Concise asymmetric synthesis of (-)-halosaline and (2R,9aR)-(+)-2-hydroxy- quinolizidine by ruthenium-catalyzed ring-rearrangement metathesis

Article abstract of DOI:10.1016/j.tet.2004.06.051

A ruthenium-catalyzed ring opening-ring closing metathesis reaction serves as the key step in the stereoselective synthesis of a new enantiopure 2-substituted-4,5-dehydropiperidine skeleton, a valuable intermediate for the synthesis of piperidine alkaloid

Full text of DOI:10.1016/j.tet.2004.06.051

Tetrahedron 60 (2004) 6437–6442
Concise asymmetric synthesis of (2)-halosaline and
(2R,9aR)-(1)-2-hydroxy-quinolizidine by ruthenium-catalyzed
ring-rearrangement metathesis
*
Giordano Lesma, Sergio Crippa, Bruno Danieli, Daniele Passarella, Alessandro Sacchetti,
*
Alessandra Silvani and Andrea Virdis
Dipartimento di Chimica Organica e Industriale e Centro Interdisciplinare Studi biomolecolari e applicazioni Industriali (CISI),
`
Universita degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy
Received 20 April 2004; revised 19 May 2004; accepted 10 June 2004
Abstract—A ruthenium-catalyzed ring opening–ring closing metathesis reaction serves as the key step in the stereoselective synthesis of a
new enantiopure 2-substituted-4,5-dehydropiperidine skeleton, a valuable intermediate for the synthesis of piperidine alkaloids (such as (2)-
halosaline) and of hydroxylated quinolizidines (such as (2R,9aR)-(þ)-2-hydroxy-quinolizidine).
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
1) for the asymmetric synthesis of 2-substituted-4-hydroxy-
piperidines. The utility of this new synthon is enhanced by
its availability in both enantiomeric forms, which can be
prepared in high yields from the enzymatically derived
cyclohept-3-ene-1,6-diol monoacetate 5. Particularly,
starting from ent-1, we described a concise approach to
cis-4-hydroxy-2-pipecolic acid 2 and to biologically
relevant cis-2-alkyl-4-hydroxy-piperidines 3 and 4.
(Scheme 1). It was therefore interesting to further explore
applications of these versatile intermediates for the asym-
metric synthesis of piperidine alkaloids.
The piperidine ring is a ubiquitous structural feature of
many biologically active alkaloids and useful chemo-
therapeutic agents. For this reason, substituted piperidine
ring systems have been the subject of considerable synthetic
efforts, prompting an exceptional development of method-
ologies for the asymmetric approach to these kinds of
compounds.1
As part of a program aimed at the design and preparation of
polyfunctionalized chiral building blocks useful for the
asymmetric synthesis of natural nitrogen-containing com-
pounds, we recently reported2 the application of optically
pure, protected, trans-6-aminocyclohept-3-enols (1 and ent-
Recently, the Blechert3 and Hoveyda4 groups have made an
important contribution to synthetic routes for heterocyclic
compounds, by combining ring closing metathesis (RCM)
Scheme 1.
Keywords: Piperidine alkaloids; Quinolizidine; Ring rearrangement metathesis; Grubbs’ catalyst.
*
Corresponding authors. Tel.: þ39-250314080; fax: þ39-250314078; e-mail addresses: alessandra.silvani@unimi.it; giordano.lesma@unimi.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.051

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G. Lesma et al. / Tetrahedron 60 (2004) 6437–6442
Scheme 2.
with ring opening metathesis (ROM) and cross metathesis
(CM). By starting from easily accessible chiral cyclic olefin
precursors, properly equipped with olefin substituents,
intramolecular domino processes involving ring rearrange-
ment metathesis (RRM) have been applied, to afford various
N- and O-heterocycles, using ruthenium-based Grubbs’
catalysts. This synthetic tool is highly modular, since both
the ring size and the olefin-containing side chains in the final
compounds can be easily varied, with complete transfer of
chirality from carbocycles to newly formed heterocycles.
esting synthetic targets, due to their ability to inhibit
glycohydrolases resulting in many potential pharmaceutical
activities. As an example, here we also report the formation
of the bicyclic skeleton of the 2-hydroxy-quinolizidine 9, by
means of appropriate elaborations of the 2-acetoxy-pent-4-
enyl side chain of 7. As the first step in our synthetic plan,
we devised the preparation of the all-protected trans-N-
allyl-aminoalcohol 6a (P1¼Boc, P2¼TBS), by direct
N-allylation of the corresponding N–H precursor 1, under
standard conditions. However, this reaction step afforded
the desired product in low yields, probably because of the
presence of the sterically-demanding Boc protecting group.
The diolefinic substrate 6b was then achieved by a four-step,
high yield sequence, as described in Scheme 3. Enantiopure
alcohol 102 was treated under Mitsunobu conditions with
N-(tert-butoxycarbonyl)-p-toluenesulfonamide,5 to give
cleanly the all-protected trans-aminoalcohol 11. Double
N- and O-deprotection by means of TFA, followed by
O-acetylation, furnished 12 in quantitative yield, from
which 6b was derived (85% yield) by reaction with sodium
hydride and allyl bromide. In the next stage, ring
rearrangement metathesis on 6b was preliminarily per-
formed according to Blechert,3a with first generation
Grubbs’s ruthenium catalyst in variable amounts from 7 to
1 mol%. Although the reaction was performed in 0.05–
0.10 M concentration of 6b in CH2Cl2, the only isolable
compound was in our case the homo-dimerization product
2. Results and discussion
We envisaged that the suitably substituted cycloheptene 6
(Scheme 2), easily derivable from 1, could provide a
properly functionalized substrate for a RRM reaction, to
afford the new 2-substituted-4,5-dehydropiperidine skeleton
7. This latter compound can be regarded as a valuable
precursor of enantiopure piperidine alkaloids and non-
natural N-heterocycles (Scheme 2).
The utility of 6, as a polyfunctionalized chiral building
block, is well illustrated by the concise, high-yielding
enantioselective synthesis of natural (2)-halosaline 8.
Moreover, 7 could represent a useful intermediate in the
synthesis of hydroxylated quinolizidines, which are inter-
Scheme 3. Reagent and conditions: (a) BocNHTs, PPh3, THF, DEAD, 50%; (b) TFA, CH2Cl2; then Ac2O, Py, 98%; (c) NaH, DMF, allyl iodide, 85%; (d)
Grubbs catalyst 2nd generation, CH2Cl2, 82%; (e) 0.5 M NaOH, MeOH, 98%; (f) Na/naph 1 M, THF, 278 8C, 79%; (g) PtO2, H2, MTBE, 94%.

G. Lesma et al. / Tetrahedron 60 (2004) 6437–6442
6439
16, which derives from the competitive reaction of the
desired 13 with the intermediately formed ruthenium–
carbene complex.
cleaved with sodium periodate to afford the highly unstable
aldehyde 19. After work up, 19 was directly subjected to
intramolecular reductive amination (10% Pd/C, H2) afford-
ing the saturated bicycle 9 in 52% yield (over two steps).9
Together with 16 as the main product, a low yield (25%) of
13 was then achieved, running the reaction in even more
diluted CH2Cl2 solution (0.01 M) and at long reaction time
(24 h). We reasoned that a more active catalyst could speed
up the reaction, promoting the desired ring rearrangement
and thus depleting the dimerization process. So, the reaction
was performed at the same 0.01 M dilution with 3 mol% of
a more active catalyst, namely the second generation
Grubbs ruthenium-based complex6 equipped with the
more basic saturated imidazole ligands. In these conditions,
the dehydropiperidine 13 was achieved as the unique
product, in satisfactory 92% yield. The compound 13
constitutes a highly functionalized intermediate and its
versatility was preliminary demonstrated by straightforward
conversion to the alkaloid (2)-halosaline 8.7 This natural
product was isolated from Haloxylon salicornicum together
with many other 2-(2-hydroxyalkyl)piperidines and it has
been the target of a few asymmetric syntheses in the last few
years.8 According to Scheme 3, 13 was subjected to
deprotection of the hydroxyl group (NaOH, MeOH,
quantitative yield) to yield 14, followed by efficient
cleavage of the N-tosyl group with sodium naphthalenide.
Catalytic hydrogenation of both double bonds of 15 using
PtO2 afforded 8 in quantitative yield, whose optical rotation
([a]2D0¼218.1 (c 1, EtOH)) was consistent with that
reported for natural (2)-halosaline ([a]2D0¼219.5 (c 0.6,
EtOH)). The 1H NMR, 13C NMR and MS spectra of
synthetic 8 were also in good agreement with the reported
values.
3. Conclusion
In conclusion, the highly functionalized chiral piperidine 13
was prepared from diolefinic heptacycle 6b, by means of an
efficient ruthenium-catalyzed RRM process, and then
converted into the natural product (2)-halosaline 8. In
addition, piperidine 13 can be regarded as a valuable
intermediate for the synthesis of various hydroxylated
quinolizidines, as exemplified by the synthesis of (2R,9aR)-
2-hydroxy-quinolizidine 9.
4. Experimental
4.1. General
All solvents were distilled and properly dried, when
necessary, prior to use. During usual workup, all organic
extracts were dried (Na2SO4 or MgSO4) and evaporated. All
reactions were monitored by thin layer chromatography
(TLC) on precoated silica gel 60 F254 (Merck); spots were
visualized with UV light or by treatment with 1% aqueous
KMnO4 solution. Products were purified by flash chroma-
1
tography (FC) on Merck silica gel 60 (230–400 mesh). H
and 13C NMR spectra were recorded with Bruker AC 300
and AC 400 spectrometers in CDCl3 solutions (if not
otherwise stated) with TMS as internal standard. HR, EI
(70 eV) and FAB mass spectra in the positive mode, were
measured on VG 70-70 EQ-HF instrument equipped with its
standard sources. Optical rotations were measured with
Perkin–Elmer 241 polarimeter. Analytical liquid chroma-
tography was carried out with a Kontron HPLC system
equipped with a UV detector and a Chiracel OD HPLC
column.
In order to explore the usefulness of this RRM methodology
for the asymmetric synthesis of substituted quinolizidines,
we addressed the regioselective dihydroxylation of the
terminal double bond in 14 (Scheme 4). By employing a
catalytic amount of OsO4 and 1 equiv. of NMO, the triol 17
was isolated in 54% yield, as a 1:1 mixture of two
diastereoisomers at the newly created stereogenic centre.
Probably, the complete regioselectivity achieved in this step
is due to the better accessibility of the terminal double bond
with respect to the endocyclic bond. Lack of stereoselection
at the side chain is not a problem at this stage, since the
configuration of the new secondary hydroxyl group is not
important in the synthesis. The triol 17 was successfully
deprotected at the piperidine nitrogen to give 18, and then
4.1.1. (1R,6R)-N-(tert-Butoxycarbonyl)-N-[(6-tert-butyl-
dimethyl-silanyloxy)-cyclohept-3-enyl]-toluensulfona-
mide 11. To a stirred solution of 10 (1.28 g, 5.3 mmol)
in anhydrous THF (30 mL), PPh3 (2.07 g, 7.9 mmol) and
N-tert-butoxycarbonyl-p-toluene-sulfonamide
(2.2 g,
7.9 mmol) were added under nitrogen atmosphere. The
reaction mixture was cooled to 0 8C and after 5 min DEAD
(1.26 mL, 7.9 mmol) was added dropwise. The reaction
mixture was stirred at room temperature for 2 h. Then, the
solvent was evaporated and the residue was purified by flash
chromatography (SiO2, ethyl acetate/hexane 1:5) to afford
1.2 g of pure 11, as a pale yellow oil (50% yield): Rf (ethyl
acetate/hexane 1:2) 0.56; [a]2D5¼21.44 (c 1, CHCl3); H
1
NMR (CDCl3, 400 MHz) d 7.72 (2H, d, J¼8.5 Hz), 7.28
(2H, d, J¼8.5 Hz), 5.86 (1H, m), 5.63 (1H, m), 4.80 (1H, tt,
J¼11.3, 2.9 Hz), 4.02 (1H, t, br, J¼7.7 Hz), 3.12 (1H, t, br
J¼13.2 Hz), 2.70 (1H, ddd, J¼13.8, 11.5, 3.4 Hz), 2.55 (1H,
m), 2.44 (3H, s), 2.40–2.20 (3H, m), 1.38 (9H, s); 0.85 (9H,
s), 0.04 (6H, s); 13C NMR (CDCl3, 100.6 MHz) dC 150.6,
143.7, 138.1, 129.2, 127.5, 126.5, 84.3, 69.9, 52.7, 40.1,
34.9, 31.9, 27.8, 26.0, 21.3, 18.1, 24.0; HRMS calcd for
C25H41NO5SSi: 495.7592. Found: 495.7575. Anal. calcd for
Scheme 4. Reagent and conditions: (a) OsO4, NMO, acetone/water, 0 8C,
60%; (b) Na/naph 1 M, THF, 278 8C, 68%; (c) NaIO4, dioxane/H2O, then
(d) 10% Pd/C, H2, methanol, rt, 52%.

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G. Lesma et al. / Tetrahedron 60 (2004) 6437–6442
C25H41NO5SSi: C, 60.57; H, 8.34; N, 2.83; S, 6.47. Found:
C, 60.71; H, 8.50; N, 2.71; S, 6.55.
chromatography (CH2Cl2/ethyl acetate 100:1) to afford
250 mg of pure 13 (82% yield), as an oil: Rf (CH2Cl2/ethyl
1
acetate 100:5) 0.46; [a]2D5¼26.5 (c 1, CHCl3); H NMR
4.1.2. (1R,6R)-Acetic acid 6-(N-p-toluene-sulfonyl-
amino)-cyclohept-3-enyl ester 12. To a stirred solution of
11 (446 mg, 0.9 mmol) in CH2Cl2 (5 mL), TFA (5 mL) was
added dropwise. After 30 min, the reaction mixture was
cooled to 0 8C and a solution 2.5 M NaOH was slowly added
until pH 9. The organic phase was separated and the
aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried with Na2SO4 and concentrated.
The crude N-Boc deprotected product was dissolved in
anhydrous CH2Cl2, Ac2O (1.1 equiv.) and TEA (1.1 equiv.)
were added and the reaction was stirred for 12 h. Then, the
mixture was poured into 5% aq. H3PO4 and extracted with
ethyl ether. The organic layer was dried over Na2SO4 and
concentrated to give, after flash chromatography (ethyl
acetate/hexane 1:2), 290 mg of pure 12 (98% yield), as an
oil: Rf (ethyl acetate/hexane 1:2) 0.32; [a]2D5¼22.8 (c 1,
CHCl3); 1H NMR (CDCl3, 300 MHz) d 7.75 (2H, d,
J¼8.3 Hz), 7.28 (2H, d, J¼8.3 Hz), 5.75 (1H, dt, J¼11.6,
6.2 Hz), 5.64 (1H, dt, J¼11.6, 6.2 Hz), 4.80 (1H, m), 4.54
(1H, d, br, J¼8.7 Hz), 3.66 (1H, m), 2.41 (3H, s), 2.40–2.10
(5H, m), 1.95 (3H, s), 1.88 (1H, m); 13C NMR (CDCl3,
100.6 MHz) d 170.0, 143.4, 138.0, 129.6, 128.8, 128.4,
127.0, 67.6, 48.6, 42.8, 33.6, 33.5, 21.5, 21.1; HRMS calcd
for C16H21NO4S: 323.4141. Found: 323.4157. Anal. calcd
for C16H21NO4S: C, 59.42; H, 6.54; N, 4.33; S, 9.91. Found:
C, 59.59; H, 6.71; N, 4.25; S, 9.73.
(CDCl3, 400 MHz) d 7.66 (2H, d, J¼8.4 Hz), 7.24 (2H, d,
J¼8.4 Hz), 5.71 (1H, m), 5.62–5.52 (2H, m), 5.08 (1H, d,
br, J¼10.9 Hz), 5.06 (1H, d, br, J¼17.5 Hz), 4.91 (1H, m),
4.24 (1H, m), 4.11 (1H, d, br, J¼19.1 Hz), 3.55 (1H, d, br,
J¼19.1 Hz), 2.40 (3H, s), 2.36 (2H, t, br, J¼7.3 Hz), 2.15
(1H, d, br, J¼19.4 Hz), 2.05 (3H, s), 1.80 (1H, m), 1.76 (1H,
d, J¼19.4 Hz), 1.58 (1H, m); 13C NMR (CDCl3,
100.6 MHz) d 170.5, 143.0, 137.7, 133.2, 129.6, 127.0,
123.5, 122.5, 118.1, 70.5, 47.0, 40.3, 38.7, 35.1, 27.9, 21.5,
21.2; HRMS calcd for C19H25NO4S: 363.4794.
Found: 363.4802. Anal. calcd for C18H25NO2S: C, 67.67;
H, 7.89; N, 4.38; S, 10.04. Found: C, 67.60; H, 8.02; N,
4.31; S, 9.86.
4.1.5. (2R,20R)-1-[10-(Toluene-4-sulfonyl)-10,20,30,60-tetra-
hydro-pyridin-20-yl]-pent-4-en-2-ol 14. To a solution of
13 (305 mg, 0.8 mmol) in MeOH (10 mL), 0.5 M NaOH
(3 mL, 1.5 mmol) was added and the mixture was stirred at
45 8C for 10 h. The mixture was neutralized with HCl 1 N
until pH 7 and MeOH was evaporated in vacuo. Then, water
was added and the aqueous phase was extracted with ethyl
acetate. The organic layer were dried over Na2SO4 and the
solvent was removed under reduced pressure to yield
264 mg (98%) of pure 14, as an oil: Rf (CH2Cl2/ethyl acetate
100:5) 0.31; [a]D25¼24.8 (c 1, CHCl3); H NMR (CDCl3,
1
300 MHz) dH 7.66 (d, 2H, J¼8.9 Hz), 7.24 (d, 2H,
J¼8.9 Hz), 5.97 (1H, dt, J¼10.1, 2.2 Hz), 5.88 (1H, m),
5.78 (1H, dt, J¼10.1, 3.4 Hz), 5.11 (1H, dd, J¼16.1,
1.6 Hz), 4.89 (1H, dd, J¼9.0, 1.6 Hz), 4.33 (1H, m), 4.07
(1H, m), 3.27 (1H, dd, J¼17.7, 3.5 Hz), 3.20 (1H, dd,
J¼17.7, 3.5 Hz), 2.41–2.23 (4H, m), 2.33 (3H, s), 1.72–
1.35 (2H, m), 0.77 (1H, br s); HRMS calcd for C17H23NO3S:
321.4418. Found: 321.4415. Anal. calcd for C17H23NO3S:
C, 63,52; H, 7.21; N, 4.36; S, 9.98. Found: C, 63.71; H, 7.29;
N, 4.21; S, 9.90.
4.1.3. (1R,6R)-Acetic acid 6-(N-allyl-N-p-toluene-sul-
fonylamino)-cyclohept-3-enyl ester 6b. To sodium
hydride (174 mg, 6.0 mmol, 80% dispersion in mineral
oil) in anhydrous DMF (10 mL) a solution of 12 (980 mg,
3.0 mmol) in DMF (10 mL) was added at 0 8C. After stirring
15 min, allyl iodide (563 l, 6.0 mmol) was added dropwise
and the reaction mixture was stirred at room temperature for
1 h. Then, the mixture was poured into 5% aq. H3PO4 and
extracted with ethyl ether. The organic layer was dried over
Na2SO4 and concentrated to give, after flash chromato-
graphy (ethyl acetate/hexane 1:5), 933 mg of pure 6b (85%
yield), as an oil: Rf (ethyl acetate/hexane 1:2) 0.44;
4.1.6. (2R,20R)-1-(10,20,30,60-Tetrahydro-pyridin-20-yl)-
pent-4-en-2-ol 15. A solution 1 M of sodium naphthalide
in THF was prepared as follows: to a stirred solution of
naphthalene (5 g, 39 mmol) in 39 mL of THF, sodium metal
(1.1 g, 47 mmol) was added under nitrogen atmosphere, and
the solution was stirred for 1 h.
1
[a]2D5¼þ20.0 (c 1, CHCl3); H NMR (CDCl3, 400 MHz) d
7.68 (2H, d, J¼8.3 Hz), 7.28 (2H, d, J¼8.3 Hz), 5.85 (1H,
ddt, J¼16.3, 10.5, 6.1 Hz), 5.74 (1H, m), 5.56 (1H, m), 5.21
(1H, dq, J¼17.1, 1.5 Hz), 5.13 (1H, dq, J¼10.1, 1.5 Hz,),
5.05 (1H, m), 4.10 (1H, tdd, J¼11.2, 4.0, 2.1 Hz), 3.85–
3.80 (2H, m), 2.52–2.45 (2H, m), 2.42 (3H, s), 2.02 (3H, s),
2.25–1.98 (3H, m); 13C NMR (CDCl3, 100.6 MHz) d 170.2,
143.1, 139.1, 136.0, 129.6, 128.9, 127.0, 126.9, 117.3, 69.4,
51.9, 47.6, 40.5, 34.7, 31.8, 21.5, 21.2; HRMS calcd for
C19H25NO4S: 363.4794. Found: 363.4782. Anal. calcd for
C19H25NO4S: C, 62.79; H, 6.93; N, 3.85; S, 8.82. Found: C,
62.85; H, 7.04; N, 3.95; S, 8.63.
A solution of 14 (263 mg, 0.8 mmol) in anhydrous THF
(15 mL) was cooled to 278 8C under nitrogen atmosphere
and 3.3 mL (3.3 mmol) of 1 M sodium naphthalenide in
THF was added dropwise. The mixture was stirred for
40 min at this temperature and then 15 mL of saturated
NH4Cl aqueous solution was added. The solution was left to
warm up to room temperature and the aqueous layer was
extracted with ethyl acetate. The organic layer was dried
over Na2SO4 and concentrated to give 264 mg (79% yield)
of pure 15, as an oil: Rf (ethyl acetate 5% NH4OH) 0.18;
[a]2D5¼22.1 (c 1, CHCl3); 1H NMR (CDCl3, 300 MHz) dH
5.91 (1H, m), 5.77 (1H, dt, J¼10.1, 3.6 Hz), 5.64 (1H, dt,
J¼10.1, 3.6 Hz), 5.11 (1H, dd, J¼16.1, 1.7 Hz), 4.89 (1H,
dd, J¼8.9, 1.7 Hz), 4.04 (1H, m), 3.46 (1H, dd, J¼17.8,
3.6 Hz), 3.21 (1H, dd, J¼17.8, 3.6 Hz), 3.15 (1H, m), 2.38–
2.26 (2H, m), 2.12–1.68 (2H, m), 1.61 (2H, m), 1.42–1.09
(2H, m); HRMS calcd for C10H17NO: 167.2531. Found:
4.1.4. (1R,20R)-Acetic acid 1-[10-(toluene-4-sulfonyl)-
10,20,30,60-tetrahydro-pyridin-20-ylmethyl]-but-3-enyl
ester 13. To a solution of 6b (305 mg, 0.8 mmol) in CH2Cl2
(80 mL) under nitrogen atmosphere, was added 2nd
generation Grubbs catalyst (21 mg, 3 mol%) and the
reaction mixture was stirred for 2 h. Then, DMSO (90 ml,
1.2 mmol) was added and this mixture was stirred overnight.
The solvent was evaporated and the residue purified by flash

G. Lesma et al. / Tetrahedron 60 (2004) 6437–6442
6441
167.2539. Anal. calcd for C10H17NO: C, 71.81; H, 10.25; N,
8.37. Found: C, 71.97; H, 10.37; N, 8.41.
(5 mL), cooled to 0 8C, sodium periodate (105 mg,
0.50 mmol) was added. The mixture was stirred for 2 h,
diluted with Et2O, washed with saturated NaHCO3 solution,
dried over Na2SO4 and concentrated. The residue was
dissolved in MeOH (5 mL), 10% Pd/C (6 mg) was added
and the solution was stirred under hydrogen atmosphere for
12 h. After filtration of the catalyst and evaporation of the
solvent, 24 mg (52% overall yield) of pure 9 were obtained:
Rf (ethyl acetate/MeOH 10:1, sat. NH4OH) 0.25;
4.1.7. (2)-Halosaline 8. 20 mg of PtO2 was added to a
solution of 15 (210 mg, 1.3 mmol) in MTBE (20 mL) under
H2 atmosphere. The suspension was stirred for 8 h. The
catalyst was filtered off and the solvent was removed under
vacuum to give 204 mg (94% yield) of pure 8, as an oil: Rf
(ethyl acetate 5% NH4OH) 0.10; [a]2D5¼218.1 (c 1, EtOH);
1H NMR (CDCl3, 300 MHz) dH 3.90 (1H, m), 3.50–3.45
(2H, s, br), 3.10 (1H, dd, J¼12.2, 3.3 Hz), 2.91 (1H, m),
2.60 (1H, ddt, J¼14.1, 12.2, 3.3 Hz), 2.00–1.25 (12H, m),
0.90 (3H, t, J¼6.5 Hz); 13C NMR (CDCl3, 100.6 MHz) d
68.4, 54.9, 46.5, 41.8, 31.5, 25.5, 24.7, 18.6; HRMS calcd
for C10H21NO: 171.2850. Found: 171.2837. Anal. calcd for
C10H21NO: C, 70.12; H, 12.36; N, 8.18. Found: C, 69.92; H,
12.25; N, 8.24.
1
[a]2D5¼þ20.1 (c 1, MeOH); H NMR (CDCl3, 300 MHz) d
3.80 (1H, tt, J¼12.9, 2.8 Hz), 3.00 (1H, d, br, J¼12.0 Hz),
2.90–2.78 (2H, m), 2.70 (1H, dt, J¼12.0, 2.2 Hz), 2.55 (1H,
s, br), 2.40 (1H, dt, J¼11.0, 2.1 Hz), 1.90–1.75 (2H, m),
1.80–1.35 (8H, m); 13C NMR (CDCl3, 100.6 MHz) d 68.7,
60.7, 55.6, 54.5, 42.5, 35.0, 33.1, 25.7, 24.1; HRMS calcd
for C9H17NO: 155.2419. Found: 155.2432. Anal. calcd for
C9H17NO: C, 69.63; H, 11.04; N, 9.02. Found: C, 69.70; H,
11.16; N, 8.90.
4.1.8. (20R,4S)-5-[10-(Toluene-4-sulfonyl)-10,20,30,60-tetra-
hydro-pyridin-20-yl]-pentane-1,2,4-triol 17. To an ice-
cooled solution of 14 (256 mg, 0.80 mmol) in acetone/water
(2:1 v/v; 24 mL) were added 480 l of OsO4, 0.039 M in
water (0.019 mmol). After 5 min N-methylmorfoline-N-
oxide (80 l, 0.80 mmol) was added to the solution in two
portions. The mixture was allowed to warm up to room
temperature and stirred overnight. Ethyl acetate and brine
was added and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were dried over
Na2SO4 and concentrated in vacuum. The resulting crude
product was purified by flash chromatography on silica gel
(ethyl acetate/hexane 10:0.5) to give 170 mg (60% yield) of
17, as a colorless oil: Rf (ethyl acetate/MeOH 10:1) 0.59; 1H
NMR (CDCl3, 300 MHz) d 7.69 (2H, d, J¼8.9 Hz), 7.29
(2H, d, J¼8.9 Hz), 5.65–5.55 (2H, m), 4.25 (1H, m), 4.12
(1H, dd, J¼17.6, 1.6 Hz), 4.00 (1H, m), 3.75–3.60 (3H, m),
3.50 (1H, m), 2.39 (s, 3H), 1.95–1.50 (6H, m); 13C NMR
(CDCl3, 100.6 MHz) d 143.1, 136.6, 129.7 (2C), 127.0 (2C),
123.4, 122.5, 69.8, 67.1, 66.8, 46.9, 40.4, 39.2, 38.1, 27.8,
21.3; HRMS calcd for C17H25NO5S: 355.4565. Found:
355.4554. Anal. calcd for C17H25NO5S: C, 57.44; H, 7.09;
N, 3.94; S, 9.02. Found: C, 57.21; H, 7.00; N, 4.02; S, 9.22.
Acknowledgements
`
The authors thank Ministero dell’Istruzione dell’Universita
e della Ricerca (MIUR) for financial support.
References and notes
1. For reviews on the synthesis of substituted piperidines, see:
(a) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding,
D. R. Tetrahedron 2003, 59, 2953–2989. (b) Laschat, S.;
Dickner, T. Synthesis 2000, 13, 1781. (c) Bailey, P. D.;
Millwood, P. A.; Smith, P. D. J. Chem. Soc., Chem. Commun.
1998, 633. (d) Leclercq, S.; Daloze, D.; Braekman, J.-C. Org.
Prep. Proc. Int. 1996, 28, 499. (e) Wang, C.-L. J.; Wuonola,
M. A. Org. Prep. Proc. Int. 1992, 24, 585.
2. Celestini, P.; Danieli, B.; Lesma, G.; Sacchetti, A.; Silvani, A.;
Passerella, D.; Virdis, A. Org. Lett. 2002, 4, 1367–1370.
3. (a) Stragies, R.; Blechert, S. Tetrahedron 1999, 55, 8179–8188.
(b) Ovaa, H.; Stragies, R.; van der Marel, G. A.; van Boom,
J. H.; Blechert, S. Chem. Commun. 2000, 1501–1502.
(c) Stragies, R.; Blechert, S. J. Am. Chem. Soc. 2000, 122,
9584–9591. (d) Blechert, S.; Voigtmann, U. Org. Lett. 2000, 2,
3971–3974. (e) Blechert, S.; Voigtmann, U. Synthesis 2000,
893–898. (f) Zaminer, J.; Stapper, C.; Blechert, S. Tetrahedron
Lett. 2002, 43, 6739–6741. (g) Buschmann, N.; Ru¨ckert, A.;
Blechert, S. J. Org. Chem. 2002, 67, 4325–4329. (h) Stapper,
C.; Blechert, S. J. Org. Chem. 2002, 67, 6456–6460. (i) Ovaa,
H.; Stapper, C.; van der Marel, G. A.; Overkleeft, H. S.; van
Boom, J. H.; Blechert, S. Tetrahedron 2002, 58, 7503–7518.
(j) Blechert, S.; Stapper, C. Eur. J. Org. Chem. 2002,
2855–2858. (k) Blechert, S.; Randl, S. J. Org. Chem. 2003,
68, 8879–8882.
4.1.9. (20R,4S)-5-(10,20,30,60-Tetrahydro-pyridin-20-yl)-
pentane-1,2,4-triol 18.
A solution of 17 (150 mg,
0.42 mmol) in anhydrous THF (10 mL) was cooled to
278 8C under nitrogen atmosphere and 1.6 mL (1.6 mmol)
of 1 M sodium naphthalenide in THF was added dropwise.
The mixture was stirred for 30 min at this temperature and
then 10 mL of saturated NH4Cl aqueous solution was added.
The solution was left to warm up to room temperature and
the aqueous layer was extracted with ethyl acetate. The
organic layer was dried over Na2SO4 and concentrated to
give 67 mg (79% yield) of pure 18, as an oil: Rf (ethyl
1
acetate/MeOH 10:1, sat. NH4OH) 0.15; H NMR (CDCl3,
300 MHz) d 5.55–5.50 (2H, m), 3.90 (1H, m), 3.73 (1H, m),
3.56 (2H, m), 3.45 (1H, dd, J¼17.6, 2.5 Hz), 3.22 (1H, dd,
J¼17.6, 1.7 Hz), 3.15 (1H, m), 2.30 (4H, s, br), 2.05–1.10
(6H, m); HRMS calcd for C10H19NO3: 201.2678. Found:
201.2695. Anal. calcd for C10H19NO3: C, 59.68; H, 9.52; N,
6.96. Found: C, 59.72; H, 9.68; N, 6.77.
4. (a) Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda,
A. H. J. Am. Chem. Soc. 1997, 119, 1488–1489. (b) Harrity, J. P.
A.; La, D. S.; Cefalo, D. R.; Visser, M. S.; Hoveyda, A. H. J. Am.
Chem. Soc. 1998, 120, 2343–2351. (c) Adams, J. A.; Ford, J. G.;
Stamatos, P. J.; Hoveyda, A. H. J. Org. Chem. 1999, 64,
9690–9696. (d) Cefalo, D. R.; Kiely, A. F.; Wuchrer, M.;
Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2001, 123, 3139–3140.
4.1.10. (2R,9aR)-(1)-2-Hydroxy-quinolizidine 9. To a
solution of 18 (60 mg, 0.30 mmol) in dioxane/H2O 1:1
5. Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;

6442
G. Lesma et al. / Tetrahedron 60 (2004) 6437–6442
Harris, G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 42,
5709–5712.
8. (a) See Ref. 3(a). (b) Takahata, H.; Kubota, M.; Momose, T.
Tetrahedron Lett. 1997, 38, 3451–3454. (c) Takahata, H.;
Kubota, M.; Ikota, N. J. Org. Chem. 1999, 64, 8594–8601.
(d) Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276–11282.
6. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
7. (a) Micel, K.-H.; Sandberg, F.; Haglid, F.; Norin, T. Acta
Pharm. Suec. 1967, 4, 97. (b) Micel, K.-H.; Sandberg, F.;
Haglid, F.; Norin, T.; Chan, R. P. K.; Craig, J. C. Acta Chem.
Scand. 1969, 23, 3479.
9. Bohlmann, F.; Zeisberg, R. Chem. Ber. 1975, 108, 1043–1049.