4 min at room temperature, then isopropenyl acetate (180 mg,
1.8 mmol) was added, and the reaction mixture was stirred at 50
°C for 72 h. Then the reaction mixture was filtered through a silica
gel plug with EtOAc to remove the enzyme, and the filtrate was
concentrated to give a brown crude product, which was purified by
column chromatography (CHCl3:MeOH 10:1) to give the diacetates
as a sticky light brown oil (164 mg, 94%, 97:3 cis:trans ratio). The
diastereomers could be separated by careful column chromatography
(pentane:EtOAc 20:1 f 3:1) to give cis-5 (144 mg, 83%) as white
tively transformed to cis-diacetate (3R,5S)-5 in a dynamic
process catalyzed by PS-C and ruthenium complex 2. Further
transformations of cis-diacetate 5 delivered cis-diol (3R,5S)-3
and cis-monoacetate (3R,5S)-4, both of which are interesting
subunits in pharmaceutical investigations. Finally, trans-mono-
acetate (3R,5R)-4 could be obtained by stopping the DYKAT
at the monoacetate stage. To summarize, an efficient, divergent
synthesis of 3,5-oxygen-substituted piperidines has been devel-
oped, delivering products with high enantio- and diastereose-
lectivities. As several of these targets are novel, or only reported
in multistep syntheses, this strategy should facilitate the synthesis
of a range of 3,5-substituted piperidines that could be formed
by further transformations of compounds 3-5.
1
needles: mp 81-83 °C. H NMR (400 MHz, CDCl3): δ 7.33-
7.22 (m, 5H), 4.88 (tt, 2H, J ) 10.5, 4.4 Hz), 3.60 (s, 2H), 2.98
(dd, 2H, J ) 10.1, 4.4 Hz), 2.35 (m, 1H), 2.05-1.97 (m, 2H), 2.00
(s, 6H), 1.40 (app. q, 1H, J ) 11.0 Hz). 13C NMR (100 MHz,
CDCl3): δ 169.9, 137.2, 128.8, 128.2, 127.2, 67.5, 61.9, 55.8, 35.3,
21.0. IR (neat): 2955, 2809, 1744, 1233 cm-1. HRMS (ESI) calcd
for C16H22NO4 (M + H): 292.1543. Found: 292.1532.
Experimental Section
b. Transformation of cis-5 to (3R,5S)-1-Benzyl-3-acetoxy-5-
hydroxypiperidine (cis-(3R,5S)-4) via Desymmetrization of cis-
3. cis-Diacetate 5 (144 mg, 0.494 mmol) was refluxed in 5 M NaOH
(1.5 mL) and MeOH (6 mL) for 1 h. The mixture was cooled and
concentrated, dissolved in EtOAc and H2O, extracted with 3 ×
EtOAc, dried (Na2SO4), and concentrated to yield crude cis-3 (98
mg, 96%). For analysis data see above.
1. Synthesis of 1-Benzylpiperidine-3,5-diol (cis:trans-3). a.
Condensation of 6 to 5-Acetoxy-1-benzyl-3-oxo-1,2,6-tetrahy-
dropyridine (7).18 A solution of t-BuOK (2.68 g, 23.9 mmol) in
anhydrous THF (60 mL) was cooled to 0 °C before addition of
glycinate 624 (5.68 g, 22.8 mmol) in THF (20 mL) via cannula
over 15 min. The mixture turned red and was stirred at 0 °C for 2
h; this was then allowed to reach room temperature and stirred
overnight (16 h). The reaction was then recooled to 0 °C, and
distilled Ac2O (2.26 mL, 23.9 mmol) was added. After stirring at
0 °C for 1 h EtOAc and H2O were added and the mixture was
extracted with EtOAc, washed twice with brine, dried (Na2SO4),
and concentrated to give crude 7 (5.70 g) as an orange oil.
Compound 7 slowly decomposed upon storage but was stable when
frozen in benzene. 1H NMR (400 MHz, CDCl3): δ 7.37-7.27 (m,
5H), 6.10 (s, 1H), 3.71 (s, 2H), 3.39 (s, 2H), 3.24 (s, 2H), 2.20 (s,
3H).
b. Deacetylation to Give 1-Benzylpiperidine-3,5-dione (8).
Crude 7 (5.70 g) was dissolved in anhydrous toluene (56 mL) and
i-PrOH (36 mL, 20 equiv). Immobilized CALB (1.14 g) was added,
and the mixture was stirred at room temperature overnight (16 h).
The enzyme was filtered off and washed with toluene (5 mL), and
the solution of 8 was immediately used in the next step. 1H NMR
(300 MHz, CDCl3): δ 7.39-7.23 (m, 5H), 3.72 (s, 2H), 3.62 (br
s, 1H), 3.27 (s, 4H), 2.36 (s, 1H).
To the crude cis-3 (98 mg, 0.473 mmol) in toluene (2.4 mL)
was added isopropenyl acetate (142 mg, 1.42 mmol) and PS-C
Amano II (47 mg). The mixture was stirred at room temperature
for 4 h, then the reaction mixture was filtered through a silica gel
plug with EtOAc, and the filtrate was concentrated to yield cis-
(3R,5S)-4 (112 mg, 91% over 2 steps) as a light yellow oil, which
solidified in the freezer. The enantiomeric excess was analyzed by
i
HPLC (ChiralCel OD-H Hexane:iPrOH 97:3, 0.5 mL/min, λ )
210.5 nm) to >99%: mp 92-93 °C. 1H NMR (300 MHz, CDCl3):
δ 7.35-7.22 (m, 5H), 4.96 (app. quin, 1H, J ) 4.6 Hz), 3.85 (app.
quin, 1H, J ) 4.6 Hz), 3.58 (AB-q, 2H, J ) 13.3 Hz), 2.72 (br s,
1H), 2.53 (m, 4H), 2.06 (s, 3H), 1.93 (dt, 1H, J ) 13.6, 3.9 Hz),
1.77 (dt, 1H, J ) 13.6, 5.4 Hz). 13C NMR (100 MHz, CDCl3): δ
170.0, 137.4, 128.7, 128.1, 127.0, 68.3, 65.2, 62.0, 59.3, 55.9, 36.6,
21.0. IR (neat): 3410, 2950, 2805, 1736, 1371, 1243, 1031 cm-1
.
[R]D: +25.9 (c 1.35, CH2Cl2). HRMS (ESI) calcd for C14H20NO3
(M + H): 250.1438. Found: 250.1426.
c. DYKAT Used in Monoacetylation to (3R,5R)-1-Benzyl-3-
acetoxy-5-hydroxypiperidine (trans-(3R,5R)-4). A solution of
tBuOK (0.5 M in THF, 40 µL, 0.02 mmol, 5 mol %) was added to
Ru-cat. 210 (12.8 mg, 0.02 mmol), PS-C Amano II (20 mg), and
Na2CO3 (21 mg, 0.20 mmol) in anhydrous toluene (0.5 mL). The
resulting mixture was stirred for 6 min at room temperature under
argon, followed by addition of cis:trans-3 (41 mg, 0.20 mmol)
dissolved in toluene (0.5 mL). The mixture was stirred for 4 min
at room temperature, then isopropenyl acetate (66 µL, 0.6 mmol)
was added, and the reaction mixture was stirred at room temperature
for 6 h. Then the reaction mixture was filtered through a silica gel
pad with EtOAc to remove the enzyme, and the filtrate was
concentrated to give crude cis/trans-(3R)-4 as a light yellow oil
(49 mg, 99% yield, 1.6:1 cis:trans). The enantiomeric excess of
the two diastereomers was determined to 98% ee by HPLC
(ChiralCel OD-H, iHexane:iPrOH 97:3, 0.5 mL/min). The cis:trans
mixture of 4 was separated by column chromatography (pentane:
EtOAc 9:1 f 1:9) to give trans-(3R,5R)-4 (14.1 mg, 29%) as a
yellow oil and cis-(3R,5S)-4 (22.5 mg, 45%). cis-4 can, however,
be obtained in higher yield via the diacetate route described above.
Analysis data for trans-4: 1H NMR (400 MHz, CDCl3) δ 7.34-
7.22 (m, 5H), 5.11 (tt, 1H, J ) 8.6, 4.4 Hz), 3.99 (tt, 1H, J ) 5.1,
3.1 Hz), 3.58 (AB-q, 2H, J ) 13.2 Hz), 2.84 (dd, 1H, J ) 10.8,
3.8 Hz), 2.58 (dd, 1H, J ) 11.3, 4.7 Hz), 2.47 (br s, 1H), 2.40 (dd,
1H, J ) 11.3, 1.7 Hz), 2.20 (dd, 1H, J ) 11.5, 8.6 Hz), 2.02 (s,
3H), 1.98 (m, 1H), 1.60 (ddd, 1H, J ) 13.1, 9.2, 3.1 Hz); 13C NMR
(100 MHz, CDCl3) δ 170.2, 137.2, 128.9, 128.3, 127.3, 67.5, 65.2,
62.2, 58.9, 56.4, 36.8, 21.1; IR (neat) 3411, 2950, 2805, 1734,
c. Reduction of 8 to cis/trans-1-Benzylpiperidine-3,5-diols (3).
To the solution of 8 was added Shvo catalyst 19 (495 mg, 0.02
equiv, 0.45 mmol), and the solution was heated to 90 °C with a
reflux condenser under Ar overnight (16 h). Alternatively, the
reaction could be heated at 110 °C for 2 h in a sealed tube. The
reaction mixture was then concentrated, and the residue was purified
by column chromatography (EtOAc f EtOAc:MeOH 4:1 with 1%
aq NH4OH) to give 3 as a sticky brown oil (3.32 g, cis:trans 1.6:1,
70% yield from 6). This material could be either used directly in
the DYKAT reactions or treated with CH2Cl2 to crystallize out cis-
3, leaving a 1:2 cis:trans mixture in the mother liquid. cis-(3R,-
5S)-3: white solid, mp 128-129 °C; 1H NMR (300 MHz, CDCl3)
δ 7.35-7.22 (m, 5H), 3.93 (m, 2H), 3.59 (s, 2H), 2.72 (dd, 2H, J
) 11.4, 3.6 Hz), 2.62 (br s, 2H), 2.38 (dd, 2H, J ) 11.4, 1.6 Hz),
1.88 (tt, 1H, J ) 13.9, 4.4 Hz), 1.75 (tt, 1H, J ) 13.9, 3.6 Hz); 13
C
NMR (75 MHz, CDCl3) δ 137.8, 129.0, 128.3, 127.2, 66.4, 62.5,
59.5, 37.6; IR (neat) 3426, 2939, 2817, 1370 cm-1. For analysis
data of trans-3, see refs 15 and 16.
2. Transformations of Diol Mixture 3. a. Transformation of
Diols 3 to cis-(3R,5S)-1-Benzyl-3,5-diacetoxypiperidine (cis-5).
A solution of tBuOK (0.5 M in THF, 60 µL, 0.03 mmol, 5 mol %)
was added to Ru-cat. 210 (19.2 mg, 0.03 mmol, 5 mol %), PS-C
Amano II (60 mg), and Na2CO3 (63 mg, 0.6 mmol) in anhydrous
toluene (1 mL). The resulting mixture was stirred for 6 min at room
temperature under argon, followed by addition of cis:trans-3 (124
(24) The synthesis of 6 is described in the Supporting Information.
J. Org. Chem, Vol. 71, No. 21, 2006 8259

Olofsson et al.
20
1372, 1244 cm-1; [R]D +28.9 (c 0.85, CH2Cl2). HRMS (ESI) calcd
for C14H20NO3 (M): 250.1438. Found: 250.1430.
ature.15,16 [R]D: +10.6 (c 1.00, EtOH). Literature values: [R]D
+15.2 (c 0.99, EtOH);15 +151 (c 0.5, EtOH),16 which confirm the
(R,R) configuration.
3. Determination of Absolute Configuration. a. Hydrolysis
of (3R,5R)-4 to (3R,5R)-1-Benzylpiperidine-3,5-diol (trans-
(3R,5R)-3). trans-4 (46 mg, 0.18 mmol) was refluxed in 5 M NaOH
(0.5 mL) and MeOH (2 mL) for 1 h. The mixture was cooled to
room temperature and concentrated; then water (1 mL) and CH2-
Cl2 (2 mL) were added followed by filtration through an Ex-
trelut NT3 tube. The organic phase was eluted with CH2Cl2
(15 mL) and concentrated to yield crude trans-3. Purification
through a silica plug (EtOAc f EtOAc:MeOH 4:1 with 1% aq.
NH4OH) delivered trans-(3R,5R)-3 (36 mg, 96%) as a white solid,
the NMR data of which were in agreement with the liter-
Acknowledgment. This work was financially supported by
the Swedish Research Council.
Supporting Information Available: General experimental
conditions, synthesis of 6, and NMR spectra of compounds 3-8.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0615091
8260 J. Org. Chem., Vol. 71, No. 21, 2006