Enantioselective access to all-trans 5-alkylpiperidine-3,4-diols: Application to the asymmetric synthesis of the 1-n-iminosugar (+)-isofagomine

Article abstract of DOI:10.1055/s-0029-1216935

Access to 3,4-disubstituted N-benzylprolinol derivatives is described that, after optimization of the ring-enlargement reaction conditions, could be efficiently transformed into the corresponding 3-hydroxypiperidines. This approach was applied to the asym

Full text of DOI:10.1055/s-0029-1216935

PAPER
3251
Enantioselective Access to All-trans 5-Alkylpiperidine-3,4-diols: Application
to the Asymmetric Synthesis of the 1-N-Iminosugar (+)-Isofagomine
Enantioselective
A
r
ccess to
n
A
ll-trans 5-A
a
lkylpiperi
u
dine-3,4-diol
d
s
Rives,a Yves Génisson,*a Vanessa Faugeroux,a Nathalie Saffon,b Michel Baltasa
a
SPCMIB, UMR CNRS 5068, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France
Fax +(33)(5)61556011; E-mail: genisson@chimie.ups-tlse.fr
b
SFTCM, FR2599, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France
Received 9 March 2009; revised 12 May 2009
Dedicated to the memory of Dr. Christian Marazano
quential procedure: treatment of the starting prolinol with
trifluoroacetic anhydride in tetrahydrofuran, prolonged
heating in the presence of an excess of triethylamine, and
smooth saponification of the ring-expanded trifluoroace-
Abstract: Access to 3,4-disubstituted N-benzylprolinol derivatives
is described that, after optimization of the ring-enlargement reaction
conditions, could be efficiently transformed into the corresponding
3-hydroxypiperidines. This approach was applied to the asymmetric
synthesis of (+)-isofagomine relying on regio- and stereoselective tate.10 The scope of this procedure was illustrated through
synthetic work directed toward zamifenacin,11
oxirane opening with the cyanide anion of a pivotal epoxypyrroli-
pseudoconhydrine,12 the velbanamine piperidine core,13
dine.
as well as more recently Ro 67-886714 and (–)-swainso-
Key words: iminosugar, piperidine, ring enlargement, epoxide
nine;15 it was also used in the bicyclic series.16 Yet, appli-
opening
cations of these conditions to N-alkylated 3,4-
disubstituted prolinol substrates remain scarce and does
Iminosugars represent a large family of naturally occur- not concern all-trans substituted pyrrolidines.9f,10b The
ring polyhydroxylated alkaloids with potent glycosidase ring enlargement of such a trisubstituted pyrrolidine into
inhibitory properties.1 Due to their wide biological ef- the corresponding 3-chloropiperidine, relying on the use
fects, they hold promise for great therapeutic develop- of mesyl chloride as an activating agent, was employed in
ment.2 Two iminosugar-based drugs have been a formal synthesis of paroxetine, which implied a subse-
commercialized3 and the recent phase II clinical trial for quent radical dehalogenation step.17
the use of N-butyldeoxynojirimycin in the treatment of
We first selected the prolinol 2 as a representative starting
cystic fibrosis (mucoviscidosis) further illustrates their
material. The latter was obtained from the key epoxypyr-
pharmacological potential.4 As a consequence, iminosug-
rolidine 1 according to a three-step sequence including the
ars have constantly stimulated the synthetic chemistry
opening of the oxirane by a cuprate reagent and the ozo-
community.5
nolytic cleavage of the vinyl moiety (Scheme 1).7
In the course of our ongoing program aimed at the asym-
metric synthesis of iminosugars,6 we gained access to the
high value-added enantioenriched epoxypyrrolidine 1.6c
Notably, the regio- and stereoselective oxirane-opening
reaction of 1 allowed smooth C4 functionalization of the
pyrrolidine ring. We recently reported an in-depth study
of this transformation as well as its use in the synthesis of
biologically active sphingolipid mimics.7 We envisioned
that the substituted prolinol derivatives used in this former
study might also represent suitable precursors of all-trans
3,4,5-trisubstituted piperidines by means of ring-enlarge-
ment reactions. We already briefly communicated prelim-
inary results along this line and wish to report here a full
account of this work.8
OBn
O
Me
OBn
n-Bu
regioselective
oxirane opening
or
olefin
ozonolysis
N
N
N
Bn
Bn
Bn
OH
OH
1
2
3
Scheme 1 Preparation of the starting prolinol derivatives 2 and 3
When the trisubstituted pyrrolidine 2 was treated with tri-
fluoroacetic anhydride in tetrahydrofuran and refluxed for
64 hours in the presence of triethylamine, the expected pi-
peridine 4 was isolated, after saponification, in 27% yield
along with 38% of the starting pyrrolidine, i.e., 43.5%
yield based on recovered starting material (brsm) at 62%
conversion (Scheme 2). The steric bulk generated by the
flexible benzyloxy group adjacent to the site of nucleo-
philic attack in the aziridinium intermediate 10 might ac-
count for this sluggish reaction (Scheme 3). Indeed,
kinetically favored opening of the aziridinium ion at the
more accessible secondary position would lead to a non-
productive pathway giving back the starting trifluoroace-
tate (pathway a vs pathway b, Scheme 3).
The stereospecific ring enlargement of 2-(halomethyl)- or
2-(hydroxymethyl)pyrrolidines via an aziridinium inter-
mediate is a well-studied process.9 In particular, Cossy
and co-workers have developed efficient access to enan-
tiopure 3-hydroxypiperidines based on the following se-
SYNTHESIS 2009, No. 19, pp 3251–3258
x
x.
x
x
.
2
0
0
9
Advanced online publication: 28.08.2009
DOI: 10.1055/s-0029-1216935; Art ID: T05509SS
© Georg Thieme Verlag Stuttgart · New York

3252
A. Rives et al.
PAPER
OBn
OBn
OBn
R
OBn
Me
+
Me
b
OCOCF3
R
X
OBn
Me
BnN
i or ii or iii
N
Bn
a
N
N
N
OH
b
Bn
Bn
Bn
OCOCF3
a
_
10
OCOCF3
9
11
2, R = Me
3, R = n-Bu
4, R = Me, X = OH (27–77%)
5, R = Me, X = Cl (34%)
6, R = n-Bu, X = OH (67%)
+
OH
R
H5
H3
OH
R
BnN
iv
OBn
b
_
N
H
a
_
X
H4
OCOCF3
7, R = Me (71%)
8, R = n-Bu (78%)
4, JH3H4 = JH4H5 = 9.5 Hz
5, JH3H4 = JH4H5 = 9.3 Hz
Scheme 3 Ring enlargement of 3,4-disubstituted prolinol substrates
butylprolinol 3.7 The use of 1,4-dioxane as solvent also
proved efficient with this substrate, affording the ring-ex-
panded product 6 in 78% yield (brsm, 86% conversion).
Scheme 2 Reagents and conditions: (i) (a) TFAA, THF, –78 °C, (b)
Et3N, THF, reflux, 64 h, (c) aq NaOH, 4: 27%; (ii) (a) TFAA, DCE,
–78 °C, (b) Et3N, DCE, 70 °C, 72 h, (c) aq NaOH, 4: 34%, 5: 34% ;
(iii) (a) TFAA, 1,4-dioxane, 10 °C to r.t., (b) Et3N, 1,4-dioxane, 90
°C, 72 h, (c) aq NaOH, 4: 77% or 6: 67%; (iv) H2, 20% Pd/C, concd
HCl, MeOH, 7: 71%, 8: 78%.
The final hydrogenolysis step proceeded uneventfully, de-
livering the unprotected piperidines in good yields. Our
spectral data for 5¢-deoxyisofagomine 7, which was first
prepared in 2004, were in agreement with the literature.18
This reaction sequence also allowed the preparation of the
hitherto unknown 5-butylpiperidine-3,4-diol 8.
In an attempt to obtain a better conversion, we briefly ex-
plored the use of solvents with a higher boiling point. The
transformation was reported not to take place in toluene or
hexane.10 When the reaction was run in 1,2-dichloroeth-
ane, heating at 70 °C for 72 hours led to the clean forma-
tion of two piperidines, isolated along with the starting
material (94% global yield brsm, 73% conversion). The
two products were identified as the expected 3-hydroxy-
piperidine 4 and the corresponding 3-chloro derivative 5.
Participation of chloride anion as a nucleophile has been
reported in dichloromethane.10 In our case, it seemed that
this concurrent pathway was somewhat time dependent.
Indeed, when N-benzylprolinol itself was reacted in 1,2-
dichloroethane at 70 °C for only five hours, the expected
3-hydroxypiperidine was the sole product formed (100%
We then decided to further illustrate the relevance of the
present synthetic route with an asymmetric synthesis of
(+)-isofagomine (21). This synthetic derivative is the rep-
resentative member of a class of sugar mimic, referred to
as 1-N-iminosugars.19 Defined by the location of the nitro-
gen atom in place of the anomeric carbon of the parent
sugar, 1-N-iminosugars were originally proposed as selec-
tive b-glycosidases inhibitors.20 More recently, isofagom-
ine has been the subject of a renewed interest. In
particular, it proved an excellent scaffold to elaborate glu-
cocerebrosidase ligands, either as inhibitors21 or as phar-
macological chaperones.22 Due to its high biological
relevance, isofagomine has been the object of intense syn-
thetic efforts.23
1
yield brsm, 80% conversion). H NMR analysis of the
chlorinated piperidine 5 was in agreement with an all-
trans relative configuration (JH3H2 = JH3H4 = 9.5 Hz).
Opening of the aziridinium intermediate by the chloride
anion would account for such a stereochemical result.
Slow dehydrohalogenation of 1,2-dichloroethane under
prolonged reflux in basic media [Et3N (4 equiv)] might be
responsible for the liberation of chloride anions. 1,4-Di-
oxane was then considered as a substitute for tetrahydro-
furan. To our satisfaction, an efficient transformation took
place at 90 °C after 72 hours, allowing isolation of the pi-
peridine 4 in 91% at 85% conversion. When applied to N-
benzylprolinol itself, this procedure (Et3N, 1,4-dioxane,
90 °C, 18 h, 90% yield) gave essentially the same results
as the standard reaction protocol (Et3N, THF, reflux, 20 h,
85% yield).
Our plan was to use a cyano group as a synthetic equiva-
lent of the required hydroxymethyl residue. We thus first
studied the oxirane-opening step. The use of Sharpless’
conditions [Ti(Oi-Pr)4, KCN, TBAI, DMSO, r.t.],24 hy-
pervalent silicate cyanide (TBAF, TMSCN, THF, 65
°C),25 or in situ generated HCN (KCN, TFA, EtOH, 65
°C)26 left the starting material unaffected. In contrast, a
smooth transformation was obtained due to the use of an
excess of freshly prepared lithium cyanide–acetone com-
plex.27 After heating at 70 °C for 36 hours in tetrahydro-
furan, we observed the clean formation of the expected
trans-cyanohydrins 12 and 13, isolated as a mixture of
isomers (90:10 ratio, based on 1H NMR analysis) in 87%
yield (brsm, 97% conversion) (Scheme 4).
In order to further illustrate the usefulness of these condi-
tions, we looked at other substrates. Our previously de-
scribed synthetic approach also afforded access to the 4-
The structure of the major product 12 was unambiguously
determined by X-ray diffraction analysis of a single crys-
tal obtained from an HPLC-purified sample (Figure 1).28
Synthesis 2009, No. 19, 3251–3258 © Thieme Stuttgart · New York

PAPER
Enantioselective Access to All-trans 5-Alkylpiperidine-3,4-diols
3253
products proved easily separable, but only the major com-
ponent of the starting mixture was transformed; the minor
cyanohydrin 13 was recovered unaffected. This allowed
its full characterization as the C3-opening product. The
identity of the methyl ester 16 (81% yield based on the re-
covery of the unreacted minor isomer 13) was confirmed
by means of X-ray crystallographic analysis (Figure 2).29
The preparation of the prolinol derivative 19, required for
the ring-enlargement step, relied on the oxidative cleav-
age of the vinyl moiety. This was accomplished as fol-
lows: the ester function was first reduced to the primary
alcohol by action of lithium aluminum hydride and per-
benzylation of the diol 17 led to the vinyl pyrrolidine 18
(62% overall yield). The latter, once acidified with hydro-
gen chloride in methanol, was quickly reacted with ozone
at –78 °C in methanol. Immediate reduction of the highly
sensitive aminoaldehyde intermediate with an excess of
sodium borohydride allowed isolation of the expected N-
benzylprolinol 19 in 65% yield.
OH
CN
NC
HO
a
O
O
N
Bn
i or ii
12/13
(90:10)
(85%)
12
NBn
N
Bn
a
b
_
b
1
NC
N
T > 70 °C
Bn
13
_
c
O
OH
NC
_
c
NC
N+
Bn
N
15
Bn
14
Scheme 4 Reagents and conditions: (i) LiCN·acetone, THF, 70 °C,
36 h, 85%, ratio 12/13 (90:10); (ii) LiCN·acetone, THF, reflux, 24 h,
70%, ratio 12/13/14 (88:6:6).
OH
OR
OH
MeOOC
RO
NC
ii
i
N
N
N
Bn
Bn
Bn
12
16 (76%)
17, R = H (82%)
18, R = Bn (75%)
iii
(as a 90:10
mixture with 13)
iv
Figure 1 Molecular view of the cyanohydrin 12 in the solid state
(thermal ellipsoids at 50% probability); hydrogen atoms are omitted
for clarity
OR
OBn
BnO
OH
RO
v
This result is in line with our precedent studies showing
that the opening of the oxirane at the less hindered 4-posi-
tion is always the most favorable pathway.7 The present
reaction thus further illustrates the generality of this pro-
cess. The structure of the C3-opening product 13 was as-
N
R
N
Bn
OH
19 (65%)
20, R = Bn (64%)
vi
R = H, (+)-isofagomine (21) (66%)
Scheme 5 Reagents and conditions: (i) HCl, MeOH, 76%; (ii)
signed to the minor component of this mixture on the basis LiAlH4, THF, 0 °C to r.t., 82%, (iii) BnBr, NaI, NaH, DMF, 0 °C to
r.t., 75%; (iv) (a) HCl, MeOH (b) O3, MeOH, –78 °C (c) NaBH4,
MeOH, –10 °C, 65%; (v) (a) TFAA, 1,4-dioxane, 10 °C to r.t., (b)
Et3N, 1,4-dioxane, 90 °C, 96 h, (c) aq NaOH, 64%; (vi) H2, Pd(OH)2,
MeOH, 66%.
of spectral analysis after its separation at the next step of
the synthesis (vide infra). It is worth noting that refluxing
in tetrahydrofuran for 24 hours led to a much less efficient
transformation, a mixture of three isomeric opening prod-
ucts (88:6:6 ratio based on HPLC analysis) being in this
case isolated in 83% yield (brsm, 84% conversion). The
additional reaction product was clearly identified as a dia-
stereoisomeric C4 opening product from mass spectra
and 1D and 2D NMR analysis (COSY, HSQC, HMBC ex-
periments). The cis-cyanohydrin 14 may indeed arise,
upon heating at higher temperature, from a double inver-
sion process involving the intramolecular attack of the ox-
irane by the tertiary amine and the formation of a bicyclic
azetidinium intermediate 15 (Scheme 4). Alternatively 14
may also arise from base-catalyzed epimerization of 12.
We thus decided to carry on the synthesis with the mixture
of trans-cyanohydrins 12 and 13. Clean conversion of the
Figure 2 Molecular view of the hydroxy ester 16 in the solid state
(thermal ellipsoids at 50% probability); hydrogen atoms are omitted
for clarity
nitrile into an ester functionality was achieved upon treat-
ment with anhydrous hydrogen chloride solution in meth-
anol (Scheme 5). Gratifyingly, not only the two reaction
Synthesis 2009, No. 19, 3251–3258 © Thieme Stuttgart · New York

3254
A. Rives et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 15.7, 35.4, 58.1, 59.4, 62.2, 71.4,
The end of the synthesis proved straightforward. Thanks
to the use of 1,4-dioxane as solvent, the ring-enlargement
74.0, 88.4, 127.3, 127.8 (2 peaks), 128.3, 128.5, 129.1, 138.7.
reaction delivered the desired piperidine 20 in 75% yield MS (DCI/NH3): m/z (%) = 312 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C20H26NO2: 312.1964;
found: 312.1961.
(brsm, 85% conversion) after heating at 90 °C for 96
hours. The targeted (+)-isofagomine (21) was finally ob-
tained upon catalytic hydrogenation. Spectral data record-
ed for 21 were in agreement with that reported in the
literature for isofagomine.
(3R,4R,5S)-1-Benzyl-4-(benzyloxy)-3-chloro-5-methylpiperi-
dine (5)
To a soln of 2 (78.1 mg, 0.25 mmol) in anhyd DCE (2.5 mL) at 0 °C
under an inert atmosphere was added TFAA (39.0 mL, 0.28 mmol).
The mixture was stirred at this temperature for 3 h and then Et3N
(140 mL, 1.02 mmol) was added. After 15 min, the mixture was
heated to 70 °C for 3 d and then allowed to cool and 2.5 M aq NaOH
(0.9 mL, 2.25 mmol) was added. After 1 h, the aqueous layer was
extracted with CH2Cl2. The combined organic phases were washed
with brine, dried (Na2SO4), filtered, and evaporated to dryness. The
crude product was purified by flash column chromatography (silica
gel, PE–i-PrOH, 95:5 to 85:15 + 0.15% Et3N) to give 4 (26.9 mg,
34%) and the chlorinated compound 5 (28.0 mg, 34%) as a colorless
oil along with starting material (21.4 mg, 27% recovery); Rf = 0.49
(PE–i-PrOH, 90:10 + 0.15% Et3N).
[a]D25 +16 (c 1.1, CHCl3).
IR (neat): 1603 (C=C), 1265 cm–1 (C–O).
1H NMR (300 MHz, CDCl3): d = 1.02 (d, 3J = 6.2 Hz, 3 H), 1.84–
2.01 (m, 2 H), 2.30 (pseudo t, 2J ≈ 3J ≈ 11.2 Hz, 1 H), 2.83–2.87 (m,
1 H), 3.04 (pseudo t, 3J ≈ 3J ≈ 9.5 Hz, 1 H), 3.17 (ddd, 2J = 11.2 Hz,
3J = 4.7 Hz, 4J = 2.4 Hz, 1 H), 3.58 (s, 2 H), 4.09 (ddd, 3J = 11.1 Hz,
3J = 9.6 Hz, 3J = 4.7 Hz, 1 H), 4.66 (d, 2J = 10.5 Hz, 1 H), 4.99 (d,
2J = 10.5 Hz, 1 H), 7.28–7.46 (m, 10 H).
In conclusion, thanks to the use of 1,4-dioxane as solvent,
we extended the scope of the N-alkylated prolinol ring en-
largement to the preparation of all-trans 5-alkylpiperi-
dine-3,4-diols.
When
applied
to
2-(hydroxy-
methyl)pyrrolidines obtained via the regio- and stereose-
lective oxirane opening of a key epoxypyrrolidine precur-
sor with the cyanide anion, these conditions proved useful
for the asymmetric synthesis of 1-N-iminosugars such as
(+)-isofagomine (21).
NMR spectroscopic data were obtained with Bruker Avance 300,
ARX 400 and Avance 500 relative to residual solvent peak. IR spec-
tra were recorded on a Perkin-Elmer FT-IR 1725X spectrophotom-
eter. MS data were obtained on a ThermoQuest TSQ 7000
spectrometer. HRMS were performed on a ThermoFinnigan MAT
95 XL spectrometer. For chromatography, petroleum ether = PE.
Optical rotations were measured on a Perkin-Elmer model 241
spectrometer. For crystallographic analysis, the selected crystals
were mounted on a glass fiber using perfluoropolyether oil and
cooled rapidly in a stream of cold N2. The data were collected on a
Bruker-AXS APEX II diffractometer equipped with the Bruker
Kryo-Flex cooler device and using a graphite-monochromated
MoKa radiation. The structures were solved by direct methods
(SHELXS-97)30 and all non-hydrogen atoms were refined anisotro-
pically using the least-squares method on F2.31
13C NMR (75 MHz, CDCl3): d = 15.8, 37.6, 59.2, 60.2, 60.7, 61.7,
75.1, 87.9, 127.3, 127.7, 128.1, 128.3, 128.9, 137.5, 138.3.
MS (DCI/NH3): m/z (%) = 330 (100) [M + H]+.
HRMS (DCI/NH3): m/z [M + H]+ calcd for C20H25ClNO: 330.1625;
found: 330.1626.
Ring-Enlargement Reaction; General Procedure A
(3R,4R,5S)-1-Benzyl-4-(benzyloxy)-5-butylpiperidin-3-ol (6)
Following general procedure A using prolinol 3 (30.0 mg, 85.0
mmol). The crude product was purified by flash column chromatog-
raphy (silica gel, PE–EtOAc, 70:30 to 60:40 + 0.8% NH4OH) to
give 6 (20.0 mg, 67%) as a yellow amorphous solid along with start-
ing material (4.20 mg, 14% recovery); Rf = 0.22 (PE–EtOAc, 70:30
+ 0.8% NH4OH).
To a 0.1 M soln of the prolinol substrate in anhyd 1,4-dioxane at 10
°C under inert atmosphere was added TFAA (1.2 equiv). The mix-
ture was stirred at r.t. for 1 h and then Et3N (4.0 equiv) was added.
After 15 min, the mixture was heated to 90 °C for 3 to 4 d and then
allowed to cool and 2.5 M aq NaOH (9.0 equiv) was added. After 1
h, brine was added and the aqueous layer was extracted with
CH2Cl2. The combined organic phases were washed with brine,
dried (Na2SO4), filtered, and evaporated to dryness.
[a]D25 +16 (c 1.0, CHCl3).
IR (neat): 3400 (O–H), 1604 (C=C), 1065 cm–1 (C–O).
(3R,4R,5S)-1-Benzyl-4-(benzyloxy)-5-methylpiperidin-3-ol (4)
Following general procedure A using prolinol 2 (22.6 mg, 72.7
mmol). The crude product was purified by flash column chromatog-
raphy (silica gel, PE–i-PrOH, 95:5 to 85:15 + 0.15% Et3N) to give
4 (17.5 mg, 77%) as a white amorphous solid along with starting
material (3.30 mg, 15% recovery); Rf = 0.24 (PE–i-PrOH, 90:10 +
0.15% Et3N).
3
1H NMR (300 MHz, CDCl3): d = 0.90 (t, J = 6.9 Hz, 3 H), 1.11–
1.39 (m, 5 H), 1.70–1.87 (m, 3 H), 1.96 (pseudo t, 2J ≈ 3J ≈ 10.3 Hz,
1 H), 2.01–2.20 (m, 1 H), 2.88–2.98 (m, 1 H), 2.98 (pseudo t, 3J ≈
2J ≈ 8.7 Hz, 1 H), 3.01 (ddd, 2J = 10.7 Hz, 3J = 4.7 Hz, 4J = 2.1 Hz,
2
1 H), 3.56 (AB system, J = 13.2 Hz, da–db = 45.6 Hz, 2 H), 3.78
(ddd, 3J = 9.8 Hz, 3J = 8.5 Hz, 3J = 4.7 Hz, 1 H), 4.73 (AB system,
2J = 11.4 Hz, da–db = 6.5 Hz, 2 H), 7.25–7.41 (m, 10 H).
[a]D25 –4 (c 1.3, CHCl3).
IR (neat): 3434 (O–H), 1604 (C=C), 1266 cm–1 (C–O).
13C NMR (75 MHz, CDCl3): d = 14.0, 23.0, 29.1, 29.6, 40.2, 57.3,
57.9, 62.4, 71.6, 73.8, 86.8, 127.1, 127.8 (2 peaks), 128.2, 128.5,
129.0, 137.9, 138.7.
MS (DCI/NH3) m/z (%) = 354 (100) [M + H]+.
HRMS (ESI+) m/z [M + H]+ calcd for C23H32NO2: 354.2433; found:
3
1H NMR (300 MHz, CDCl3): d = 1.04 (d, J = 6.5 Hz, 3 H), 1.84
(pseudo t, 2J ≈ 3J ≈ 11.1 Hz, 1 H), 1.89–1.97 (m, 1 H), 2.01 (pseudo
t, 2J ≈ 3J ≈ 10.5 Hz, 1 H), 2.15–2.45 (m, 1 H), 2.82 (ddd, 2J = 11.2
Hz, 3J = 3.5 Hz, 4J = 2.0 Hz, 1 H), 2.91 (pseudo t, 3J ≈ 3J ≈ 9.3 Hz,
2
3
1 H), 3.08 (ddd, J = 10.6 Hz, J = 4,6 Hz, 4J = 2.0 Hz, 1 H), 3.58
354.2431.
(AB system, 2J = 13.2 Hz, da–db = 13.4 Hz, 2 H), 3.79–3.85 (m, 1
H), 4.75 (AB system, J = 11.4 Hz, da–db = 13.3 Hz, 2 H), 7.27–
2
Catalytic Hydrogenation; General Procedure B
To a 0.1 M soln of N-benzylpiperidine in MeOH was added succes-
sively Pd(OH)2 (20% w/w) and 12 M HCl (1–2 drops). The flask
was purged with N2 and then loaded with H2 (8–10 bar). The mix-
7.41 (m, 10 H).
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PAPER
Enantioselective Access to All-trans 5-Alkylpiperidine-3,4-diols
3255
ture was stirred at r.t. until disappearance of the starting material
(24–90 h). The catalyst was then removed by filtration through
Celite and the filtrate was evaporated to dryness. The intermediate
was taken up in MeOH–H2O (2:1, 25 mL/mmol) and Dowex
50WX8-200 ion-exchange resin (12 g/mmol) was added. The mix-
ture was stirred for 1 h and the resin was successively filtered and
washed with H2O and MeOH. 3 M NH4OH was then added (50 mL/
mmol) and the resin was stirred for 1 h and then it was filtered and
rinsed with 3 M NH4OH (500 mL/mmol). The resulting soln was
evaporated to dryness under reduced pressure.
complex [from acetone cyanohydrin (570 mL, 6.23 mmol) and 1.6
M MeLi in hexane (2.7 mL, 4.32 mmol)].27 The mixture was gently
heated at 70 °C for 36 h and allowed to cool and H2O (90 mL) was
added. The aqueous layer was extracted with Et2O. The combined
organic phases were then dried (Na2SO4), filtered, and evaporated
to dryness. The crude product was purified by flash column chroma-
tography (silica gel, PE–CH2Cl2–EtOAc, 50:40:10 to 30:56:14) to
give a mixture of isomers 12 and 13 (280 mg, 85%) along with start-
ing material (8.00 mg, 3% recovery). When formed upon prolonged
reflux, the minor isomer 14 was isolated by simple flash column
chromatography (silica gel, PE–EtOAc, 90:10 to 60:40). An analyt-
ically pure sample of the major product 12 was obtained as a white
amorphous solid by HPLC purification (XTerra MSC18 5 mm
100 × 19 column, 3 mM Et3N in H2O–MeCN, 70:30, 15 mL/min).
(3R,4R,5S)-5-Methylpiperidine-3,4-diol (5¢-Deoxyisofagomine,
7)
Following general procedure B using N-benzylpiperidine 4 (37.5
mg, 0.12 mmol). The crude product was purified by flash column
chromatography (silica gel, MeOH–EtOH–NH4OH–CH2Cl2,
12:15:6:67 to 15:20:10:55) to give 7 (11.1 mg, 71%) as a white
amorphous solid; Rf = 0.21 (MeOH–EtOH–NH4OH–CH2Cl2,
12:15:6:67).
(3R,4R,5S)-1-Benzyl-4-hydroxy-5-vinylpyrrolidine-3-carbo-
nitrile (12)
Rf = 0.22 (PE–EtOAc, 70:30).
[a]D25 +88 (c 1.2, CHCl3).
IR (neat): 3436 (O–H), 2245 (C≡N), 1666, 1645, 1604 cm–1 (C=C,
aromatic C=C).
[a]D25 +8 (c 0.75, EtOH).
1H NMR (300 MHz, CD3OD): d = 0.98 (d, 3J = 6.5 Hz, 3 H), 1.45–
1.60 (m, 1 H), 2.18–2.27 (m, 1 H), 2.37 (dd, 2J = 12.2 Hz, 3J = 10.8
Hz, 1 H), 2.86–2.95 (m, 2 H), 3.08 (ddd, 2J = 12.2 Hz, 3J = 5.0 Hz,
3J = 1.5 Hz, 1 H), 3.36 (ddd, 3J = 10.8 Hz, 3J = 8.8 Hz, 3J = 5.0 Hz,
1 H).
1H NMR (300 MHz, CDCl3): d = 2.69 (m, 1 H), 2.82–2.91 (m, 2 H),
3.14 (dd, 2J = 9.8 Hz, 3J = 2.9 Hz, 1 H), 3.23 (d, 2J = 13.5 Hz, 1 H),
4.03 (d, 2J = 13.5 Hz, 1 H), 4.26–4.30 (m, 1 H), 5.40 (dd, 3J = 10.1
2
3
Hz, J = 1.5 Hz, 1 H), 5.47 (br d, J = 17.2 Hz, 1 H), 5.87 (ddd,
1H NMR (300 MHz, D2O): d = 0.80 (d, 3J = 6.5 Hz, 3 H), 1.31–1.48
3J = 17.2 Hz, 3J = 10.1 Hz, 3J = 8.4 Hz, 1 H), 7.28–7.39 (m, 5 H).
2
3
(m, 1 H), 2.09 (pseudo t, J ≈ J ≈ 12.2 Hz, 1 H), 2.24 (pseudo t,
13C NMR (75 MHz, CDCl3): d = 35.1, 53.5, 56.4, 74.5, 79.5, 120.5,
121.3, 127.2, 128.3, 128.5, 136.5, 137.4.
MS (DCI/NH3): m/z (%) = 229 (100) [M + H]+.
HRMS (DCI/NH3): m/z [M + H]+ calcd for C14H17N2O: 229.1341;
2
2J ≈ 3J ≈ 11.5 Hz, 1 H), 2.76 (dd, J = 13.0 Hz, 3J = 3.6 Hz, 1 H),
2.90 (pseudo t, 3J ≈ 3J ≈ 9.7 Hz, 1 H), 2.96 (dd, 2J = 12.2 Hz, 3J = 4.7
Hz, 1 H), 3.29 (ddd, 3J = 10.4 Hz, 3J = 9.7 Hz, 3J = 5.0 Hz, 1 H).
13C NMR (75 MHz, CD3OD): d = 15.4, 39.4, 52.2, 52.9, 73.8, 80.7.
13C NMR (75 MHz, D2O): d = 13.3, 36.7, 49.0, 49.8, 71.1, 78.1.
MS (DCI/NH3): m/z (%) = 132 (50) [M + H]+, 149 (100) [M +
found: 229.1340.
(2S,3S,4S)-1-Benzyl-3-hydroxy-2-vinylpyrrolidine-4-carbo-
nitrile (13)
+
NH4 ].
Rf = 0.22 (PE–EtOAc, 70:30).
[a]D25 +59 (c 0.8, CHCl3).
HRMS (DCI/NH3): m/z [M + H]+ calcd for C6H14NO2: 132.1025;
found: 132.1026.
1H NMR (300 MHz, CDCl3): d = 2.06 (dd, J = 10.2 Hz, J = 5.5
Hz, 1 H), 3.03 (dd, 3J = 7.0 Hz, 3J = 3.1 Hz, 1 H), 3.25 (d, 2J = 13.3
Hz, 1 H), 3.35–3.42 (m, 2 H), 4.01 (d, 2J = 13.3 Hz, 1 H), 4.55–4.60
2
3
(3R,4R,5S)-5-Butylpiperidine-3,4-diol (8)
Following general procedure B using N-benzylpiperidine 6 (39.0
mg, 0.11 mmol). The crude product was purified by flash column
chromatography (silica gel, MeOH–NH4OH–CH2Cl2, 10:3:87) to
give 8 (14.9 mg, 78%) as a white amorphous solid; Rf = 0.19
(MeOH–NH4OH–CH2Cl2 10:3:87).
3
(m, 1 H), 5.43 (m, 1 H), 5.49 (m, 1 H), 5.96 (ddd, J = 17.6 Hz,
3J = 9.6 Hz, 3J = 8.8 Hz, 1 H), 7.24–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 44.1, 56.3, 59.6, 66.4, 73.2, 119.0,
121.2, 127.2, 128.3, 128.6, 135.1, 137.8.
MS (ESI+): m/z (%) = 229 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C14H17N2O: 229.1341;
[a]D25 +30 (c 1.3, MeOH).
1H NMR (300 MHz, CD3OD): d = 0.92 (t, 3J = 6.9 Hz, 3 H), 1.03–
1.49 (m, 6 H), 1.76–1.87 (m, 1 H), 2.18 (pseudo t, 2J ≈ 3J ≈ 12.4 Hz,
1 H), 2.34 (dd, 2J = 12.1 Hz, 3J = 10.7 Hz, 1 H), 2.97 (dd, 3J = 10.1
Hz, 3J = 8.7 Hz, 1 H), 2.99–3.05 (m, 1 H), 3.07 (ddd, 2J = 12.1 Hz,
3J = 5.0 Hz, 4J = 1.5 Hz, 1 H), 3.35 (ddd, 3J = 10.7 Hz, 3J = 8.7 Hz,
3J = 5.0 Hz, 1 H).
found: 229.1372.
(3S,4R,5S)-1-Benzyl-4-hydroxy-5-vinylpyrrolidine-3-carbo-
nitrile (14)
Rf = 0.13 (PE–EtOAc, 70:30).
13C NMR (75 MHz, CD3OD): d = 14.4, 24.2, 30.3, 30.4, 44.5, 50.6,
52.2, 74.1, 79.3.
1H NMR (300 MHz, CDCl3): d = 2.34 (br s, 1 H), 2.52–2.64 (m, 1
H), 2.89–2.94 (m, 1 H), 3.05–3.18 (m, 2 H), 3.20 (d, 2J = 13.2 Hz,
MS (DCI/NH3): m/z (%) = 174 (100) [M + H]+, 191 (66) [M +
2
1 H), 3.91 (d, J = 13.2 Hz, 1 H), 4.04–4.14 (m, 1 H), 5.28 (dd,
+
NH4 ].
3J = 10.1 Hz, 2J = 1.1 Hz, 1 H), 5.39 (br d, 3J = 17.1 Hz, 1 H), 5.68–
HRMS (DCI/NH3): m/z [M + H]+ calcd for C9H20NO2: 174.1494;
5.79 (m, 1 H), 7.18–7.28 (m, 5 H).
found: 174.1497.
13C NMR (75 MHz, CDCl3): d = 33.8, 53.8, 57.1, 74.8, 75.0, 117.9,
120.1, 127.5, 128.4, 128.9, 136.2.
(3R,4R,5S)-1-Benzyl-4-hydroxy-5-vinylpyrrolidine-3-carboni-
trile (12), (2S,3S,4S)-1-Benzyl-3-hydroxy-2-vinylpyrrolidine-4-
carbonitrile (13), and (3S,4R,5S)-1-Benzyl-4-hydroxy-5-vinyl-
pyrrolidine-3-carbonitrile (14)
MS (DCI/NH3): m/z (%) = 229 (100) [M + H]+, 246 (18) [M +
+
NH4 ]
To epoxypyrrolidine 1 (292 mg, 1.45 mmol) in soln in THF (15 mL)
was added under an inert atmosphere to freshly prepared LiCN·acetone
Synthesis 2009, No. 19, 3251–3258 © Thieme Stuttgart · New York

3256
A. Rives et al.
PAPER
Methyl (3S,4R,5S)-1-Benzyl-4-hydroxy-5-vinylpyrrolidine-3-
carboxylate (16)
tracted with Et2O, and the combined organic phases were washed
with brine, dried (Na2SO4), filtered, and evaporated to dryness. The
crude product was purified by flash column chromatography (silica
gel, PE–EtOAc, 95:5 to 80:20) to give 18 (133 mg, 75%) as a col-
orless oil; Rf = 0.26 (PE–EtOAc, 90:10).
[a]D25 +58 (c 1.6, CHCl3).
IR (neat): 1643, 1604 cm–1 (C=C, aromatic C=C).
1H NMR (300 MHz, CDCl3): d = 2.30–2.39 (m, 1 H), 2.45 (pseudo
t, 3J ≈ 3J ≈ 8.7 Hz, 1 H), 2.71 (br d, 2J = 9.1 Hz, 1 H), 2.94 (pseudo
t, 3J ≈ 3J ≈ 7.2 Hz, 1 H), 3.09 (d, 2J = 13.4 Hz, 2 H), 3.40 (d, 3J = 7.6
Hz, 1 H), 3.59 (dd, 3J = 6.0 Hz, 2J = 3.1 Hz, 1 H), 3.96 (d, 2J = 13.4
Hz, 1 H), 4.46 (s, 2 H), 4.56 (AB system, 2J = 12.0 Hz, da–db = 14.5
Hz, 2 H), 5.23 (dd, 3J = 10.1 Hz, 2J = 1.7 Hz, 1 H), 5.38 (dd,
3J = 17.2 Hz, 2J = 1.7 Hz, 1 H), 5.85 (m, 1 H), 7.18–7.33 (m, 15 H).
13C NMR (75 MHz, CDCl3): d = 43.6, 54.1, 57.1, 71.6, 72.3, 73.0,
74.5, 86.5, 118.4, 126.7, 127.4, 127.5, 127.6 (2 peaks), 128.1,
128.2, 128.6, 138.4, 138.5, 139.0, 139.2.
To a mixture of 12/13 (90:10, 280 mg, 1.23 mmol) in soln in MeOH
(3.5 mL) was added 20 wt% methanolic HCl soln (2.6 g, 12 equiv)
and the mixture was allowed to stir at r.t. for 3 d. The soln was then
neutralized by addition of solid NaHCO3 (1.2 g, 12 equiv) and the
MeOH was evaporated under vacuum. The residue was taken up in
THF, filtered over Celite, and concentrated to dryness. The result-
ing crude mixture was purified by flash column chromatography
(silica gel, CH2Cl2–EtOAc, 80:20) to give the minor starting cyano-
hydrin 13 (15.2 mg, 0.07 mmol) and the ester 16 (245 mg, 76%) as
a white amorphous solid; Rf = 0.34 (CH2Cl2–EtOAc, 80:20).
[a]D25 +92 (c 1.3, CHCl3).
IR (neat): 3350 (O–H), 1745 (C=O), 1682, 1661, 1623 cm–1 (C=C,
aromatic C=C).
1H NMR (300 MHz, CDCl3): d = 2.34 (br s, 1 H), 2.60 (pseudo t,
2
3J ≈ 3J ≈ 10.0 Hz, 1 H), 2.80–2.87 (m, 2 H), 3.16 (dd, J = 9.7 Hz,
3J = 3.9 Hz, 1 H), 3.17 (d, 2J = 13.5 Hz, 1 H), 3.67 (s, 3 H), 3.94 (d,
2J = 13.5 Hz, 1 H), 4.22 (pseudo t, 3J ≈ 3J ≈ 7.5 Hz, 1 H), 5.31 (dd,
3J = 10.1 Hz, 2J = 1.7 Hz, 1 H), 5.38 (dd, 3J = 17.2 Hz, 2J = 1.7 Hz,
1 H), 5.80 (ddd, 3J = 17.2 Hz, 3J = 10.1 Hz, 3J = 8.4 Hz, 1 H), 7.18–
7.31 (m, 5 H).
MS (ESI+): m/z (%) = 414 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C28H32NO2: 414.2433;
found: 414.2426.
13C NMR (75 MHz, CDCl3): d = 49.4, 52.1, 52.7, 57.2, 74.8, 78.2,
119.9, 126.9, 128.2, 128.7, 137.8, 138.1, 173.9.
{(2S,3R,4R)-1-Benzyl-3-(benzyloxy)-4-[(benzyloxy)methyl]pyr-
rolidin-2-yl}methanol (19)
To the olefin 18 (78.0 mg, 0.19 mmol) in soln in MeOH (2.4 mL)
under inert atmosphere at 0 °C was added 24 wt% methanolic HCl
soln (290 mg, 10 equiv). The soln was stirred for 30 min at this tem-
perature and evaporated to dryness. The residue was then dissolved
in MeOH (3.2 mL) and cooled to –78 °C. Ozone was bubbled into
the soln until it became bluish (3 min). NaBH4 (3 × 7 equiv) was
then added portionwise and the mixture was vigorously stirred at
–78 °C for 1 h and at –10 °C overnight. The reaction was then
quenched by addition of sat. aq NH4Cl and the aqueous phase was
extracted with EtOAc. The combined organic phases were dried
(Na2SO4), filtered, and evaporated to dryness. The crude product
was purified by flash column chromatography (silica gel, PE–
EtOAc, 90:10 + 0.4% NH4OH to 80:20 + 0.8% NH4OH) to give 19
(51.5 mg, 65%) as a colorless oil; Rf = 0.21 (PE–EtOAc, 80:20 +
0.8% NH4OH).
MS (ESI+): m/z (%) = 262 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C15H20NO3: 262.1443;
found: 262.1433.
(2S,3R,4R)-1-Benzyl-4-(hydroxymethyl)-2-vinylpyrrolidin-3-ol
(17)
To a soln of the ester 16 (213 mg, 0.82 mmol) in anhyd THF (6.0
mL) under an inert atmosphere at 0 °C was added LiAlH4 (47.0 mg,
1.5 equiv). The mixture was allowed to stir at 0 °C for 1 h and at r.t.
for 2 h. The reaction was then treated successively with H2O (50
mL), 15% aq NaOH (50 mL), and H2O (150 mL). The white precipi-
tate formed was filtered off over Celite and the filtrate concentrated
to dryness. The resulting crude mixture was purified by flash chro-
matography (silica gel, CH2Cl2–MeOH, 92:8 + 0.3% Et3N) to give
diol 17 (156 mg, 82%) as a white amorphous solid; Rf = 0.27
(CH2Cl2–MeOH, 98:2 + 0.3% Et3N).
[a]D25 +4 (c 0.7, CHCl3).
IR (neat): 3447 (O–H), 1604 (aromatic C=C), 1266 cm–1 (C–O).
[a]D25 +106 (c 0.7, CHCl3).
IR (neat): 3433 (O–H), 1645, 1604 cm–1 (C=C, aromatic C=C).
1H NMR (300 MHz, CDCl3): d = 2.30–2.41 (m, 1 H), 2.59–2.74 (m,
2
2 H), 2.77–2.87 (m, 1 H), 3.29 (d, J = 13.3 Hz, 1 H), 3.36 (d,
2
3
1H NMR (300 MHz, CDCl3): d = 2.06–2.17 (m, 1 H), 2.64 (AB of
ABX, 2J ≈ 3J ≈ 9.7 Hz, 3J = 2.7 Hz, da–db = 39.5 Hz, 2 H), 2.67 (br
s, 2 H), 2.81 (dd, 3J = 8.4 Hz, 3J = 6.6 Hz, 1 H), 3.12 (d, 2J = 13.2
Hz, 1 H), 3.60–3.70 (m, 2 H), 3.92–4.00 (m, 2 H), 5.31 (dd,
3J = 10.1 Hz, 2J = 1.6 Hz, 1 H), 5.39 (dd, 3J = 17.2 Hz, 2J = 1.6 Hz,
1 H), 5.85 (ddd, 3J = 17.2 Hz, 3J = 10.1 Hz, 3J = 8.6 Hz, 1 H), 7.22–
7.33 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 45.6, 53.9, 57.4, 65.1, 76.1, 79.1,
119.5, 127.0, 128.2, 128.9, 137.8, 137.9.
MS (ESI+): m/z (%) = 234 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C14H20NO2: 234.1494;
3J = 7.6 Hz, 2 H), 3.64 (AB of ABX, J = 11.5 Hz, J = 3.2 Hz,
3J = 15 Hz, da–db = 36.9 Hz, 2 H), 3.86 (dd, J = 5.3 Hz, J = 2.4
Hz, 1 H), 3.91 (d, 2J = 13.3 Hz, 1 H), 4.40–4.49 (m, 3 H), 4.56 (d,
2J = 11.7 Hz, 1 H), 7.21–7.30 (m, 15 H).
3
2
13C NMR (75 MHz, CDCl3) d 43.0, 55.2, 57.9, 59.1, 71.5, 71.8 (2
peaks), 73.2, 83.7, 127.4, 126.6, 127.7, 127.8, 128.4 (2 peaks),
128.5, 128.8, 129.6, 138.3 (2 peaks).
MS (ESI+): m/z (%) = 418 (100) [M + H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C27H32NO3:418.2382; found:
418.2416.
found: 234.1507.
(3R,4R,5R)-1-Benzyl-4-(benzyloxy)-5-[(benzyloxy)methyl]pipe-
ridin-3-ol (20)
(2S,3R,4R)-1-Benzyl-3-(benzyloxy)-4-[(benzyloxy)methyl]-2-
vinylpyrrolidine (18)
Following general procedure A using prolinol 19 (67.5 mg, 0.16
mmol). The crude product was purified by flash column chromatog-
raphy (silica gel, PE–EtOAc, 80:20 to 70:30 + 0.8% NH4OH) to
give 20 (43.2 mg, 64%) as a colorless oil along with starting mate-
rial (10.0 mg, 15% recovery); Rf = 0.16 (PE–EtOAc, 80:20 + 0.8%
NH4OH).
To the diol 17 (97.0 mg, 0.42 mmol) in soln in dry DMF (2.9 mL)
at 0 °C under an inert atmosphere were successively added 4 Å mo-
lecular sieves (29.0 mg, 30% w/w), NaI (5.00 mg, 0.08 equiv), BnBr
(170 mL, 2.4 equiv), and NaH (24.0 mg, 2.4 equiv). The mixture was
stirred at 0 °C for a further 10 min and at r.t. overnight. The reaction
was then quenched by addition of H2O, the aqueous phase was ex-
[a]D25 +20 (c 0.8, CHCl3).
Synthesis 2009, No. 19, 3251–3258 © Thieme Stuttgart · New York

PAPER
Enantioselective Access to All-trans 5-Alkylpiperidine-3,4-diols
3257
IR (neat): 3435 (O–H), 1641 (C=C), 1092 cm–1 (C–O).
(6) (a) Ayad, T.; Génisson, Y.; Baltas, M.; Gorrichon, L. Synlett
2001, 866. (b) Ayad, T.; Génisson, Y.; Baltas, M.;
Gorrichon, L. Chem. Commun. 2003, 582. (c) Ayad, T.;
Génisson, Y.; Broussy, S.; Baltas, M.; Gorrichon, L. Eur. J.
Org. Chem. 2003, 2903. (d) Ayad, T.; Génisson, Y.; Baltas,
M. Org. Biomol. Chem. 2005, 3, 2626.
(7) Rives, A.; Génisson, Y.; Faugeroux, V.; Zedde, C.; Lepetit,
C.; Chauvin, R.; Saffon, N.; Andrieu-Abadie, N.; Colié, S.;
Levade, T.; Baltas, M. Eur. J. Org. Chem. 2009, 2474.
(8) Part of this work has been published as a preliminary
communication: Faugeroux, V.; Génisson, Y.; Andrieu-
Abadie, N.; Colié, S.; Levade, T.; Baltas, M. Org. Biomol.
Chem. 2006, 4, 4437.
1H NMR (300 MHz, CDCl3): d = 1.94 (pseudo t, 2J ≈ 3J ≈ 10.3 Hz,
3
1 H), 1.98–2.06 (m, 1 H), 2.14 (pseudo t, 2J ≈ J ≈ 10.3 Hz, 1 H),
2.86–2.98 (m, 2 H), 3.23 (pseudo t, 3J ≈ 3J ≈ 9.1 Hz, 1 H), 3.50 (AB
2
system, J = 13.0 Hz, da–db = 30.3 Hz, 2 H), 3.51–3.59 (m, 2 H),
2
3.69–3.76 (m, 1 H), 4.41 (AB system, J = 12.0 Hz, da–db = 16.2
2
Hz, 2 H), 4.60 (AB system, J = 11.5 Hz, da–db = 15.6 Hz, 2 H),
7.20–7.33 (m, 15 H).
13C NMR (75 MHz, CDCl3): d = 41.4, 55.4, 57.8, 62.3, 69.2, 71.8,
73.0, 73.9, 82.6, 127.1, 127.6 (2 peaks), 127.8 (2 peaks), 128.2,
128.3, 128.5, 129.0, 138.0, 138.2, 138.6.
MS (ESI+): m/z (%) = 418 (100) [M + H]+.
(9) (a) Fuson, R. C.; Zirkle, C. L. J. Am. Chem. Soc. 1948, 70,
2760. (b) Paul, R.; Tchelitcheff, S. Bull. Soc. Chim. Fr.
1958, 736. (c) Hammer, C. F.; Heller, S. R.; Craig, J. H.
Tetrahedron 1972, 28, 239. (d) Hammer, C. F.; Weber, J. D.
Tetrahedron 1981, 37, 2173. (e) Harding, K. E.; Burks, S.
R. J. Org. Chem. 1984, 49, 40. (f) Calvez, O.; Chiaroni, A.;
Langlois, N. Tetrahedron Lett. 1998, 39, 9447. (g) Lee, J.;
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R. P.; Reider, P. J. Tetrahedron Lett. 2001, 42, 6223.
(h) Deyine, A.; Deleroix, J.-M.; Langlois, N. Heterocycles
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Synlett 2005, 1170.
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Bonjosh, J.; Gomez Pardo, D.; Cossy, J. J. Org. Chem. 2006,
71, 5930.
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2002, 3543.
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Tetrahedron Lett. 2004, 45, 7053. (b) Ouchi, H.; Mihara,
Y.; Takahata, H. J. Org. Chem. 2005, 70, 5207.
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T.; Lundt, I.; Bols, M. Angew. Chem., Int. Ed. Engl. 1994,
33, 1778. (b) Jespersen, T. M.; Bols, M.; Sierks, M. R.;
Skrydstrup, T. Tetrahedron 1994, 50, 13449.
HRMS (ESI+): m/z [M + H]+ calcd for C27H32NO3: 418.2382;
found: 418.2414.
(+)-Isofagomine (21)
Following general procedure B using N-benzylpiperidine 20 (53.0
mg, 0.13 mmol). The crude product was purified by flash column
chromatography (silica gel, i-PrOH–H2O–NH4OH, 70:20:10) to
give 21 (12.7 mg, 66%) as a white amorphous solid. For the sake of
NMR data comparison, a sample of 21 was acidified by addition of
1 M aq HCl soln to the free base in soln in MeOH at 0 °C; Rf = 0.35
(i-PrOH–H2O–NH4OH, 70:20:10).
[a]D25 +19 (c 1.3, EtOH).
1H NMR (500 MHz, D2O) (chlorohydrate): d = 1.90–1.97 (m, 1 H),
2.85 (t, 3J = 11.9 Hz, 1 H), 2.95 (t, 3J = 12.8 Hz, 1 H), 3.48–3.52 (m,
3 H), 3.71–3.85 (m, 3 H).
1H NMR (125 MHz, D2O) (chlorohydrate): d = 43.8, 47.6, 49.4,
61.8, 71.3, 73.9.
MS (ESI+): m/z (%) = 148 (100) [M + H]+.
Acknowledgment
The Pierre Fabre group and the CERPER (Centre d’Etudes et de Re-
cherche sur la Peau et les Epithéliums de Revêtement Pierre Fabre)
are gratefully acknowledged for their support and a Ph.D. grant to
A.R.
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PAPER
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retrieving.html [or from the CCDC, 12 Union Road,
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retrieving.html [or from the CCDC, 12 Union Road,
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Synthesis 2009, No. 19, 3251–3258 © Thieme Stuttgart · New York