Enantio- and diastereoselective syntheses of 3-hydroxypiperidines through iridium-catalyzed allylic substitution

Article abstract of DOI:10.1002/ejoc.201300445

Stereoselective syntheses of 3-hydroxypiperidines have been developed. Key intermediates are N-protected allylamines that are prepared by an enantioselective iridium-catalyzed allylic amination. A subsequent catch and release procedure that involves an epoxidation and base-mediated elimination yields δ-lactams that are suitably functionalized to prepare biologically active 3-hydroxypiperidines. In addition, applications of this method to the total syntheses of deoxymannojirimycin, D-erythro-sphingosine, and chiral building blocks of interest for medicinal chemistry are described. Stereoselective syntheses of 3-hydroxypiperidines are reported. The key reactions are an iridium-catalyzed allylic amination and a catch and release procedure that consists of a highly diastereoselective epoxidation and a base-mediated ring opening of the epoxide. This method was applied to the total syntheses of sphingosine, deoxymannojirimycin, and pharmaceutically relevant small molecules. Copyright

Full text of DOI:10.1002/ejoc.201300445

FULL PAPER
DOI: 10.1002/ejoc.201300445
Enantio- and Diastereoselective Syntheses of 3-Hydroxypiperidines through
Iridium-Catalyzed Allylic Substitution
Johannes Hoecker,[a][‡][#] Georg C. Rudolf,[a][‡‡][#] Florian Bächle,[a][‡]
Steffen Fleischer,[a][‡‡‡] Benjamin D. Lindner,[a] and Günter Helmchen*[a]
Keywords: Nitrogen heterocycles / Lactams / Alkaloids / Azasugars / Iridium / Amination / Epoxidation
Stereoselective syntheses of 3-hydroxypiperidines have been
developed. Key intermediates are N-protected allylamines
that are prepared by an enantioselective iridium-catalyzed
allylic amination. A subsequent catch and release procedure
that involves an epoxidation and base-mediated elimination
yields δ-lactams that are suitably functionalized to prepare
biologically active 3-hydroxypiperidines. In addition, appli-
cations of this method to the total syntheses of deoxymannoj-
irimycin,
D-erythro-sphingosine, and chiral building blocks
of interest for medicinal chemistry are described.
Introduction
The 3-hydroxypiperidine unit is a chemically and biolo-
gically important structural motif that is found in natural
products, particularly alkaloids[1] and azasugars.[2] It can
also be found in a number of pharmaceutically relevant
small molecules. Typical examples (see Figure 1) of 3-hy-
droxypiperidines and their derivatives are the neurokinin
NK-1 receptor antagonist (+)-L-733.060,[3] prosopinine,
which is a member of the Cassia and Prosopis families of
alkaloids,[4] and the azasugar miglustat (Zavesca), a drug
used for the treatment of Gauchers’ disease.[5]
Figure 1. Examples of 3-hydroxypiperidines that are found among
alkaloids and drugs.
Given their interesting biological properties, the stereose-
lective syntheses of 3-hydroxypiperidines have been pursued
with some intensity.[6] The preferred targets have been aza-
sugars, which are mostly synthesized through carbohydrate-
based routes.[7] For the large group of monohydroxypiperi-
dines, a great variety of diastereoselective total syntheses
have been developed. Chirality was mostly introduced by
using a chiral pool approach or with the help of stoichio-
metric chiral auxiliaries.[6] Asymmetric catalysis has only
been applied to a comparatively small number of synthe-
ses.[8]
In the course of our work on the stereoselective syntheses
of piperidine and pyrrolidine alkaloids,[9] we have developed
an enantio- and diastereoselective route to α,β-unsaturated
hydroxylactams D and related cyclohexenones that is a
combination of an iridium-catalyzed asymmetric allylic
substitution reaction,[10] a ring-closing metathesis (RCM),
and a catch and release methodology that involves an epox-
[a] Organisch-Chemisches Institut der Universität Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: +49-6221-544205
E-mail: G.Helmchen@oci.uni-heidelberg.de
Homepage: http://www.uni-heidelberg.de/institute/fak12/OC/
helmch/
[‡] Present address: Organisch-Chemisches Departement der
Universität Basel,
St. Johanns-Ring 19, 4056 Basel, Switzerland
[‡‡]Present address: Fakultät für Chemie, Technische Universität
München,
Lichtenbergstraße 4, 85747 Garching, Germany
[‡‡‡]Present address: Leibniz-Institut für Katalyse e.V. an der
Universität Rostock,
Albert-Einstein-Straße 29a, 18059 Rostock, Germany
[#]These authors contributed equally.
Scheme 1. Strategy for the enantio- and diastereoselective synthesis
of 3-hydroxypiperidines (Σ = protecting group, LG = leaving
group).
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300445.
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G. Helmchen et al.
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idation and elimination reaction (see Scheme 1).[11] Knight
et al. have developed a route to compounds of type B that
employs a Pd-catalyzed decarboxylative carbonylation of 5-
vinyloxazolidin-2-ones, which are derived from amino acids,
that is, an exchiral pool approach.[12] Independence of our
approach from amino acids with their limited set of substit-
uents R allows to widen the range of compounds of types
B–D. A further variety of targets can be synthesized with
this approach as will be shown below.
Results and Discussion
The lactams 5a–5d (see Schemes 2 and 3) were synthe-
sized by two different routes, that is, either by allylic amin-
ation[13] and a subsequent N-acylation to give 5a–5c (see
Scheme 2) or by allylic amination with an amide,[14] in this
case with N,N-diacylamine 2d,[15] followed by deproton-
ation/reprotonation to give 5d (see Scheme 3). The direct
amination with N-Boc-but-3-enamide (Boc = tert-butoxy-
carbonyl) could not be accomplished because of the com-
peting isomerization of the double bond under basic condi-
tions to give N-boc-but-2-enamide.
Scheme 3. Reagents and conditions: (a) [Ir(COD)Cl]2, L2, TBD,
THF, 45 °C, 87%, b/l, 93:7, 98%ee; (b) KHMDS, THF/DMPU,
–78 °C, then dimethyl malonate, –78 °C, 85%; (c) Grubbs I,
CH2Cl2, reflux, 73%.
Carbamate 3d (see Scheme 3) was prepared in 87% yield
(b/l, 93:7, 98%ee) by treating carbonate 1d with pronucleo-
phile 2d under salt-free conditions as previously re-
ported.[15] The shift of the double bond to the terminal po-
sition was accomplished in 85% yield by deprotonation at
–78 °C with potassium hexamethyldisilazide (KHMDS) in
THF followed by the addition of 1,3-dimethyltetra-
hydropyrimidin-2(1H)-one (DMPU) and dimethyl malon-
ate as a proton source. A subsequent ring closure to give
lactam 5d was carried out through a ring-closing metathesis
as described above for 5a–5c.
With 5a–5d available, we investigated the catch and re-
lease procedure to yield α,β-unsaturated hydroxylactam
building blocks 6a–6d (see Table 1). For the epoxidation, we
used the reaction conditions that were reported by Knight
et al. for their synthesis of d-mannolactam, that is, Oxone
(2 KHSO5·KHSO4·K2SO4) in a mixture of a saturated
aqueous NaHCO3 solution and acetone at room tempera-
ture (see Table 1, Entry 1).[11c,17] In the case of 5 in which
R = CH2OTBS (TBS = tert-butyldimethylsilyl) and Σ = H,
these authors obtained a trans/cis diastereoselectivity of
4.1:1 (see Table 1, Entry 1). The diastereoselectivities with
the N-protected amides were generally high, even in case of
Scheme 2. Reagents and conditions: (a) [Ir(COD)Cl]2 (2 mol-%,
COD = 1,5-cyclooctadiene), L1 or L2 (4 mol-%), 1,5,7-triazabicy-
clo[4.4.0]dec-5-ene (TBD), tetrahydrofuran (THF), 45 °C; 3a: L2,
89%, b/l, 93:7, 97%ee; 3b: L2, 77%, b/l, 97:3, 98%ee; 3c: L1, 70%, 5a with R = Me (see Table 1, Entry 3). With the sterically
b/l, 81:19, 96%ee; (b) But-3-enoic acid, DMAP, CH2Cl2, DCC,
more demanding substituents (i.e., 5c and 5d, see Table 1,
0 °C to room temp.; 4a: 90%; 4b: 95%; 4c: 92%; (c) Grubbs I or
Entries 5 and 6), the trans isomer was produced almost ex-
II, CH2Cl2, reflux; 5a: 93%; 5b: 91%; 5c: 100%.
clusively.[18]
The chiral phosphoramidite ligands L1 and L2[13e] were
The synthesis of azasugar 1-deoxymannojirimycin (11)
used for the allylic amination reactions (see Scheme 2). The was carried out using chiral building block 6c as the start-
reactions of the amines [BnNH2 or PMBNH2 (PMB = ing material (see Scheme 4). A similar synthesis was re-
para-methoxybenzyl)] with carbonates 1a–1c proceeded ported by Knight et al.[11c] The reaction of 6c with NaH/
with high enantio- and regioselectivity [3a: 89%, branched benzyl bromide/NBu4I gave 7 in excellent yield. Dihydrox-
(b)/linear (l), 93:7, 97%ee; 3b: 77%, b/l, 97:3, 98%ee; 3c: ylation under standard conditions (OsO4 in tert-butanol
70%, b/l, 81:19, 96%ee], essentially as reported for 3a,[16] with water and pyridine as additives) gave dia-
3b,[13a] and 3c.[13f] The amines were acylated by using Steg- stereomerically pure 8 in 74% yield. The reduction of 8 with
lich’s method with but-3-enoic acid, 4-(dimethylamino)pyr- LiAlH4 furnished piperidine derivative 9 in 86% yield. The
idine (DMAP), and N,NЈ-dicyclohexylcarbodiimide (DCC) deprotection of 9 was effected by treatment with acetic acid
to give amides 4 in 90–95% yield. Finally, the ring closure followed by a catalytic hydrogenation reaction to give the
of dienes 4a–4c was carried out by employing a ring-closing azasugar 1-deoxymannojirimycin, which was isolated as its
metathesis in good to excellent yields.
hydrochloride 11·HCl in 47% yield from 8.
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Enantio- and Diastereoselective Syntheses of 3-Hydroxypiperidines
Table 1. Epoxidation/elimination of lactams 5a–5d.
the two steps with diastereoselectivities of 92:8 and Ͼ99:1,
respectively. The lactam cis-12b has been used by Huang
and co-workers in the synthesis of the neurokinin 1 antago-
nist (+)-L-733.060 (cf. Figure 1).[20]
Entry
5
5[d]
5a
5a
5b
ent-5c
5d
Conditions[a]
trans-6/cis-6[b]
% Yield[c]
90
Scheme 5. Reagents and conditions: (a) for trans-12a: Pd/C, H2,
EtOAc, room temp.; for trans-12b: Rh/C, H2, EtOAc/MeOH, room
temp.; (b) for 13a: DMP, CH2Cl2, 0 °C, 99% (over 2 steps); for 13b:
(COCl)2, dimethyl sulfoxide (DMSO), NEt3, CH2Cl2, 84% (over 2
steps); (c) NaBH4, MeOH, room temp., cis-12a: 81%; cis-12b: 97%.
1
2
3
4
5
6
Oxone
m-CPBA[e]
Oxone[g]
Oxone
Oxone
Oxone
4.1:1
82:18
92:8
[f]
–
68
61
85
90
93:7
Ͼ50:1[h]
Ͼ50:1[h]
Finally, the reductive ring-opening reaction of hydroxy-
lactams trans-6 appeared of interest. This was investigated
with a derivative of trans-6d to access d-erythro-sphingosine
(18, see Scheme 6).[21]
[a] See GP4 in the Exp. Section. [b] Regioselectivity was determined
by 1H NMR analysis of the crude allylic alcohol or by isolation of
the regioisomers. [c] Isolated yield of the mixture of both regioiso-
mers. [d] Starting material is 5 with R = CH2OTBS and Σ = H
(see ref.[11c]). [e] m-CPBA = meta-chloroperoxybenzoic acid. [f] The
yield was not determined. [g] Epoxidation was performed at 0 °C.
1
[h] The cis isomer was not detected by H NMR spectroscopy.
Scheme 4. Reagents and conditions: (a) NaH (2.5 equiv.), NBu4I,
PhCH2Br, THF, 0 °C to room temp., 97%; (b) OsO4, N-methyl-
morpholine-N-oxide (NMO), tBuOH/H2O/pyridine, room temp.,
74%; (c) LiAlH4, Et2O, room temp., 86%; (d) AcOH, reflux, 79%;
(e) Pd(OH)2/C, H2, room temp., 69%.
Scheme 6. Reagents and conditions: (a) N-methylimidazole, I2,
TBSCl, CH2Cl2, 0 °C to room temp., 2 h, 91%; (b) CeCl3·7H2O,
NaBH4, MeOH/CH2Cl2/H2O, –10 °C to –2 °C, 1 h, 88% (corr.) of
15; (c) (i) O3, MeOH/CH2Cl2, –78 °C, 5 min; (ii) Me2S, –78 °C to
room temp., 76%; (d) (i) 1-phenyl-5-tetradecylsulfonyl-1H-tetraz-
ole, KHMDS, dimethoxyethane (DME), –56 °C, 1 h; (ii) 16 in
DME, 3 h, 64% (E/Z, 88:12); (e) trifluoroacetic acid (TFA),
CH2Cl2, room temp., 2 h, 40%.
To access cis-configured hydroxypiperidines, which are
also encountered in pharmaceuticals and alkaloids (cf. Fig-
ure 1), the inversion of the relative configuration at C-3 of
the trans-lactams 6 was studied and accomplished. Catalytic
Lactam trans-6d was treated with TBSCl/iodine[22] to
hydrogenation gave lactams 12 (see Scheme 5), which were give derivative 14 in 91% yield. The ring-opening reaction
oxidized by treatment with Dess–Martin periodinane of N-acyl-δ-lactams is commonly accomplished by using
(DMP) or under Swern conditions to give ketones 13a and NaBH4.[23] The reductive ring-opening reaction of unsatu-
13b, respectively. The potential racemization was of concern rated lactam 14 required application under Luche condi-
at this stage, therefore, the ee values of the ketones were tions[24] to avoid reduction of the double bond. Initially, an
carefully determined by HPLC analysis. The values were N,O-acetal was formed as a byproduct, but its formation
determined to be 96.5 and 98%ee, respectively, which dem- could be avoided by screening the reaction conditions. The
onstrated that the degree of racemization was small. Re- optimized reaction involved using an excess amount of
duction of ketones 13 with a large excess amount of CeCl3 and the reducing agent (1.5 equiv. of CeCl3, 4 equiv.
[19]
NaBH4
in methanol at room temp. furnished the cis- of NaBH4) in combination with a reaction temperature
hydroxypiperidines cis-12a and cis-12b in Ͼ80% yield over slightly below 0 °C. Apparently, other rare earth metal salts,
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G. Helmchen et al.
FULL PAPER
son-305 pump that was coupled with the Knauer UV detector 2600
and a silica gel column (ProntoSIL, 250ϫ20 mm, 5 m silica,
15 mL/min, 45 bar) were used. The iridium-catalyzed allylic substi-
tutions (GP1) are described in the Supporting Information.
CCDC-947888 (for 5b), -947889 (for trans-6b), and -947890 (for
cis-12b) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
for example, ErI3, induced deprotection of the Boc group.
The α,β-unsaturated hydroxylactam 15 was finally obtained
in 88% yield (8% recovered starting material).
Treatment of allylic alcohol 15 with ozone gave aldehyde
16 (76% yield), which is a valuable building block for syn-
theses of azasugars. The alkenyl side chain of the sphingo-
sine target was introduced by a Julia–Kocienski reaction,[25]
which involved the reaction of a tetradecylsulfonyltetraz-
ole[26] with KHMDS and then with aldehyde 16 to obtain
protected sphingosine 17 in moderate yield (64%) with an
E/Z selectivity of 88:12. Finally, deprotection gave (–)-d-
erythro-sphingosine (18) in 9 linear steps and 5% overall
yield. Analytical data were in full agreement with those re-
ported.[27,28]
General Procedure for Acylation with 3-Butenoic Acid (GP2): A
solution of 3-butenoic acid (1.2 equiv.), DMAP (20–30 mol-%), and
amine 3 (1.0 equiv.) in CH2Cl2 (0.5–0.3 m with respect to 3) at 0 °C
was treated slowly with DCC (1.2 equiv.), and the resulting mixture
was stirred at 0 °C (in case of 4b and 4c at room temp.) until there
was complete conversion as monitored by TLC. The reaction mix-
ture was diluted with ethyl acetate, and the suspension was filtered
through a pad of Celite. Water was added, and the mixture was
extracted with ethyl acetate and CH2Cl2. The combined organic
layers were washed with brine, dried with Na2SO4, and concen-
trated in vacuo. The crude product was subjected to flash column
chromatography on silica gel.
Conclusions
The combination of an iridium-catalyzed allylic amin-
ation, a ring-closing metathesis, and a catch and release
procedure based on epoxidation/elimination reactions al-
lows chiral 3-hydroxypiperidines to be prepared in a highly
stereoselective way. This route was applied to the total syn-
theses of 1-deoxymannojirimycin and d-erythro-sphingo-
sine.
(–)-N-Benzyl-N-[(1S)-1-methylprop-2-en-1-yl]but-3-enamide
(4a):
GP2 was carried out using 3-butenoic acid (1.21 g, 14.0 mmol),
DMAP (428 mg, 3.50 mmol), DCC (2.89 g, 14.0 mmol), and 3a
(1.88 g, 11.7 mmol) in CH2Cl2 (40 mL) for a reaction time of 3.5 h.
TLC [petroleum ether/diethyl ether, 1:2; Rf = 0.22 (3a) and Rf =
0.40 (4a); KMnO4]. The crude product was subjected to flash col-
umn chromatography on silica gel [petroleum ether/ethyl acetate,
4:1; Rf = 0.18 (4a)] to yield 4a contaminated with 3% of the iso-
merized product (2.41 g combined yield, 90%) as a pale yellow oil.
The latter was removed in the next step (metathesis). [α]2D0 = –82 (c
Experimental Section
1
General Methods: The H NMR spectroscopic data were recorded
at room temp. in CDCl3, unless otherwise reported, with a Bruker
Avance 300 (300 MHz) or 500 (500 MHz) spectrometer. Chemical
shifts are given in δ (ppm) relative to CHCl3 (δH = 7.26 ppm) or
TMS (δH = 0.00 ppm). For system of numbering the atoms, see the
Supporting information. The 13C NMR spectroscopic data were
recorded at room temp. in CDCl3, unless otherwise reported, with
a Bruker Avance 300 (75 MHz) or 500 (125 MHz) spectrometer.
1
= 1.01, CHCl3); 97%ee. H NMR (300 MHz, toluene, 90 °C): δ =
1.02 (d, J = 6.9 Hz, 3 H, CH3), 2.93 (d, J = 6.2 Hz, 2 H, 2-H), 4.14
(d, J = 16.7 Hz, 1 H, PhCHaHb), 4.40 (d, J = 16.7 Hz, 1 H,
PhCHaHb), 4.71–4.84 (m, 1 H, 1Ј-H), 4.84–5.00 (m, 4 H, 4-H and
3Ј-H), 5.69 (ddd, J = 16.3, 10.4, 5.2 Hz, 1 H, 2Ј-H), 6.00 (ddt, J =
16.9, 10.5, 6.4 Hz, 1 H, 3-H), 6.94–7.03 (m, 1 H, Ar), 7.03–7.12
(m, 4 H, Ar) ppm. 13C NMR (75 MHz, toluene, 90 °C): δ = 17.90
(q, CH3), 39.57 (t, C-2), 47.38 (t, PhCH2), 53.83 (d, C-1Ј), 115.42
(t, C-3Ј), 116.78 (t, C-4), 127.26, 127.37, 128.83 (3 d, Ar), 133.31
(d, C-3), 139.62 (d, C-2Ј), 140.19 (s, Ar), 170.74 (s, C-1) ppm. GC–
MS: tR = 10.6 min. HRMS (EI+): calcd. for C15H19NO+ [M]+
229.1467; found 229.1456.
Chemical shifts are given in δ (ppm) relative to CDCl3 [δC
=
77.16 ppm (central line of the triplet)]. The abbreviations are s (sin-
glet), d (doublet), t (triplet), q (quartet), m (multiplet), and br.
(broad). The assignment of signals was confirmed by 1H,1H-COSY,
1H,13C-COSY, and DEPT spectroscopic data. Optical rotations
were measured with a Perkin–Elmer 341 polarimeter in a thermo-
stated cuvette (1 dm) and with a mercury lamp. HRMS were re-
corded with either a JEOL JMS-700 instrument (EI and FAB) or a
(+)-N-(4-Methoxybenzyl)-N-[(1R)-1-phenylprop-2-en-1-yl]but-3-en-
amide (4b): GP2 was carried out using 3-butenoic acid (1.53 g,
Bruker ApexQe instrument (ESI). GC–MS chromatograms/spectra 17.7 mmol), DMAP (360 mg, 2.95 mmol), DCC (3.66 g,
were recorded with the HP 5890 Series II Plus instrument that was
coupled with the HP 5972 Mass Selective Detector. For a capillary
column, the HP-1 cross-linked methyl silicone gum (25 mϫ
0.2 mm, 0.33 μm film thickness) was employed with helium as the
carrier gas. All given retention times (tR) refer to the default tem-
perature program [isothermal 50 °C (1 min), heating rate of 20 °C/
17.7 mmol), and 3b (3.74 g, 14.8 mmol, 98%ee) in CH2Cl2 (45 mL)
for a reaction time of 30 min at 0 °C and 90 min at room temp.
TLC [petroleum ether/ethyl acetate, 2:1; Rf = 0.28 (3b) and Rf =
0.39 (4b); KMnO4]. The crude product was subjected to flash col-
umn chromatography on silica gel (petroleum ether/ethyl acetate,
from 6:1 to 4:1) to give 4b (4.51 g, 95%) as a colorless foam. [α]2D0
1
min (10 min), isothermal 250 °C (14 min), injector temperature: = +60.6 (c = 1.05, CHCl3); 98%ee. H NMR (300 MHz, [D8]tolu-
250 °C]. Enantiomeric excess values were determined either by
HPLC analysis with the HP 1090 or HP 1100 instrument or by GC
with the HP 5890 instrument. For HPLC analysis, the employed
Daicel columns were Chiralpak AD-H (250ϫ4.6 mm, 5 μm) with
guard cartridge AD-H (10ϫ4 mm, 5 μm) and Chiralcel OD-H
(250ϫ4.6 mm, 5 μm) with guard cartridge OD-H (10ϫ4 mm,
5 μm). For GC analysis, a permethyl-β-cyclodextrin column from
ene, 80 °C): δ = 2.97 (d, J = 6.2 Hz, 2 H, 2-H), 3.34 (s, 3 H, OCH3),
4.22 (d, J = 16.4 Hz, 1 H, 1ЈЈ-Ha), 4.39 (d, J = 16.4 Hz, 1 H, 1ЈЈ-
Hb), 4.85–5.10 (m, 4 H, 4-H, 3Ј-H), 5.85–6.15 (m, 3 H, 3-H, 2Ј-H,
1Ј-H), 6.60 (d, J = 8.5 Hz, 2 H, 3ЈЈЈ-H), 6.86 (d, J = 8.3 Hz, 2 H,
2ЈЈЈ-H), 6.90–7.20 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, [D8]-
toluene, 80 °C): δ = 40.41 (t, C-2), 49.02 (d, C-1ЈЈ), 55.74 (q,
OCH3), 63.07 (d, C-1Ј), 115.20 (d, C-3ЈЈЈ), 117.64, 118.92 (2d, C-
Chrompack (WCOT fused silica, Cp-cyclodextrin-B-236-M-19, 3Ј, C-4), 128.44 (d, Ar), 129.27 (d, Ar), 129.49 (d, Ar), 129.52 (d,
25 mϫ0.25 mm) was used. For preparative HPLC analysis, a Gil- Ar), 132.19 (s, C-1ЈЈЈ), 133.97, 137.35 (d, C-3, C-2Ј), 141.04 (s, Ph),
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Enantio- and Diastereoselective Syntheses of 3-Hydroxypiperidines
160.36 (s, C-4ЈЈЈ), 171.88 (s, C-1) ppm. GC–MS: tR = 16.72 min. (–)-(6S)-1-Benzyl-6-methyl-3,6-dihydropyridin-2(1H)-one (5a): GP3
HRMS (ESI+): calcd. for C21H24NO2+ [M + H]+ 322.18063; found was carried out using 4a (2.10 g, 9.16 mmol), Grubbs II catalyst
322.18016.
(77.8 mg, 91.6 μmol), and dry CH2Cl2 (300 mL) for a reaction time
of 5 h. TLC [petroleum ether/diethyl ether, 1:1; Rf = 0.20 (4a) and
Rf = 0.05 (5a); KMnO4]. The mixture was concentrated in vacuo,
and the residue was subjected to flash column chromatography on
silica gel (petroleum ether/diethyl ether, 1:1) to yield 5a (1.65 mg,
93%) as a pale brown oil. [α]2D0 = –54.9 (c = 1.19, CHCl3), 96.5%ee;
ref.[29a] [α]2D0 = –34.5 (c = 0.23, CHCl3). HPLC analysis (Daicel
(–)-N-Benzyl-N-{(1S)-1-[(trityloxy)methyl]prop-2-en-1-yl}but-3-en-
amide (ent-4c): GP2 was carried out using 3-butenoic acid (90%,
1.21 g, 12.7 mmol), DMAP (358 mg, 2.93 mmol), DCC (2.62 g,
12.07 mmol), and 3c (4.10 g, 9.77 mmol) in CH2Cl2 (68 mL) for a
reaction time of 25 min at 0 °C and 3 h at room temp. TLC [petro-
leum ether/ethyl acetate, 5:1; Rf = 0.37 (3c) and Rf = 0.36 (ent-
4c); KMnO4]. The crude product was subjected to flash column
chromatography on silica gel (petroleum ether/ethyl acetate, 7:1) to
yield 4c (4.36 g, 92%) as a colorless oil. [α]2D0 = –32.2 (c = 1.38,
CHCl3); 94%ee. 1H NMR (300 MHz, [D8]toluene, 85 °C): δ = 3.05
(d, J = 4.5 Hz, 2 H, 2Ј-H), 3.32–3.54 (m, 2 H, 1ЈЈ-H), 4.35 (d, J =
16.6 Hz, 1 H, 1ЈЈЈ-Ha), 4.46 (d, J = 16.7 Hz, 1 H, 1ЈЈЈ-Hb), 4.79–
5.08 (m, 5 H, 1-H, 3-H, and 4Ј-H), 5.67–5.91 (m, 1 H, 2-H), 5.98–
6.17 (m, 1 H, 3Ј-H), 6.96–7.19 (m, 14 H, Ar), 7.38–7.47 (m, 6 H,
Ar) ppm. 13C NMR (75 MHz, [D8]toluene, 85 °C): δ = 39.76 (t, C-
2), 60.03 (d, C-1), 65.21 (t, C-1ЈЈ), 88.17 [s, C(Ph)3], 117.03 (t, C-
3), 117.10 (t, C-4Ј), 127.33, 127.54, 128.28, 128.84, 129.50 (5 d, Ar),
133.35 (d, C-3Ј), 135.87 (d, C-2), 139.80 (s, NCH2Ph), 144.84 (s,
Chiralpak OJ-H, n-hexane/isopropanol, 90:10, 0.5 mL/min): tR
=
22.7 [(–)-(S)-5a] and tR = 27.1 min [(+)-(R)-5a]. 1H NMR
(300 MHz, CDCl3): δ = 1.24 (d, J = 6.6 Hz, 3 H, CH3), 3.03–3.07
(m, 2 H, 3-H), 3.81–3.94 (m, 1 H, 6-H), 4.05 (d, J = 15.2 Hz, 1 H,
PhCHaHb), 5.43 (d, J = 15.2 Hz, 1 H, PhCHaHb), 5.64–5.78 (m, 2
H, 4-H and 5-H), 7.20–7.35 (m, 5 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 20.51 (q, CH3), 32.18 (t, C-3), 46.53 (t, PhCH2), 52.84
(d, C-6), 121.39 (d, C-4 or C-5), 127.78 (d, Ar), 127.87 (d, C-4 or
C-5), 128.63 (d, Ar), 137.61 (s, Ar), 167.94 (s, C-2) ppm. GC–MS:
tR = 10.7 min. HRMS (EI+): calcd. for C13H15NO+ [M]+ 201.1154;
found 201.1157.
(+)-(6R)-1-(4-Methoxybenzyl)-6-phenyl-3,6-dihydropyridin-2(1H)-
one (5b): GP3 was carried out using 4b (4.38 g, 13.6 mmol),
Grubbs II catalyst (290 mg, 2.5 mol-%), and dry CH2Cl2 (450 mL)
for a reaction time of 2 h. TLC [petroleum ether/ethyl acetate, 2:1;
Rf = 0.37 (4b) and Rf = 0.14 (5b); KMnO4]. The mixture was con-
centrated in vacuo, and the residue was subjected to flash column
chromatography on silica gel (petroleum ether/ethyl acetate, from
2:1 to 1:1) to give 5b (3.66 g, 91%) as colorless plates; m.p. 68
–70 °C, which were suitable for X-ray crystal structure analysis.
[α]2D0 = +98 (c = 0.88, CHCl3); 98%ee). 1H NMR (300 MHz,
CDCl3): δ = 3.08 (m, 1 H, 3-Ha), 3.13–3.24 (m, 1 H, 3-Hb), 3.26
(d, J = 14.8 Hz, 1 H, 1Ј-Ha), 3.72 (s, 3 H, OCH3), 4.73 (m, 1 H, 6-
H), 5.48 (d, J = 14.7 Hz, 1 H, 1Ј-Hb), 5.55–5.70 (m, 2 H, 4-H, 5-
H), 6.77 (d, J = 8.7 Hz, 2 H, 3ЈЈ-H), 7.02–7.13 (m, 4 H, Ar), 7.20–
7.34 (m, 3 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 32.25 (t,
C-3), 45.74 (d, C-1Ј), 55.36 (q, OCH3), 61.47 (d, C-6), 114.07 (d,
C-3ЈЈ), 120.52 (d, C-4 or C-5), 126.50 (d, C-4 or C-5), 127.13 (d,
C-Ar), 128.25 (d, C-Ar), 128.90 (s, C-1ЈЈ), 129.19 (d, C-Ar), 129.79
(d, C-Ar), 140.24 (s, C-Ph), 159.08 (s, C-4ЈЈ), 167.57 (s, C-2) ppm.
+
Ar), 171.30 (s, C-1Ј) ppm. HRMS (ESI+): calcd. for C34H34NO2
[M + H]+ 488.2584; found 488.2584.
(+)-tert-Butyl But-3-enoyl{(1R)-1-[(trityloxy)methyl]prop-2-en-1-
yl}carbamate (4d): Under argon, a solution of KHMDS (0.5 m in
toluene, 19.50 mL, 9.75 mmol) was added over a period of 30 min
through a syringe to a stirred, cooled (–78 °C) solution of carb-
amate 3d (2.21 g, 4.44 mmol) in dry THF (15 mL). After stirring
for an additional 20 min, DMPU (11 mL) was added over a period
of 20 min. The resultant orange solution was stirred for 30 min
and then treated with dimethyl malonate (2.09 mL, 17.76 mmol) by
dropwise addition. For this step to be successful, it was crucial to
maintain a temperature of –75Ϯ5 °C. The mixture was warmed to
room temp. within 4 h and then was treated with HCl (2 m solution,
10 mL) to give a clear solution. TLC [petroleum ether/ethyl acetate,
4:1; Rf = 0.41 (3d), Rf = 0.50 (4d), and Rf = 0.19 (dimethyl malon-
ate); KMnO4]. After evaporation of the solvent, the residue was
dissolved in diethyl ether (200 mL), and the solution was washed
with saturated NaHCO3 solution (2ϫ 50 mL), water (2ϫ 50 mL),
and brine (50 mL) and then dried with Na2SO4 and concentrated
in vacuo. The residue was subjected to flash column chromatog-
raphy on silica gel (petroleum ether/diethyl ether, 10:1) to give 4d
(1.88 g, 85%) as a colorless foam. [α]2D0 = –36.6 (c = 1.01, CHCl3);
+
GC–MS: tR = 17.80 min. HRMS (ESI+): calcd. for C19H20NO2
[M + H]+ 294.14929; found 294.14886.
(+)-(S)-1-Benzyl-6-[(trityloxy)methyl]-3,6-dihydropyridin-2(1H)-one
(ent-5c): GP3 was carried out using ent-4c (4.24 g, 8.70 mmol),
Grubbs II catalyst (440 mg, 0.52 mmol), and dry CH2Cl2 (100 mL)
for a reaction time of 19 h. TLC [petroleum ether/ethyl acetate, 5:1;
Rf = 0.25 (ent-4c) and Rf = 0.08 (ent-5c); KMnO4]. The solvent
was evaporated in vacuo, and the residue was subjected to flash
column chromatography on silica gel (petroleum ether/ethyl acet-
ate, 3:1) to yield ent-5c (4.03 g, quantitative) as a colorless oil.
[α]2D0 = +12.7 (c = 1.16, CHCl3); 94%ee. 1H NMR (300 MHz,
CDCl3): δ = 2.98–3.19 (m, 2 H, 3-H), 3.19–3.29 (m, 2 H, 1Ј-H),
3.72 (d, J = 15.3 Hz, 1 H, 1ЈЈ-Ha), 3.82–3.93 (m, 1 H, 6-H), 5.43
(d, J = 15.3 Hz, 1 H, 1ЈЈ-Hb), 5.67–5-79 (m, 1 H, 5-H), 5.91 (dt, J
= 10.0, 3.2 Hz, 1 H, 4-H), 7.02–7.11 (m, 2 H, Ar), 7.15–7.35 (m,
12 H, Ar), 7.35–7.44 (m, 6 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 32.98 (t, C-3), 47.02 (t, C-1ЈЈ), 57.11 (d, C-6), 63.88
(t, C-1Ј), 87.22 [s, C(Ph)3], 124.33 (d, C-4), 124.61 (d, C-5), 127.31,
127.34, 127.85, 128.01, 128.66, 128.77 (6 d, Ar), 137.05 (s,
NCH2Ph), 143.70 (s, Ar), 168.85 (s, C-2) ppm. HRMS (ESI+):
1
98%ee. H NMR (300 MHz, CDCl3): δ = 1.32 [s, 9 H, C(CH3)3],
3.29–3.35 (m, 1 H, OCHaHb), 3.41 (dd, J = 8.4, 8.4 Hz, 1 H,
OCHaHb), 3.60 (ddd, J = 17.2, 6.9, 1.4 Hz, 1 H, 2Ј-Ha), 3.68 (ddd,
J = 17.6, 6.6, 1.1 Hz, 1 H, 2Ј-Hb), 5.08–5.18 (m, 4 H, 3-H and 4Ј-
H), 5.57–5.64 (m, 1 H, 1-H), 5.84 (ddd, J = 17.1, 10.7, 6.1 Hz, 1
H, 2-H), 5.96–6.10 (m, 1 H, 3Ј-H), 7.19–7.42 (m, 15 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 27.97 [3 q, C(CH3)3], 43.29 (t, C-
2Ј), 56.21 (d, C-1), 64.14 (t, C-1ЈЈ), 83.38 [s, C(CH3)3], 86.60 [s,
C(Ph)3], 117.41 (t, C-3 or C-4Ј), 118.11 (t, C-3 or C-4Ј), 127.09 (3
d, C-Ar), 127.90 (6 d, C-Ar), 128.90 (6 d, C-Ar), 131.85 (d, C-3Ј),
135.25 (d, C-2), 144.05 (3 s, C-Ar), 153.15 [s, COOC(CH3)3], 174.25
+
(s, C-1Ј) ppm. HRMS (ESI+): calcd. for C32H36NO4 [M + H]+
498.2639; found 498.2646.
General Procedure for Ring-Closing Metathesis (GP3): In a dry
Schlenk flask under argon, a solution of diene 4 (1.0 equiv.) and
Grubbs II catalyst [1.0–6.0 mol-%; for the preparation of 5d,
Grubbs I catalyst (5 mol-%)] in dry CH2Cl2 (0.1–0.03 m) was heated
at reflux until TLC indicated complete conversion. The mixture
was concentrated in vacuo, and the residue was subjected to flash
column chromatography on silica gel to yield lactam 5.
calcd. for C32H30NO2 [M + H]+ 460.2271; found 460.2272.
+
(+)-tert-Butyl (6R)-2-Oxo-6-[(trityloxy)methyl]-3,6-dihydropyridine-
1(2H)-carboxylate (5d): GP3 was carried out using 4d (1.69 g,
Eur. J. Org. Chem. 2013, 5149–5159
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5153

G. Helmchen et al.
FULL PAPER
3.39 mmol), Grubbs I catalyst (168 mg, 5 mol-%), and dry CH2Cl2
(137 mL) for a reaction time of 16 h. TLC [petroleum ether/ethyl
acetate, 4:1; Rf = 0.51 (4d) and Rf = 0.24 (5d); KMnO4]. The sol-
vent was evaporated in vacuo, and the residue was subjected to
flash column chromatography on silica gel (pentane/diethyl ether/
C-6), 66.48 (d, C-5), 127.60 (d, C-3), 128.29, 128.73 (2 d, Ar),
137.16 (s, Ar), 137.22 (d, C-4), 162.34 (s, C-2) ppm. GC–MS: tR
= 11.5 min (trans-6a). HRMS (EI+): calcd. for C13H15NO2 [M]+
+
217.1103; found 217.1087. Data for (S,S)-cis-6a: M.p. 122–124 °C.
NMR spectroscopic data are in accordance with reported data.[29b]
diethylamine, 3:1:0.02) to yield 5d (1.16 g, 73%) as a colorless foam. [α]2D0 = +22.2 (c = 0.96, CHCl3), 96.5%ee; ref.[29b] [α]2D0 = +21.8 (c
[α]2D0 = +103 (c = 1.09, CHCl3); 98%ee. 1H NMR (300 MHz,
= 0.45, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 1.17 (d, J =
CDCl3): δ = 1.44 [s, 9 H, C(CH3)3], 3.04–3.27 (m, 3 H, 3-H and 6.7 Hz, 3 H, CH3), 3.42–3.54 (m, 1 H, 6-H), 3.84 (d, J = 15.1 Hz,
OCHaHb), 3.40 (dd, J = 9.2, 4.5 Hz, 1 H, OCHaHb), 4.79 (m, 1 H,
6-H), 5.80–5.91 (m, 2 H, 4-H and 5-H), 7.19–7.38 (m, 15 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.10 [3 q, C(CH3)3],
35.67 (t, C-3), 57.08 (d, C-6), 64.78 (t, C-1Ј), 83.23 [s, C(CH3)3],
1 H, PhCHaHb), 4.62 (ddd, J = 6.3, 2.2, 2.2 Hz, 1 H, 5-H), 5.20
(d, J = 15.1 Hz, 1 H, PhCHaHb), 5.81 (dd, J = 10.0, 2.2 Hz, 1 H,
3-H), 6.34 (ddd, J = 10.0, 1.8, 1.8 Hz, 1 H, 4-H), 7.18–7.34 (m, 5 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = 10.97 (q, CH3), 47.39 (t,
87.21 [s, C(Ph)3], 123.77 (d, C-4 or C-5), 124.79 (d, C-4 or C-5), PhCH2), 55.25 (d, C-6), 67.20 (d, C-5), 123.40 (d, C-3), 127.56,
127.22 (3 d, C-Ar), 127.95 (6 d, C-Ar), 128.86 (6 d, C-Ar), 143.69
(3 s, C-Ar), 151.99 [s, COOC(CH3)3], 169.76 (s, C-2) ppm. HRMS
127.82, 128.74 (3 d, Ar), 137.73 (s, Ar), 143.08 (d, C-4), 163.61 (s,
C-2) ppm. GC–MS: tR = 11.8 min (cis-6a).
(ESI+): calcd. for C30H31NNaO4 [M + Na]+ 492.2145; found
+
(–)-(5R,6S)-5-Hydroxy-1-(4-methoxybenzyl)-6-phenyl-5,6-dihydro-
pyridin-2(1H)-one (6b): GP4 was carried out using Oxone (31.45 g,
51.15 mmol), lactam 5b (3.00 g, 10.22 mmol), and NaHCO3
(12.87 g, 153.3 mmol) in acetone/H2O (2:1, v/v, 132 mL) for a reac-
tion time of 7 h. TLC [petroleum ether/ethyl acetate, 1:2; Rf = 0.22
(5b) and Rf = 0.30 (epoxide); KMnO4] indicated incomplete conver-
sion, and, therefore, Oxone (6.29 g, 10.30 mmol) and NaHCO3
(2.57 g, 30.66 mmol) were added. After another 1 h, TLC indicated
complete conversion. After workup, the elimination reaction was
carried out with the crude product, DBU (2.02 g, 13.29 mmol), and
CH2Cl2 (167 mL), and the reaction mixture was heated at reflux
for 3 h. TLC [petroleum ether/ethyl acetate, 1:2; Rf (6b) = 0.22;
KMnO4]. Chromatography on silica gel (petroleum ether/ethyl
acetate/dichloromethane, 1:2:1) afforded 6b (1.922 g, 61%, trans-
6b/cis-6b, 93:7) as a colorless foam. Separation of the diastereomers
was accomplished by preparative HPLC (petroleum ether/ethyl
acetate/dichloromethane, 5:5:4). Data for trans-6b: Colorless plates
(1.640 g, 52%) that were suitable for X-ray crystal structure analy-
492.2143.
General Procedure for Epoxidation/Elimination (GP4): Oxone
(5.0 equiv.) was added in a few portions to a suspension of lactam
5 (1.0 equiv.) and NaHCO3 (15.0 equiv.) in acetone/H2O (2:1, v/v;
2.1–9.2 mL per 100 mg of 5). The mixture was stirred at room
temp. (for the preparation of 6a at 0 °C and afterwards at room
temp.) until TLC indicated complete consumption of the starting
material. The suspension was diluted with ethyl acetate, and the
resulting solution was treated with aqueous Na2S2O5 (10% in H2O)
as the mixture was vigorously stirred. The aqueous phase was sepa-
rated and extracted with ethyl acetate. The combined organic layers
were washed with saturated NaHCO3 solution and brine, dried
with Na2SO4, and then concentrated in vacuo. A solution of the
crude product and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.3–
2.0 equiv.) in CH2Cl2 (1.9–5.6 mL per 100 mg of 5) was stirred and
heated at reflux (for the preparation of 6a at room temp. followed
by stirring and heating at reflux) until TLC indicated complete con-
version. The workup was initiated by the addition of a saturated
aqueous NH4Cl solution or stirring for 1 h with Amberlite IR-120.
The phases were separated, and the aqueous phase was extracted
with ethyl acetate and washed with brine. The combined organic
phases were dried with Na2SO4 and concentrated in vacuo. The
crude product was purified by flash column chromatography on
1
sis; m.p. 108–109 °C. [α]2D0 = –13.8, (c = 0.99, CHCl3); 98%ee. H
NMR (300 MHz, CDCl3): δ = 2.05 (br. s, 1 H, OH), 3.55 (d, J =
14.7 Hz, 1 H, 1Ј-Ha), 3.77 (s, 3 H, OCH3), 4.16 (dd, J = 5.8, 5.8 Hz,
1 H, 5-H), 4.66 (s, 1 H, 6-H), 5.47 (d, J = 14.7 Hz, 1 H, 1Ј-Hb),
6.22 (d, J = 9.7 Hz, 1 H, 3-H), 6.47 (ddd, J = 9.7, 5.6, 1.0 Hz, 1
H, 4-H), 6.82 (d, J = 8.7 Hz, 2 H, 3ЈЈ-H), 7.09–7.19 (m, 4 H, Ar),
7.25–7.38 (m, 3 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ =
47.49 (t, C-1Ј), 55.38 (q, OCH3), 65.90 (d, C-6), 68.07 (d, C-5),
114.20 (d, C-3ЈЈ), 126.87 (d, Ar), 128.00, 128.22 (2 d, C-3, C-4ЈЈЈ),
128.72 (s, C-1ЈЈ), 129.04 (d, Ar), 129.82 (d, Ar), 136.59 (d, C-4),
136.79 (s, C-1ЈЈЈ), 159.10 (s, C-4ЈЈ), 163.15 (s, C-2) ppm. HRMS
1
silica gel. Regioselectivity was determined by H NMR analysis of
the crude product or isolation of the regioisomers.
(–)-(5R,6S)-1-Benzyl-5-hydroxy-6-methyl-5,6-dihydropyridin-2(1H)-
one (6a): GP4 was carried out using Oxone (15.03 g, 24.45 mmol),
NaHCO3 (6.16 g, 73.4 mmol), and 5a (0.98 g, 4.89 mmol) in ace-
tone/H2O (2:1, v/v, 90 mL) for a reaction time of 3 h at 0 °C and
1 h at room temp. TLC [ethyl acetate; Rf = 0.36 (5a) and Rf = 0.21
(epoxide); KMnO4]. After workup, the elimination reaction was
carried out with the crude product, CH2Cl2 (50 mL), and DBU
(1.49 g, 9.78 mmol), and the reaction mixture was stirred at room
temp. for 11 h and then heated at reflux for 7 h. TLC [ethyl acetate;
Rf = 0.22 (trans-6a) and Rf = 0.30 (cis-6a); KMnO4]. Column
chromatography on silica gel (diethyl ether) afforded trans-6a
(670 mg, 63%) as colorless needles and cis-6a (56 mg, 5%) as color-
less needles. Data for (5R,6S)-trans-6a: M.p. 68–69 °C. NMR spec-
(ESI+): calcd. for C19H20NO3 [M + H]+ 310.14398; found
+
310.14404. Data for cis-6b: Colorless oil (100 mg, 3%). [α]2D0
=
1
+143, (c = 0.59, CHCl3); 98%ee. H NMR (300 MHz, CDCl3): δ
= 1.70 (br. s, 1 H, OH), 3.37 (d, J = 14.7 Hz, 1 H, 1Ј-Ha), 3.80 (s,
3 H, OCH3), 4.55 (dd, J = 7.7, 1.0 Hz, 1 H, 5-H), 4.86 (br. s, 1 H,
6-H), 5.45 (d, J = 14.7 Hz, 1 H, 1Ј-Hb), 6.02 (dd, J = 10.0, 2.6 Hz,
1 H, 3-H), 6.22 (dd, J = 10.0, 1.7 Hz, 1 H, 4-H), 6.84 (d, J = 8.7 Hz,
2 H, 3ЈЈ-H), 7.13 (d, J = 8.5 Hz, 2 H, 2ЈЈ-H), 7.18–7.24 (m, 2 H,
2ЈЈЈ-H), 7.34–7.41 (m, 3 H, 3ЈЈЈ-H, 4ЈЈЈ-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 47.12 (t, C-1Ј), 55.42 (q, OCH3), 62.21 (d,
C-5), 67.31 (d, C-6), 114.20 (d, C-3ЈЈ), 124.24 (d, C-3), 128.89 (d,
C-3ЈЈЈ), 128.93 (d, C-4ЈЈЈ), 129.31 (s, C-1ЈЈ), 129.34 (d, C-2ЈЈЈ),
129.74 (d, C-2ЈЈ), 133.37 (s, C-1ЈЈЈ), 142.24 (s, C-4), 159.25 (s, C-
troscopic data are in accordance with reported data.[29a] [α]2D0
=
–156 (c = 0.49, CHCl3), 96.5%ee; ref.[29a] [α]2D0 = –40.5 (c = 0.47,
1
CHCl3). H NMR (200 MHz, CDCl3): δ = 1.13 (d, J = 6.9 Hz, 3
+
4ЈЈ), 163.69 (s, C-2) ppm. HRMS (ESI+): calcd. for C19H20NO3
H, CH3), 1.75 (d, J = 8.9 Hz, 1 H, OH), 3.60 (qdd, J = 6.9, 1.6,
1.6 Hz, 1 H, 6-H), 3.90 (ddd, J = 8.9, 5.7, 1.6 Hz, 1 H, 5-H), 4.02
(d, J = 14.8 Hz, 1 H, PhCHaHb), 5.26 (d, J = 14.8 Hz, 1 H,
PhCHaHb), 6.14 (d, J = 9.7 Hz, 1 H, 3-H), 6.59 (ddd, J = 9.7, 5.7,
1.5 Hz, 1 H, 4-H), 7.22–7.39 (m, 5 H, Ar) ppm. 13C NMR
(75 MHz, CDCl3): δ = 17.02 (q, CH3), 48.35 (t, PhCH2), 58.24 (d,
[M + H]+ 310.14377; found 310.14404.
(+)-(5S,6R)-1-Benzyl-5-hydroxy-6-[(trityloxy)methyl]-5,6-dihydro-
pyridin-2(1H)-one (ent-trans-6c): GP4 was carried out with Oxone
(6.89 g, 11.20 mmol), lactam ent-5c (1.03 g, 2.24 mmol), NaHCO3
(2.82 g, 33.6 mmol), and acetone/water (2:1, v/v, 25 mL) for a reac-
5154
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5149–5159

Enantio- and Diastereoselective Syntheses of 3-Hydroxypiperidines
tion time of 2 h at room temp. TLC [petroleum ether/ethyl actetate,
2:1; Rf = 0.26 (ent-5c) and Rf = 0.22 (epoxide); KMnO4]. After
workup, the elimination reaction was carried out with the crude
product, CH2Cl2 (40 mL), and DBU (0.61 g, 4.03 mmol) for a reac-
tion time of 7 h. TLC [petroleum ether/ethyl actetate; 2:1; Rf = 0.22
(epoxide) and Rf = 0.15 (ent-trans-6c); KMnO4]. Chromatography
on silica gel (petroleum ether/ethyl acetate, from 2:1 to 1:1) afforded
ent-trans-6c (906 mg, 85%, single diastereoisomer) as a colorless
foam. [α]2D0 = +38.4 (c = 1.07, CHCl3); 94%ee. 1H NMR (300 MHz,
CDCl3): δ = 2.09 (d, J = 8.5 Hz, 1 H, OH), 2.90 (dd, J = 9.6,
8.8 Hz, 1 H, 1Ј-Ha), 3.16 (dd, J = 9.8, 4.9 Hz, 1 H, 1Ј-Hb), 3.50–
3.62 (m, 1 H, 6-H), 3.80 (d, J = 14.8 Hz, 1 H, 1ЈЈ-H), 4.23 (dd, J
= 6.2, 6.2 Hz, 1 H, 5-H), 5.02 (d, J = 14.8 Hz, 1 H, 1ЈЈ-H), 5.91
(d, J = 9.8 Hz, 1 H, 3-H), 6.37 (ddd, J = 9.7, 5.7, 1.3 Hz, 1 H, 4-
H), 7.06–7.31 (m, 20 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ
= 48.68 (t, C-1ЈЈ), 62.11 (t, C-1Ј), 62.21 (d, C-6), 62.83 (d, C-5),
87.57 [s, C(Ph)3], 127.25 (d, C-3), 127.40, 127.71, 128.06, 128.34,
128.65, 128.79 (6 d, Ar), 136.99 (d, C-4), 137.11 (s, NCH2Ph),
143.52 (s, Ar), 162.47 (s, C-2) ppm. HRMS (ESI+): calcd. for
2 H, Ar), 7.20–7.39 (m, 23 H, Ar) ppm. 13C NMR (125 Hz,
CDCl3): δ = 48.04 (t, C-1ЈЈ), 58.05 (d, C-6), 61.88 (t, C-1Ј), 68.69
(d, C-5), 70.24 (t, C-1ЈЈЈ), 87.63 [s, C(Ph)3], 127.41 (d, C-3), 127.45,
127.84, 127.91, 128.07, 128.18, 128.52, 128.63 (7 d, Ar), 134.56 (d,
C-4), 137.06 (s, NCH2Ph), 137.77 (s, OCH2Ph), 143.56 (s, Ar),
+
162.46 (s, C-2) ppm. HRMS (ESI+): calcd. for C39H36NO3 [M +
H]+ 566.2689; found 566.2688.
(+)-(3S,4R,5R,6R)-1-Benzyl-5-(benzyloxy)-3,4-dihydroxy-6-[(trityl-
oxy)methyl]piperidin-2-one (8): A drop of water, four drops of pyr-
idine, and osmium tetroxide (2.5% OsO4 in tert-butanol, 1.8 mL)
were added to a stirred solution of the dihydropyridinone 7
(540 mg, 0.955 mmol) and NMO (336 mg, 2.87 mmol) in tert-but-
anol (3 mL). The reaction mixture was stirred for 3.5 h at room
temp., and aqueous saturated Na2S2O5 (8 mL) and water (20 mL)
were then added. The mixture was extracted with EtOAc (50 mL).
TLC [ethyl acetate; Rf = 0.67 (7) and Rf = 0.58 (8); KMnO4]. The
organic phase was washed with a saturated NH4Cl solution
(20 mL) and then H2O (2ϫ 20 mL), dried with Na2SO4, and con-
centrated in vacuo. The crude product was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate, 3:1) to
yield diol 8 (424 mg, 74%, single diastereomer) as a colorless foam.
[α]2D0 = +2.5 (c = 1.20, CHCl3); 94%ee. 1H NMR (300 MHz,
CDCl3): δ = 2.67 (br. s, 1 H, OH), 3.38 (dd, J = 9.7, 4.7 Hz, 1 H,
1Ј-Ha), 3.60 (dd, J = 16.8, 7.0 Hz, 1 H, 1Ј-Hb), 3.58–3.69 (m, 1 H,
6-H), 3.84 (br. s, 1 H, OH), 4.01 (dd, J = 3.4, 2.7 Hz, 1 H, 5-H),
4.09 (d, J = 15.5 Hz, 1 H, 1ЈЈ-Ha), 4.33 (dd, J = 3.6, 3.6 Hz, 1 H,
4-H), 4.41 (d, J = 3.7 Hz, 1 H, 3-H), 4.43 (d, J = 11.9 Hz, 1 H,
1ЈЈЈ-Ha) 4.47 (d, J = 11.9 Hz, 1 H, 1ЈЈЈ-Hb), 5.11 (d, J = 15.5 Hz,
1 H, 1ЈЈ-Hb), 6.94–7.05 (m, 2 H, Ar), 7.11–7.49 (m, 23 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 47.68 (t, C-1ЈЈ), 59.91 (d, C-6),
63.44 (t, C-1Ј), 68.12 (d, C-3), 68.94 (d, C-4), 71.62 (t, C-1ЈЈЈ), 74.60
(d, C-5), 87.64 [s, C(Ph)3], 127.32, 127.46, 127.75, 128.03, 128.59,
128.63, 128.74 (7 d, Ar), 136.76 (s, NCH2Ph), 137.46 (s, OCH2Ph),
143.73 (s, Ar), 171.25 (s, C-2) ppm. HRMS (ESI+): calcd. for
+
C32H30NO3 [M + H]+ 476.2220; found 476.2221.
(–)-tert-Butyl (2S,3R)-3-Hydroxy-6-oxo-2-[(trityloxy)methyl]-3,6-di-
hydropyridine-1(2H)-carboxylate (6d): GP4 was carried out with
Oxone (3.70 g, 6.02 mmol), lactam 5d (565 mg, 1.20 mmol),
NaHCO3 (1.52 g, 18.06 mmol), and acetone/water (2:1, v/v, 12 mL)
for a reaction time of 4 h at room temp. TLC [petroleum ether/
ethyl acetate, 3:1; Rf = 0.33 (5d) and Rf = 0.23 (epoxide); KMnO4].
After workup, a yellowish foam (531 mg) was obtained. The elimi-
nation reaction was carried out by the addition of CH2Cl2 (11 mL)
and DBU (0.33 g, 2.20 mmol) for a reaction time of 2 h. TLC [pe-
troleum ether/ethyl actetate, 2:1; Rf = 0.36 (epoxide) and Rf = 0.18
(6d); KMnO4]. Chromatography on silica gel (diethyl ether/dieth-
ylamine, 1:0.005) afforded 6d (527 mg, 90%, single diastereomer)
as a colorless foam. [α]2D0 = –30.3 (c = 1.32, CHCl3); 98%ee. 1H
NMR (500 MHz, CD2Cl2): δ = 1.46 [s, 9 H, C(CH3)3], 2.51 (br. s,
1 H, OH), 3.04 (dd, J = 9.2, 8.2 Hz, 1 H, OCHaHb), 3.31 (dd, J =
9.2, 4.8 Hz, 1 H, OCHaHb), 4.40 (dd, J = 5.9, 1.2 Hz, 1 H, 3-H),
4.64–4.68 (m, 1 H, 2-H), 5.90 (d, J = 9.6 Hz, 1 H, 5-H), 6.61 (ddd,
J = 9.7, 5.8, 1.5 Hz, 1 H, 4-H), 7.24–7.39 (m, 15 H, Ar) ppm. 13C
NMR (125 MHz, CD2Cl2): δ = 28.27 [3 q, C(CH3)3], 61.51 (d, C-
3), 63.27 (d, C-2), 63.74 (t, C-1Ј), 83.71 [s, C(CH3)3], 87.73 [s,
C(Ph)3], 127.74 (3 d, C-Ar), 128.14 (d, C-5), 128.47 (6 d, C-Ar),
129.08 (6 d, C-Ar), 139.59 (d, C-4), 144.08 (3 s, C-Ar), 152.40 [s,
COOC(CH3)3], 162.45 (s, C-6) ppm. HRMS (ESI+): calcd. for
+
C39H37NNaO5 [M + Na]+ 622.2564; found 622.2566.
(+)-(3R,4R,5R,6R)-1-Benzyl-5-(benzyloxy)-6-[(trityloxy)methyl]pip-
eridine-3,4-diol (9): Under argon, a solution of 8 (230 mg,
0.384 mmol) in dry Et2O (20 mL) was treated with LiAlH4
(73.0 mg, 1.92 mmol). After 5 h [Rf of 8 and Rf of 9 were identical],
the suspension was cooled to 0 °C and treated with 10% aqueous
NaOH. The mixture was treated with EtOAc (40 mL), and the re-
sulting mixture was filtered through a pad of Celite. Water (40 mL)
was added, and the organic layer was separated. The aqueous layer
was extracted with EtOAc (3ϫ 30 mL). The organic phase was
dried with Na2SO4 and concentrated in vacuo. The residue was
subjected to flash column chromatography on silica gel (petroleum
ether/ethyl acetate, 3:1) to yield 9 (193 mg, 86 %) as a colorless
foam. [α]2D0 = +4.8 (c = 0.95, CHCl3); 94%ee. 1H NMR (300 MHz,
CDCl3): δ = 2.17 (dd, J = 12.3, 1.0 Hz, 1 H, 2-Ha), 2.52 (br. s, 2
H, 2 OH), 2.57 (ddd, J = 8.4, 4.2, 1.3 Hz, 1 H, 6-H), 2.89 (dd, J =
12.3, 4.2 Hz, 1 H, 2-Hb), 3.09 (d, J = 13.3 Hz, 1 H, 1ЈЈ-Ha), 3.27
(dd, J = 10.2, 4.5 Hz, 1 H, 1Ј-Ha), 3.57 (dd, J = 16.7, 8.2 Hz, 1 H,
5-H), 3.57–3.78 (m, 3 H, 4-H, 1Ј-Hb and 3-H), 4.11 (d, J = 13.0 Hz,
1 H, 1ЈЈ-Hb), 4.47 (d, J = 11.3 Hz, 1 H, 1ЈЈЈ-Ha), 4.87 (d, J =
11.2 Hz, 1 H, 1ЈЈЈ-Hb), 7.01–7.09 (m, 4 H, Ar), 7.09–7.32 (m, 15
H, Ar), 7.36–7.50 (m, 6 H, Ar) ppm. 13C NMR (75 MHz, CDCl3):
δ = 54.58 (t, C-2), 57.35 (t, C-1ЈЈ), 62.16 (t, C-1Ј), 65.65 (d, C-6),
68.20 (d, C-3), 74.19 (t, C-1ЈЈЈ), 76.45 (d, C-4), 78.54 (d, C-5), 86.93
C30H31NNaO5 [M + Na]+ 508.2094; found 508.2102.
+
(+)-(5S,6R)-1-Benzyl-5-(benzyloxy)-6-[(trityloxy)methyl]-5,6-dihy-
dropyridin-2(1H)-one (7): Under argon, a solution of ent-trans-6c
(1.00 g, 2.10 mmol) in dry THF (20 mL) was cooled to 0 °C. NaH
(126 mg, 5.26 mmol) was added, and the mixture was stirred for
20 min and then warmed to room temp. Tetrabutylammonium iod-
ide (155 mg, 0.42 mmol) and BnBr (1.26 g, 7.36 mmol) were added,
and the mixture was gently heated at reflux. After 7 h, TLC [petro-
leum ether/ethyl acetate, 2:1; Rf = 0.09 (ent-trans-6c) and Rf = 0.31
(7); KMnO4] indicated complete consumption of the starting mate-
rial. The mixture was concentrated in vacuo, and the residue was
subjected to flash column chromatography on silica gel (petroleum
ether/ethyl acetate, 3:1) to give benzyl ether 7 (1.16 g, 97%) as light
yellow foam. [α]2D0 = +58.1 (c = 1.13, CHCl3); 94%ee. 1H NMR
(500 MHz, CDCl3): δ = 3.01 (dd, J = 9.4, 9.4 Hz, 1 H, 1Ј-Ha), 3.30
(dd, J = 9.9, 4.7 Hz, 1 H, 1Ј-Hb), 3.70 (dd, J = 8.8, 4.7 Hz, 1 H, 6-
H), 3.75 (d, J = 15.2 Hz, 1 H, 1ЈЈ-Ha), 4.11 (d, J = 5.6 Hz, 1 H, 5- [s, C(Ph)3], 127.19, 127.62, 127.95, 128.13, 128.42, 128.50, 128.91,
H), 4.29 (d, J = 11.8 Hz, 1 H, 1ЈЈЈ-Ha), 4.35 (d, J = 11.8 Hz, 1 H,
1ЈЈЈ-Hb), 5.29 (d, J = 15.1 Hz, 1 H, 1ЈЈ-Hb), 6.07 (d, J = 9.8 Hz, 1
H, 3-H), 6.37 (ddd, J = 9.6, 5.7, 0.9 Hz, 1 H, 4-H), 7.11–7.19 (m,
129.06 (8 d, Ar), 138.46 (s, NCH2Ph), 138.75 (s, OCH2Ph), 143.89
+
(s, Ar) ppm. HRMS (ESI+): calcd. for C39H40NO4 [M + H]+
586.2951; found 586.2951.
Eur. J. Org. Chem. 2013, 5149–5159
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5155

G. Helmchen et al.
FULL PAPER
1
(+)-(3R,4R,5R,6R)-1-Benzyl-5-(benzyloxy)-6-(hydroxymethyl)piper-
idine-3,4-diol (10): AcOH (80% in H2O, 5 mL) was added to the
protected piperidinediol 9 (75 mg, 0.128 mmol), and the resulting
yellow mixture was stirred and heated at reflux for 6 h whereupon
TLC [ethyl acetate; Rf = 0.63 (9) and Rf = 0.19 (10); KMnO4]
indicated full conversion. The mixture was diluted with H2O
(10 mL), and the resulting mixture was treated with solid NaHCO3
until it became basic. Ethyl acetate (20 mL) was added to the re-
sulting suspension, and the organic layer was separated. The aque-
ous layer was extracted with EtOAc (3ϫ 20 mL), and the organic
layer was concentrated in vacuo. The residue was subjected to flash
column chromatography on silica gel (ethyl acetate) to yield 10
(34.7 mg, 79%) as a colorless foam. Analytical data were in accord-
ance with data from the literature.[11c] 1H NMR (300 MHz,
CDCl3): δ = 2.14–2.30 (m, 2 H, 2-Ha and 6-H), 2.53 (br. s, 3 H, 3
OH), 2.93 (dd, J = 12.6 Hz, J = 4.1 Hz, 1 H, 2-Hb), 3.31 (d, J =
13.5 Hz, 1 H, 1ЈЈ-Ha), 3.52 (dd, J = 8.7 Hz, J = 3.4 Hz, 1 H, 4-H),
3.71 (dd, J = 8.7 Hz, J = 8.7 Hz, 1 H, 5-H), 3.75–3.80 (m, 1 H, 3-
H), 3.85 (dd, J = 12.2 Hz, J = 2.1 Hz, 1 H, 1Ј-Ha), 3.95 (dd, J =
12.1 Hz, J = 2.8 Hz, 1 H, 1Ј-Hb), 4.05 (d, J = 13.5 Hz, 1 H, 1ЈЈ-
Hb), 4.68 (d, J = 11.2 Hz, 1 H, 1ЈЈЈ-Ha), 4.84 (d, J = 11.2 Hz, 1 H,
1ЈЈЈ-Hb), 7.13–7.35 (m, 10 H, Ar) ppm.
(S)-13a]; 96.5%ee. H NMR (300 MHz, CDCl3): δ = 1.36 (d, J =
7.2 Hz, 3 H, CH3), 2.63–2.87 (m, 4 H, 3-H and 4-H), 3.74 (q, J =
7.2 Hz, 1 H, 6-H), 4.04 (d, J = 14.9 Hz, 1 H, PhCHaHb), 5.25 (d,
J = 14.9 Hz, 1 H, PhCHaHb), 7.20–7.37 (m, 5 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 17.58 (q, CH3), 29.28, 35.51 (2 t, C-
3 and C-4), 47.52 (t, PhCH2), 60.73 (d, C-6), 127.95, 128.16, 128.97
(3 d, Ar), 136.52 (s, Ar), 169.55 (s, C-2), 207.10 (s, C-5) ppm. GC–
+
MS: tR = 11.1 min. HRMS (ESI+): calcd. for C13H16NO2 [M +
H]+ 218.1176; found 218.1176.
(–)-(5S,6S)-1-Benzyl-5-hydroxy-6-methylpiperidin-2-one (cis-12a):
NaBH4 (121 mg, 3.22 mmol) was added to a solution of 13a
(70.2 mg, 0.32 mmol) in methanol (9 mL) at 0 °C. The resulting
mixture was stirred for 30 min at 0 °C and 45 min at room tempera-
ture whereupon TLC showed complete conversion [ethyl acetate;
Rf = 0.36 (13a) and Rf = 0.12 (cis-12a); KMnO4]. The reaction
mixture was treated with a saturated NH4Cl solution (1 mL), and
the resulting mixture was concentrated in vacuo. The residue was
diluted with water (3 mL), and the solution was extracted with
CH2Cl2 (4ϫ 5 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated in vacuo. The residue was sub-
jected to flash column chromatography on silica gel (ethyl acetate)
to yield cis-12a (67 mg, 95%, 92:8 mixture of diastereoisomers as
determined by GC–MS) as a colorless amorphous solid. Pure cis-
12a (57 mg, 81%) was obtained as colorless plates by preparative
HPLC (petroleum ether/2-propanol, 70:30); m.p. 118–119 °C.
NMR spectroscopic data were in accordance with published data
for the racemic compound.[19] [α]2D0 = –114 (c = 1.11, CHCl3).
HPLC (Daicel Chiralpak AD-H, n-hexane/isopropanol, 90:10,
0.5 mL/min): tR = 30.2 [(+)-(R,R)-12a] and tR = 31.9 min [(–)-(S,S)-
12a]; 96%ee. 1H NMR (500 MHz, CDCl3): δ = 1.19 (d, J = 6.6 Hz,
3 H, CH3), 1.80–1.88 (m, 1 H, 4-Ha), 1.90–2.00 (m, 1 H, 4-Hb),
2.40–2.50 (m, 1 H, 3-Ha), 2.57 (ddd, J = 18.3, 7.4, 3.8 Hz, 1 H, 3-
Hb), 2.89 (br. s, 1 H, OH), 3.38–3.44 (m, 1 H, 6-H), 3.88–3.96 (m,
1 H, 5-H), 3.91 (d, J = 15.0 Hz, 1 H, PhCHaHb), 5.26 (d, J =
15.0 Hz, 1 H, PhCHaHb), 7.19 (d, J = 7.1 Hz, 2 H, Ar), 7.21–7.32
(m, 3 H, Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.32 (q,
CH3), 24.90 (t, C-4), 29.12 (t, C-3), 47.83 (t, PhCH2), 55.09 (d, C-
6), 67.37 (d, C-5), 127.46, 127.86, 128.70 (3 d, Ar), 137.43 (s, Ar),
169.52 (s, C-2) ppm. GC–MS: tR = 12.2 min. HRMS (EI+): calcd.
1-Deoxymannojirimycin Hydrochloride (11·HCl): Pd(OH)2/C (20%
Pd, 100 mg) was added to a stirred solution of piperidine 10
(40 mg, 0.116 mmol) in MeOH (1.5 mL), and the mixture was
placed under a hydrogen atmosphere (1 bar). TLC [ethyl acetate;
Rf = 0.19 (10)] indicated full conversion after 3 h. Then, concen-
trated HCl (1 mL) was added, and the mixture was stirred for an
additional 10 min and diluted with MeOH (10 mL). The resulting
mixture was filtered through a pad of Celite. The filtrate was con-
centrated in vacuo, and the residue recrystallized from MeOH to
give 1-deoxymannojirimycin hydrochloride (11·HCl, 16.0 mg, 69%)
as colorless needles. Analytical data were in accordance with data
from the literature.[11c] M.p. 190–192 °C; ref.[11c] m.p. 192–195 °C.
1H NMR (600 MHz, D2O): δ = 3.11–3.28 (m, 1 H, 5-H), 3.30 (d,
J = 13.8 Hz, 1 H, 6-Ha), 3.47 (dd, J = 13.7, 1.9 Hz, 1 H, 6-Hb),
3.75 (dd, J = 9.6, 2.0 Hz, 1 H, 3-H), 3.82–3.98 (m, 2 H, 1-Ha, 4-
H), 4.03 (dd, J = 12.5, 2.28 Hz, 1 H, 1-Hb), 4.24–4.36 (m, 1 H, 2-
H) ppm. 13C NMR (150 MHz, D2O): δ = 47.59 (t, C-6), 58.11 (t,
C-1Ј), 60.27 (d, C-2), 65.73, 65.94 (2 d, C-3 and C-4), 72.31 (d, C-
5) ppm.
+
for C13H17NO2 [M]+ 219.1259; found 219.1249.
(–)-(5R,6S)-5-Hydroxy-1-(4-methoxybenzyl)-6-phenylpiperidin-2-
one (trans-12b): A suspension of Rh/C (10%, 69 mg) and trans-6b
(690 mg, 2.23 mmol) in ethyl acetate (16 mL) and methanol (3 mL)
was vigorously stirred for 5 h under hydrogen (1 atm). The suspen-
sion was filtered through a pad of Celite, and the solvent was re-
moved in vacuo to yield 12b (688 mg, 98%) as a colorless solid;
m.p. 132–134 °C. [α]2D0 = –48.5 (c = 0.83, CHCl3); 98%ee. 1H NMR
(300 MHz, CDCl3): δ = 1.65–1.80 (m, 1 H, 4-Ha), 1.81–1.98 (m, 1
H, 4-Hb), 2.40–2.60 (m, 1 H, 3-Ha), 2.77 (ddd, J = 17.9, 10.7,
7.0 Hz, 1 H, 3-Hb), 3.31 (d, J = 14.8 Hz, 1Ј-Ha), 3.76 (s, 3 H,
OCH3), 3.95–4.03 (m, 1 H, 5-H), 4.38 (d, J = 3.0 Hz, 1 H, 6-H),
5.55 (d, J = 14.8 Hz, 1 H, 1Ј-Hb), 6.80 (d, J = 8.6 Hz, 2 H, 3ЈЈ-H),
7.08 (d, J = 8.6 Hz, 2 H, 2ЈЈ-H), 7.16 (dd, J = 7.16, 1.4 Hz, 2 H, 2ЈЈ-
H), 7.28–7.42 (m, 3 H, 3ЈЈЈ-H, 4ЈЈЈ-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 23.38 (t, C-4), 27.41 (t, C-3), 47.12 (t, C-1Ј), 55.36 (q,
OCH3), 66.83 (d, C-6), 69.99 (d, C-5), 114.07 (d, C-3ЈЈ), 127.01 (d,
C-2ЈЈЈ), 128.16 (d, C-4ЈЈЈ), 128.95 (s, C-1ЈЈ), 129.13 (d, C-3ЈЈЈ),
129.54 (d, C-2ЈЈ), 138.75 (s, C-1ЈЈЈ), 158.98 (s, C-4ЈЈ), 170.30 (s, C-
2) ppm. GC–MS (Tmax = 300 °C): tR = 16.21 min. HRMS (ESI+):
(+)-(6S)-1-Benzyl-6-methylpiperidine-2,5-dione (13a): A suspension
of Pd/C (10 % Pd, 30 wt.-%, 60 mg) and trans-6a (200 mg,
0.92 mmol) in ethyl acetate (9 mL) was vigorously stirred under a
hydrogen atmosphere (1 atm). TLC [ethyl acetate; Rf = 0.22 (trans-
6a), Rf = 0.30 (cis-6a), and Rf = 0.10 (trans-12a); KMnO4] showed
that the reaction was complete after 1 h. The suspension was fil-
tered through a pad of Celite, and the solvent was removed in
vacuo. The crude hydrogenation product was dissolved in CH2Cl2
(9 mL), and Dess–Martin periodinane (585 mg, 1.379 mmol) was
added at 0 °C. After stirring for 1 h, TLC showed complete conver-
sion [ethyl acetate; Rf = 0.36 (13a); KMnO4]. Saturated aqueous
Na2S2O3 solution (4 mL) and saturated NaHCO3 solution (8 mL)
were added at 0 °C. After stirring for 10 min, the organic layer was
separated, and the aqueous layer was extracted with diethyl ether
(3ϫ 15 mL). The combined organic layers were dried with Na2SO4
and concentrated in vacuo at a temperature not exceeding 10 °C.
The residue was subjected to flash chromatography on silica gel
(diethyl ether) to yield 13a (198 mg, 99%) as colorless needles; m.p.
63–64 °C. NMR spectroscopic data were in accordance with re-
ported data for the racemic compound.[11c] [α]2D0 = +104 (c = 0.93,
CHCl3). HPLC (Daicel Chiralpak AD-H, n-hexane/isopropanol,
90:10, 0.5 mL/min): tR = 28.6 [(–)-(R)-13a] and tR = 45.2 min [(+)-
calcd. for C19H22NO3 [M + H]+ 312.15975; found 312.15942.
+
(+)-(6S)-1-(4-Methoxybenzyl)-6-phenylpiperidine-2,5-dione (13b):
DMSO (146 μL, 2.056 mmol) was added to a solution of oxalyl
5156
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5149–5159

Enantio- and Diastereoselective Syntheses of 3-Hydroxypiperidines
chloride (90 μL, 1.028 mmol) in CH2Cl2 (1.3 mL) at –78 °C. After was stirred for 2 h whereupon TLC indicated full conversion [petro-
stirring for 10 min at the same temperature, a solution of trans-12b
(80 mg, 257 μmol) in CH2Cl2 (1.3 mL) was added dropwise, and
the suspension was stirred for an additional 20 min. NEt3 (570 μL,
4.112 mmol) was then added dropwise, and the stirring was contin-
ued at –78 °C for 30 min whereupon TLC indicated complete con-
version [petroleum ether/ethyl acetate, 1:2; Rf = 0.45 (trans-12b)
and Rf = 0.18 (13b); KMnO4]. The solution was treated with a
NaH2PO4/Na2HPO4 buffer solution (5 mL), and the resulting solu-
tion was warmed to ambient temperature and extracted with
CH2Cl2 (3ϫ 5 mL). The combined organic layers were dried with
Na2SO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate/dichloromethane, 2:1:0.2) to yield 13b (68.2 mg,
86%) as a colorless white solid; m.p. 119–121 °C. [α]2D0 = +20.1 (c
= 0.69, CHCl3). HPLC (Daicel Chiracel ADH-II, n-hexane/iPrOH,
leum ether/ethyl acetate, 2:1; Rf = 0.18 (6d) and Rf = 0.56 (14);
KMnO4]. The solution was diluted with ethyl acetate (10 mL), and
the resulting mixture was washed with saturated aqueous Na2S2O3
solution (20 mL) until the organic layer was colorless. The aqueous
layer was extracted with ethyl acetate (3ϫ 25 mL), and the com-
bined organic phases were washed with brine (10 mL), dried with
Na2SO4, and concentrated in vacuo. The residue was subjected to
flash column chromatography on silica gel (petroleum ether/ethyl
acetate, from 30:1 to 4:1) to yield 14 (551 mg, 91%) as a colorless
1
foam. [α]2D0 = –57 (c = 1.72, CHCl3); 98%ee. H NMR (300 MHz,
CDCl3): δ = 0.12, 0.17 (2 s, 6 H, OTBS), 0.90 (s, 9 H, OTBS), 1.49
[s, 9 H, C(CH3)3], 2.94 (dd, J = 9.2, 9.2 Hz, 1 H, OCHaHb), 3.35
(dd, J = 9.0, 4.9 Hz, 1 H, OCHaHb), 4.39 (dd, J = 5.9, 1.5 Hz, 1
H, 3-H), 4.66–4.71 (m, 1 H, 2-H), 5.84 (d, J = 9.5 Hz, 1 H, 5-H),
6.33 (ddd, J = 9.7, 5.7, 1.5 Hz, 1 H, 4-H), 7.21–7.44 (m, 15 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.56, –4.25 (2 q,
80:20, 0.5 mL/min): tR = 23.53 [(–)-(R)-13b] and tR = 26.93 min
1
[(+)-(S)-13b]; 98%ee. H NMR (300 MHz, CDCl3): δ = 2.64–2.74 OTBS), 18.19 (s, OTBS), 25.82 (3 q, OTBS), 28.10 [3 q, C(CH3)3],
(m, 2 H, 3-H or 4-H), 2.74–2.86 (m, 2 H, 3-H or 4-H), 3.46 (d, J 61.05 (d, C-2), 62.81 (d C-3), 62.96 (t, C-1Ј), 83.05 [s, C(CH3)3],
= 14.5 Hz, 1 H, 1Ј-Ha), 3.77 (s, 3 H, OCH3), 4.74 (s, 1 H, 6-H), 87.29 [s, C(Ph)3], 127.10 (d, C-5), 127.32 (3 d, C-Ar), 128.02 (6 d,
5.54 (d, J = 14.5 Hz, 1 H, 1Ј-Hb), 6.81 (d, J = 8.7 Hz, 2 H, 3ЈЈ-H),
7.07 (d, J = 8.5 Hz, 2 H, 2ЈЈ-H), 7.21–7.27 (m, 2 H, 2ЈЈЈ-H), 7.20–
C-Ar), 128.66 (6 d, C-Ar), 138.99 (d, C-4), 143.51 (3 s, C-Ar),
151.75 [s, COOC(CH3)3], 162.46 (s, C-6) ppm. HRMS (ESI+):
7.43 (m, 3 H, 3ЈЈЈ-H, 4ЈЈЈ-H) ppm. 13C NMR (75 MHz, CDCl3): δ calcd. for C36H45NNaO5Si+ [M + Na]+ 622.29.59; found 622.2957.
= 29.40 (t, C-4), 35.09 (t, C-3), 47.28 (t, C-1Ј), 55.43 (q, OCH3),
(+)-(4Z)-2-[(tert-Butoxycarbonyl)amino]-3-O-[tert-butyl(dimethyl)-
68.41 (d, C-6), 114.37 (d, C-3ЈЈ), 126.66 (d, C-2ЈЈЈ), 127.99 (s, C-
silyl]-2,4,5-trideoxy-1-O-trityl-D-erythro-hex-4-enitol (15): CeCl3·7
1ЈЈ), 128.78 (d, C-4ЈЈЈ), 129.44 (d, C-3ЈЈЈ), 129.97 (d, C-2ЈЈ), 134.22
H2O (58 mg, 0.16 mmol) was added portionwise to a cooled
(s, C-1ЈЈЈ), 159.47 (s, C-4ЈЈ), 170.00 (s, C-2), 202.97 (s, C-5) ppm.
(–10 °C), stirred solution of lactam 14 (85 mg, 0.14 mmol) in
HRMS (ESI+): calcd. for C19H20NO3+ [M + H]+ 310.14413; found
MeOH/H2O/CH2Cl2 (10:1:0.05, v/v, 6 mL). After stirring for 5 min,
NaBH4 (16 mg, 0.43 mmol) was added in one portion. Vigorous
310.14377.
(–)-(5S,6S)-5-Hydroxy-1-(4-methoxybenzyl)-6-phenyl-5,6-dihydro-
pyridin-2(1H)-one (cis-12b): NaBH4 (75.6 mg, 2 mmol) was added
to a solution of 13b (62 mg, 0.2 mmol) in methanol (4 mL) at 0 °C.
The resulting mixture was stirred for 30 min at 0 °C and 30 min at
room temp. whereupon TLC [petroleum ether/ethyl acetate, 1:2; Rf
= 0.19 (cis-12b); KMnO4] indicated complete consumption of the
starting material. Aqueous NH4Cl solution (3 mL) was added, and
the mixture was concentrated under reduced pressure. Water
gas evolution took place. After this had ceased, the mixture was
warmed to –2 °C and stirred precisely at this temperature for 1 h
whereupon TLC indicated complete conversion [petroleum ether/
ethyl acetate, 2:1; Rf = 0.56 (14) and Rf = 0.40 (15); KMnO4]. The
solution was neutralized to pH = 7 by the addition of HCl (1 n
solution), and the resulting solution was extracted with ethyl acet-
ate (3 ϫ 15 mL). The organic layers were washed with a saturated
NaHCO3 solution (5 mL) and brine (5 mL), dried with Na2SO4,
(2.5 mL) was added, and the mixture was extracted with CH2Cl2 and concentrated in vacuo. The residue was subjected to flash col-
(3ϫ 5 mL). The combined organic layers were dried with Na2SO4,
filtered, and concentrated in vacuo to give cis-12 (66.4 mg, 97%)
as a colorless solid, m.p. 171–173 °C; ref.[20] m.p. 172.5–173.5 °C.
umn chromatography on silica gel (petroleum ether/ethyl acetate,
4:1) to yield 15 (68 mg, 80%) as a colorless foam and 14 (7 mg,
corrected yield 88%). [α]2D0 = +7.6 (c = 1.14, CHCl3); 98%ee. 1H
NMR (300 MHz, CDCl3): δ = –0.08, –0.04 (2 s, 6 H, OTBS), 0.75
(s, 9 H, OTBS), 1.44 [s, 9 H, C(CH3)3], 2.22 (br. s, 1 H, OH), 3.23–
Analytical data are in accordance with reported data.[20] [α]2D0
=
–64.2 (c = 0.6, CHCl3); 98%ee; ref.[20] [α]2D0 = –63.39 (c = 0.6,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 1.45 (br. s, 1 H, OH), 3.33 (m, 2 H, 1-H), 3.73 (br. s, 1 H, 2-H), 4.12–4.29 (m, 2 H, 6-H),
1.68–1.78 (m, 2 H, 4-H), 2.59 (ddd, J = 18.1, 8.6, 8.6 Hz, 1 H, 3-
Ha), 2.77 (ddd, J = 18.3, 5.2, 5.2 Hz, 1 H, 3-Hb), 3.29 (d, J =
4.65–4.72 (m, 2 H, 3-H and NH), 5.45 (dd, J = 10.5, 9.1 Hz, 1 H,
4-H), 5.66 (ddd, J = 11.8, 6.2, 6.0 Hz, 1 H, 5-H), 7.21–7.44 (m, 15
14.5 Hz, 1 H, 1Ј-Ha), 3.79 (s, 3 H, OCH3), 4.03 (br. s, 1 H, 5-H), H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.93, –4.26 (2 q,
4.48 (d, J = 5.3 Hz, 1 H, 6-H), 5.42 (d, J = 14.5 Hz, 1 H, 1Ј-Hb), OTBS), 18.10 (s, OTBS), 25.85 (3 q, OTBS), 28.58 [3 q, C(CH3)3],
6.84 (d, J = 8.7 Hz, 2 H, 3ЈЈ-H), 7.06 (d, J = 8.6 Hz, 2 H, 2ЈЈ-H),
56.31 (d, C-2), 58.99 (t, C-6), 62.13 (t, C-1), 69.42 (d, C-3), 79.65
7.22 (dd, J = 7.6, 1.7 Hz, 2 H, 2ЈЈЈ-H), 7.35–7.48 (m, 3 H, 3ЈЈЈ-H, [s, C(CH3)3], 86.99 [s, C(Ph)3], 127.21 (3 d, C-Ar), 127.96 (6 d, C-
4ЈЈЈ-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.62 (t, C-4), 29.63
(t, C-3), 47.46 (t, C-1Ј), 55.41 (q, OCH3), 63.47 (d, C-6), 67.37 (d,
C-5), 114.13 (d, C-3ЈЈ), 128.68 (d, C-4ЈЈЈ), 128.74 (d, C-2ЈЈЈ), 128.93
(d, C-3ЈЈЈ), 129.02 (s, C-1ЈЈ), 129.85 (d, C-2ЈЈ), 135.45 (s, C-1ЈЈЈ),
159.19 (s, C-4ЈЈ), 169.84 (s, C-2) ppm. GC–MS: tR = 20.08 min.
HRMS (ESI+): calcd. for C19H22NO3+ [M + H]+ 312.15914; found
312.15942.
Ar), 128.90 (6 d, C-Ar), 130.29 (d, C-5), 133.47 (d, C-4), 143.98 (3
s, C-Ar), 155.91 [s, COOC(CH3)3] ppm. HRMS (ESI+): calcd. for
C36H49NNaO5Si+ [M + Na]+ 626.3272; found 626.3271.
tert-Butyl ((1S,2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-3-oxo-1-[(trit-
yloxy)methyl]-propyl)carbamate (16): A solution of 15 (45 mg,
0.075 mmol) and the indicator Sudan III in CH2Cl2/MeOH (1:1, v/
v) was exposed to ozone at –78 °C for 5 min and then treated with
(–)-tert-Butyl (2S,3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-6-oxo-2- dimethylsulfide (35 μL) at –78 °C. After stirring for 10 min, the
[(trityloxy)methyl]-3,6-dihydropyridine-1(2H)-carboxylate (14): N- solution was warmed to room temp. The crude product was puri-
Methylimidazole (0.25 mg, 3.03 mmol), iodine (0.51 mg, fied by flash column chromatography [petroleum ether (PE)/diethyl
2.02 mmol), and TBSCl (0.16 mg, 1.06 mmol) were consecutively
added to a solution of trans-6d (491 mg, 1.01 mmol) in CH2Cl2
(5 mL) at 0 °C. The mixture was allowed to reach room temp. and
ether (EE), 4:1; Rf = 0.32 (15) and Rf = 0.61 (16); KMnO4] on
silica gel (pentane/diethyl ether, 8:1) to give 16 (33 mg, 76%) as a
colorless foam. [α]2D0 = +21.5 (c = 1.22, CHCl3). 1H NMR
Eur. J. Org. Chem. 2013, 5149–5159
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5157

G. Helmchen et al.
FULL PAPER
(300 MHz, CDCl3): δ = –0.04 and 0.04 [2 s, 6 H, OSitBu-
0.05 mmol) in CH2Cl2 (1 mL), and the resulting yellow solution
(CH3)2], 0.82 [s, 9 H, OSitBu(CH3)2], 1.41 [s, 9 H, C(CH3)3], 3.11– was stirred at room temp. for 2 h. The solvent was removed under
3.24 (m, 2 H, 1Ј-H), 4.14–4.32 (m, 2 H, 2-H and 1-H), 4.50 (d, J reduced pressure, and the residual ammonium salt was dissolved in
= 8.8 Hz, 1 H, NH), 7.20–7.42 (m, 15 H, Ar), 9.61 (s, 1 H,
MeOH and subjected to an ion-exchange column (Dowex 50Wx8,
CHO) ppm. 13C NMR (75 MHz, CDCl3) = –5.10 and –4.46 {2 q,
H+ form) that was eluted with MeOH (20 mL), NH3 (4 m in
OSi[C(CH3)3](CH3)2}, 18.22 {s, OSi[C(CH3)3](CH3)2}, 25.84 {3 q, MeOH, 30 mL), and CH2Cl2/MeOH/NEt3 (8:1:0.01, 40 mL) to
OSi[C(CH3)3](CH3)2}, 28.46 [3 q, C(CH3)3], 52.79 (d, C-1), 61.04
(t, C-1Ј), 78.22 (d, C-2), 79.99 [s, C(CH3)3], 87.82 [s, C(Ph)3], 127.25
(3 d, C-Ar), 128.02 (6 d, C-Ar), 128.80 (6 d, C-Ar), 143.54 (3s, C-
Ar), 155.00 (s, COOtBu), 201.43 (d, CHO) ppm. HRMS (ESI+):
calcd. for C34H45NNaO5Si+ [M + Na]+ 598.2959; found 598.2955.
give 18 (7 mg, 40%) as white plates. Analytical data were in accord-
ance with the literature.[27] [α]2D0 = –2.4 (c = 0.90, CHCl3); ref.[27]
[α]2D0 = –1.6 (c = 0.7, CHCl3). 1H NMR (300 MHz, CDCl3): δ =
0.88 (t, J = 6.8 Hz, 3 H, 18-H), 1.26 (s, 22 H, 7-H–17-H), 2.04–
2.06 (m, 2 H, 6-H), 2.80–2.99 (2 br. s, 5 H, NH2, 2 OH, and 2-H),
3.64–3.74 (m, 2 H, 1-H), 4.14 (br. s, 1 H, 3-H), 5.46 (dd, J =
14.8 Hz, J = 5.7 Hz, 1 H, 4-H), 5.77 (ddd, J = 15.1 Hz, J = 6.1 Hz,
J = 6.1 Hz, 1 H, 5-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.27
(q, C-18), 22.85 (t, C-17), 29.33, 29.45, 29.52, 29.67, 29.80–29.86
(5 t), 32.08 (all t, C-7–C-16), 32.51 (t, C-6), 56.45 (d, C-2), 62.21
(t, C-1), 74.62 (d, C-3), 128.80 (d, C-4), 134.96 (d, C-5) ppm.
tert-Butyl
((1S,2R,3E)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-[(trit-
solution of
yloxy)methyl]-heptadec-3-en-1-yl)carbamate (17):
A
KHMDS (0.5 m in toluene, 0.50 mL, 0.25 mmol) was added to a
solution of 1-phenyl-5-tetradecylsulfonyl-1H-tetrazole (146 mg,
0.30 mmol) in dry DME (2.5 mL) under argon at –56 °C. The solu-
tion was stirred for 30 min as the color of the solution turned to
yellow. A solution of aldehyde 16 (67 mg, 0.12 mmol) in DME
(1.5 mL) was slowly added by cannula, and the mixture was stirred
at –60 to –50 °C until TLC [PE/EE, 10:1; Rf = 0.35 (16) and Rf =
0.53 (17); KMnO4] indicated full conversion of the aldehyde (4 h).
Water was then added, and the mixture was warmed to room temp.
After stirring for an additional 30 min, the mixture was extracted
with Et2O, and the organic layers were washed with water, dried,
and concentrated in vacuo. The residue was subjected to flash col-
umn chromatography on silica gel (pentane/diethyl ether, 20:1) to
give 17 (56 mg, 64%, E/Z, 88:12). The Z/E isomers were separated
by preparative HPLC [pentane/diethyl ether, 25:1; tR = 8.3 (Z-17)
HRMS (ESI+): calcd. for C18H38NO2 [M + H]+ 300.2897; found
+
300.2897.
Supporting Information (see footnote on the first page of this arti-
cle): Additional synthetic route to 18, general procedures for the
Ir-catalyzed allylic substitution, HPLC data, and 1H NMR spectra
of all compounds.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (SFB 623) and the Fonds der Chemischen Industrie. The
authors thank Dr. Frank Rominger and his team for the X-ray
crystal structure analyses.
and tR = 10.1 min (E-17)]. Data for (E)-17: Colorless oil. [α]2D0
=
+0.5 (c = 2.70, CHCl3). 1H NMR (300 MHz, CDCl3): δ = –0.00 [s,
6 H, OSitBu(CH3)2], 0.82 [s, 9 H, OSitBu(CH3)2], 0.91 (pseudo-t,
J = 6.7 Hz, 3 H, 17-H), 1.29 (s, 22 H, 6-H–16-H), 1.47 [s, 9 H,
C(CH3)3], 1.93–1.97 (m, 2 H, 5-H), 3.22 (br. d, J = 4.8 Hz, 2 H,
1Ј-H), 3.80–3.87 (m, 1 H, 1-H), 4.32 (m, 1 H, 2-H), 4.59 (br. d, J
= 8.5 Hz, 1 H, NH), 5.29 (dd, J = 15.4 Hz, J = 6.7 Hz, 1 H, 3-H),
5.60 (ddd, J = 15.6 Hz, J = 6.7 Hz, J = 6.7 Hz, 1 H, 4-H), 7.24–
7.48 (m, 15 H, Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.82
and –4.04 {2 q, OSi[C(CH3)3](CH3)2}, 14.27 (q, C-17), 22.84 (t, C-
16), 25.97 {3 q, OSi[C(CH3)3](CH3)2}, 28.61 [3 q, C(CH3)3], 29.31–
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(Z)-17: Colorless oil. H NMR (300 MHz, CDCl3): δ = –0.07 and
–0.05 [2s, 6 H, OSitBu(CH3)2], 0.75 [s, 9 H, OSitBu(CH3)2], 0.88
(pseudo-t, J = 6.5 Hz, 3 H, H-17), 1.26 (s, 22 H, 6-H–16-H), 1.44
[s, 9 H, C(CH3)3], 1.94–2.12 (m, 2 H, 5-H), 3.20–3.31 (br. d, 2 H,
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5.23 (dd, J = 11.0 Hz, J = 8.6 Hz, 1 H, 3-H), 5.37 (ddd, J =
11.4 Hz, J = 7.2 Hz, J = 7.2 Hz, 1 H, 4-H), 7.18–7.46 (m, 15 H,
Ar) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.86 and –4.10 {2 q,
OSi[C(CH3)3](CH3)2}, 14.27 (q, C-17), 22.85 (t, C-16), 25.92 {3 q,
OSi[C(CH3)3](CH3)2}, 28.64 [3 q, C(CH3)3], 29.51–30.09 {m, C-6–
C-15 and OSi[C(CH3)3](CH3)2}, 32.08 (t, C-5), 55.82 (d, C-1), 62.35
(t, C-1Ј), 69.44 (d, C-2), 77.36 [s, C(CH3)3], 86.88 [s, C(Ph)3], 127.10
(3 d, C-Ar), 127.88 (6 d, C-Ar), 128.96 (6 d, C-Ar), 130.64 (d, C-
3), 131.88 (d, C-4), 144.13 (3 s, C-Ar), 155.63 (s, COOtBu) ppm.
HRMS (ESI+): calcd. for C48H73NNaO4Si+ [M + Na]+ 778.5201;
found 778.5204.
(2S,3R,4E)-2-Aminooctadec-4-ene-1,3-diol [(–)-D-erythro-Sphingo-
sine, 18]: TFA (1 mL) was added to a solution of (E)-17 (41 mg,
5158
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Eur. J. Org. Chem. 2013, 5149–5159

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Received: March 26, 2013
Published Online: July 2, 2013
Eur. J. Org. Chem. 2013, 5149–5159
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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