A new approach for the asymmetric syntheses of 2-epi-deoxoprosopinine and azasugar derivatives

Article abstract of DOI:10.1016/j.tet.2005.09.112

A new approach to 2-epi-deoxoprosopinine 11, 1-deoxygulonojirimycin 7, and l-gulono-1,5-lactam 9 was described. The C-2 hydroxymethyl group was introduced regioselectively using SmI₂ mediated coupling of (S)-3- silyloxyglutarimide 13b with eith

Full text of DOI:10.1016/j.tet.2005.09.112

Tetrahedron 62 (2006) 190–198
A new approach for the asymmetric syntheses of
2-epi-deoxoprosopinine and azasugar derivatives
*
Bang-Guo Wei, Jie Chen and Pei-Qiang Huang
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, People’s Republic of China
Received 7 July 2005; revised 20 September 2005; accepted 23 September 2005
Available online 24 October 2005
Dedicated to, Professor Ben-Li Huang on the occasion of his 80th birthday
Abstract—A new approach to 2-epi-deoxoprosopinine 11, 1-deoxygulonojirimycin 7, and L-gulono-1,5-lactam 9 was described. The C-2
hydroxymethyl group was introduced regioselectively using SmI2 mediated coupling of (S)-3-silyloxyglutarimide 13b with either
chloromethyl benzyl ether 16a or the Beau–Skrydstrup reagent 16b, followed by debenzylation and highly cis-diastereoselective reductive
deoxygenation. Adoption of the Savoi’s chemoselective ring-opening alkylation method allowed a highly diastereoselective introduction of
the lipid side chain of 2-epi-deoxoprosopinine 11 in a straightforward manner. Dehydration followed by highly trans-diastereoselective
dihydroxylation led to polyoxygenated lactam derivative 27 as a key intermediate for the syntheses of 7 and 9.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
b-glucosidase;13 other d-lactams have been shown to be
glycosidase inhibitors.14 As a result, the synthesis of
azasugars and their synthetic analogs has attracted a great
deal of attention.12,15,16
2-Hydroxymethyl-3-piperidinol 1 is a salient structural
feature found in two classes of natural products, namely,
piperidine alkaloids1 and azasugars (or iminosugars).2
Several 2,3,6-trisubstituted piperidine alkaloids (e.g., pro-
sopinine 2 and prosophylline 3) have been isolated from the
leaves of the West African savanna tree Prosopis africana
Taub3 and from the leaves of Microcos philippinensis (Perk)
Burrett (Tiliaceae).4 These alkaloids and their deoxygen-
ated analogs (e.g., deoxoprosopinine 4 and deoxoprosophyl-
line 5) exhibit antibiotic, anesthetic, analgesic, and CNS
stimulating properties, and are of considerable pharmaceuti-
cal interest.5 Many synthetic approaches have thus been
developed.6,7 Moreover, many azasugars are inhibitors of
glycosidases and related enzymes, showing therapeutic
potential for the treatment of diseases related to metabolic
disorders such as diabetes, cancer, AIDS, and viral infec-
tions. For example, 1-deoxymannojirimycin (DMJ, 6) is a
mannosidase inhibitor;8 1-deoxygulonojirimycin9–12 (DGJ,
7) is a potent and selective inhibitor of fucosidases,12e–g
which was isolated from the back of Angylocalyx pynaertii
(Leguminosae);9 D-mannonolactam (8) is a powerful
inhibitor of rat epididymal a-mannosidases, and of apricot
As the part of our ongoing project aimed at the development
of 3-hydroxyglutarimides-based synthetic methodology,17
we wish to report herein a versatile approach to (2S,3S,6R)-
2-epi-deoxoprosopinine 11,18 L-1-deoxygulonojirimycin
7,12 and L-gulono-1,5-lactam 9.16
Keywords: Piperidine; Alkaloid; Hydroxymethylation; Diastereoselective
reaction; Regioselective reaction; Building block.
*
Corresponding author. Tel.: C86 592 218 0433; fax: C86 592 218 8054;
e-mail: pqhuang@xmu.edu.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.112

B.-G. Wei et al. / Tetrahedron 62 (2006) 190–198
191
2. Results and discussion
hydroxymethyl group in a regio- and diastereo-selective
manner. For example, in the presence of a catalytic amount
of mercury chloride(II),22 addition of benzyloxymethyl
magnesium chloride, derived from commercially available
benzyl chloromethyl ether (16a) with 13a, yielded two
regioisomers 14a and 15a in disappointing 1:1 ratio
(Scheme 2). Reaction of the Beau–Skrydstrup benzyloxy-
methylation reagent23 16b with 13a gave once again a 1:1
regioisomeric mixture, albeit in higher combined yield
(84%).
As depicted retrosynthetically in Scheme 1, our approach
featured, firstly, the use of protected (5S,6S)-5-hydroxy-6-
hydroxymethyl-2-piperidinone 12 as a common intermedi-
ate to 11, 9, and 7. The presence of the amide functionality
would not only allow the introduction of the C-6 side chain
of the Prosopis alkaloids as well as the two hydroxyl groups
of L-gulono-1,5-lactam 9 and 1-deoxygulonojirimycin 7, but
also allow its transformation into cyclic amidine sugars,
which demonstrated good to excellent inhibition toward
glycosidases.19 The second feature of the approach was the
installation of the hydroxymethyl group by a stepwise regio-
and diastereo-selective reductive hydroxymethylation pro-
cedure (13/12). The introduction of the C-6 side chain in
the piperidine ring (12/11) by a straightforward method
constituted the third feature of the approach.
After several unsuccessful attempts, including performing
the reaction at lower temperature and using less reactive
chloromethyl benzyl ether (16a)—SmI220c–f as a benzyloxy-
methylation system, we were delighted to find that the
benzyloxymethylation of O-tert-butyldimethylsilyl pro-
tected 3-hydroxyglutarimide 13b provided better results.
Thus, when a 1:1.2 mixture of glutarimide 13b and benzyl
chloromethyl ether 16a was treated with 3 molar equiv of a
freshly prepared solution of SmI2 (0.1 M in THF) at rt for
10 min, the C-2 addition product 14b and the C-6 addition
regioisomer 15b were obtained in a ratio of 81:19 with a
combined yield of 84%. Similar treatment of 13b with the
Beau–Skrydstrup reagent 16b gave similar C-2/C-6 regio-
selectivity (82:18) and slightly higher combined yield
(87%).
The observed protecting group effect (TBS vs Bn) on the
regioselectivity of the SmI2 mediated Barbier type
benzyloxymethylation of 13a/13b was contrary to the
Grignard reagents addition to malimides, where the
O-benzyl protected malimide gave excellent C-2 regio-
selectivity, whereas the O-TBS protected malimide gave
nearly 1:1 C-2/C-5 regioselectivity.24 The regioselectivity
observed during the benzyloxymethylation of 13b might be
attributed to the oxyphilicity of the samarium(III) species,
which formed a five-membered chelating structure, and
polarized the Si–O bond, thus rending the Si/I interaction
via a four-membered chelating structure plausible (Fig. 1).
In such a manner, the steric hindrance of the TBS group was
recompensed and consequently the C-2 carbonyl was
activated.
Scheme 1.
Our first task was the introduction of a hydroxymethyl
group20,21 to the C-2 position of protected 3-hydroxyglutar-
imides 13. Although the stepwise reductive alkylation of
13a with un-functionalized Grignard reagents has been
demonstrated to proceed with high C-2 regioselectivity and
high trans-diastereoselectivity,17a,c considerable difficulties
were encountered in attempts to introduce a protected
Scheme 2.

192
B.-G. Wei et al. / Tetrahedron 62 (2006) 190–198
Figure 1.
With the N,O-acetal 14b in hand, we then investigated its
reductive deoxygenation. Much to our surprise, when 14b
was subjected to ionic hydrogenation conditions (BF3$OEt2,
Et3SiH, CH2Cl2, K78 8C to rt), only the starting material
was recovered (Scheme 3). Even after heated to 40 8C for
3 days, only 5% of the desired product was isolated. Other
ionic hydrogenation conditions led to either dehydrated
product 17 (TiCl4, Et3SiH, K78 8C to rt)25 or ring-opening
product 18 (NaBH3CN, at pH 3, rt).26 It was envisioned that
the failure to perform the reductive deoxygenation might be
due to the steric hindrance of the N,O-acetal 14b. To test this
hypothesis, the benzyl group was cleaved (1 atm H2, 10%
Pd/C, rt, 8 h), and the resulted N,O-semiacetal 19 was
subjected to BF3$OEt2 mediated Et3SiH reduction. In such a
manner, the desired product 20 was obtained in 57% yield,
with a diastereoselectivity of 93:7. The stereochemistry of
the major diastereomer 20 was assigned as cis12,15,16,18,27 by
comparing with the known (5S,6R)-trans-20.28
Figure 2.
The next stage for the synthesis of 2-epi-deoxoprosopinine
11 was the introduction of the C-6 side chain in a cis-
diastereoselective manner. Most known methods for the cis-
diastereoselective installation of a C-6 side chain in a
2-substituted piperidine ring involve a-amidoallylation of
an appropriate piperidine N,O-acetal with allyltrimethyl-
silane, followed by multistep chain elongation manipula-
tion.7f–h A direct method, however, was required to prepare
the nucleophilic allylic silane C12 side chain in several
steps.7a Keeping in mind that the 2,6-cis-stereochemistry
was also a key structural feature found in prosophylline,
micropine, cassine, spectaline, azmic acid, canavaline, and
other 3-piperidinol alkaloids,1 it was desirable to develop a
flexible method enabling the diastereoselective introduction
of different C-6 side chains in a straightforward manner.
In this context, Savoia’s flexible organometallic ring-
opening method31 appeared to be promising. This turned
out to be true, when N-Boc activated d-lactam 22, prepared
from cis-20 via successive O-silylation (TBSCl, DMAP,
imid., DMF, rt, 12 h, 92%), CAN mediated cleavage of
PMB group (CAN, MeCN/H2O 9:1, 0 8C to rt, 4 h), and
lactam activation ((Boc)2O, n-BuLi, K78 8C, 0.5 h), was
treated with a solution of n-C12H25MgBr in THF at K78 8C
for 3 h, then at K40 8C for 40 min, the desired ketone 23
was obtained in 70% yield based on the recovered starting
material (81% conversion) (Scheme 4). N-Deprotection
with TFA, followed by treating with a 30% NaOH solution
led to cyclic imines 24 (containing partially desilylated
products), which, without purification, was hydrogenated
(H2, l atm, 20% Pd(OH)2, EtOH/concd HCl 10:1, rt, 30 h)7j,s
under acidic conditions to provide (C)-2-epi-deoxopro-
sopinine 11 (51% overall yield from 23) as a single
diastereomer {[a]D20C3.0 (c 0.6, CH3OH); lit.18 [a]D26C2.7
(c 1.0, CH3OH)}. The spectroscopic and physical data of the
synthetic product were identical with those reported.18
Noteworthy was that starting from the keto-amide 23, the
deprotection of t-Boc and two TBS protective groups,
cyclisation, and hydrogenation were accomplished without
chromatographic separation of the intermediates. The
stereochemistry of the newly formed chiral center in 11
was ascertained by comparing with the known compound.18
Scheme 3.
The stereochemical course of the reductive deoxygenation
of 19 deserved comments. The fact that the reductive
deoxygenation of a diastereomeric mixture of 19 led to
preponderant formation of a diastereomer, implicating that
the transformation involved an N-acyliminium intermedi-
ate17 (A/B) (Fig. 2). Among the two possible conformers A
and B, A1,2 interaction and A1,3 interaction29 existed in the
conformers A and B, respectively. Possible interactions
between and FwSi would compensate for the unfavorable
A1,2 interaction existed in A, rending thus conformer A the
more favored one. Subsequent nucleophilic attack of a
hydride was expected to take place from the axial direction
owing to the stereoelectronic effects.30 Thus, starting from
the more stable conformer A, a hydride approached from the
b-face of the ring, leading to the more stable chair
conformer (cis-20).
As regarding the stereochemical course7l of the reaction, in
the light of the preponderant formation of the cis-isomer, it
was reasonable to assume that among two possible

B.-G. Wei et al. / Tetrahedron 62 (2006) 190–198
193
Scheme 4.
conformers C and D (Fig. 3), conformer C predominated
over D due to an intramolecular hydrogen bond. The
stereoelectronic controlled axial attack of hydrogen occured
from the b-face of C leading to the desired product 11 with
chair conformation, where the formation of intramolecular
hydrogen bonds was possible.
Diastereoselective dihydroxylation11b,15d,33 of 26 was
achieved by treating with OsO4 (cat)-NMMO system in a
mixed solvent system (t-BuOH-H2O 3:1, rt, 3 h) to give 27
(yield: 75%) as the only isolable product. Lactam 27 can be
easily converted, via deprotection and/or reduction, to
azasugars 7, 9 and other analogous, such as (2R,3R,4S,5S)-
trihydroxypipecolic acid d-lactam derivative 282/b
,
according to the known procedures.11b,12g,15a,15e,27b
3. Conclusion
In summary, taking advantages of the multifunctionality of
the TBS protected 3-hydroxyglutarimide 13b and the
protecting group effect, we were able to introduce both
the C-2 hydroxymethyl group and the C-6 side chain in good
regioselectivity (C-2/C-6 81:19) and in excellent diastereo-
selectivities (C-2/C-3 93:7; C-2/C-6 100:0). Using a
Grignard reagent as a carbon nucleophile to introducing
the C-6 side chain made this method flexible, this would find
applications in the synthesis of other piperidine alkaloids.
Figure 3.
Having accomplished the synthesis of (C)-2-epi-deoxopro-
sopinine, wethenturnedourattentiontoexplore anentranceto
7 and 9. Thus, successive treatment of lactam 12a with LDA
(THF, K78 8C) and phenylselenium bromide yielded the
a-phenylselenide derivative of 12a,32 which without purifi-
cation, was subjected to H2O2 oxidation in wet CH2Cl2 at rt to
give directly 26 in 58% overall yield from 12a (Scheme 5).
4. Experimental
4.1. General methods
Melting points are uncorrected. Optical rotations were
recorded on an automatic polarimeter. IR spectra
were recorded on a FT-IR spectrophotometer. NMR spectra
wererecordedinCDCl3 (1Hat500 MHzand13Cat125 MHz),
and chemical shifts were expressed in parts per million (d)
relative to internal Me4Si. HRESIMS spectra were recorded
on a FTMS apparatus. Silica gel (300–400 mesh) was used for
column chromatography, eluting (unless otherwise stated)
with ethyl acetate/petroleum ether (PE) (60–90 8C) mixture.
Dichloromethane, DMF, and diisopropylamine were distilled
over calcium hydride under N2. Ether and THF were distilled
over sodium benzophenone ketyl under N2.
4.1.1. (5S,6S)-5-(tert-Butyldimethylsilyloxy)-6-(hydroxy-
methyl)-1-(4-methoxybenzyl)piperidin-2-one (20).
Method 1. To a mixture of 13b (1.452 g, 4.0 mmol)
Scheme 5.

194
B.-G. Wei et al. / Tetrahedron 62 (2006) 190–198
and benzyloxymethyl chloride 16a (60% purity, 1.2 mL, ca.
12 mmol) in anhydrous THF (10 mL) was quickly added a
HRESIMS calcd for (C20H33NO5SiCNa): 418.2026, found:
418.2025.
34
freshly prepared THF solution of SmI2 (12 mmol,
120 mL) under an argon atmosphere at rt. After stirring
for 45 min at rt, saturated NH4Cl (10 mL) was added. The
clear solution was poured into ether (200 mL), and the solid
was washed successively with ether (30 mL!3). The
combined organic layers were washed with saturated
aqueous NH4Cl (30 mL!3) and brine (30 mL!3), dried
over anhydrous Na2SO4, filtered and concentrated. The
residue was purified by chromatography on silica gel
(EtOAc/PE) to give 14b (C-2 addition regioisomer,
1.319 g, yield: 67%) and 15b (C-5 addition regioisomer,
304 mg) both as inseparable diastereomeric mixtures.
To a mixture of diastereomeric 19 (3.618 g, 9.16 mmol) in
anhydrous CH2Cl2 (90 mL, 0.1 M) were added dropwise
Et3SiH (14.5 mL, 91.6 mmol) and BF3$OEt2 (2.8 mL,
23 mmol) at K78 8C under a N2 atmosphere. The reaction
mixture was allowed to warm to rt and stirred for 5–7 h. The
reaction was quenched by addition of a saturated aqueous
NaHCO3. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (20 mL!2). The
combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by chromato-
graphy on silica gel (EtOAc/PE) to yield 20 (1.978 g, yield:
57%) as a colorless solid. Mp 108–109 8C (CHCl3). [a]2D0K
66.8 (c 0.7, CH3OH). IR (film) n: 3409, 2955, 2926, 2855,
Method 2. Following the same procedure as described
above, treatment of 13b with the Beau–Skrydstrup reagent
16b23 for 10 min at rt gave 14b and 15b in 82:18 ratio with a
combined yield of 87%.
1611, 1512, 1463, 1248, 1105, 1034 cmK1 1H NMR
.
(500 MHz, CDCl3) d: 7.22–7.18 (m, 2H, Ar-H), 6.86–6.82
(m, 2H, Ar-H), 5.27 (d, JZ14.5 Hz, 1H, NCH2), 4.04 (ddd,
JZ4.2, 4.9, 10.3 Hz, 1H, H-5), 3.96–3.92 (m, 1H, CH2O),
3.95 (d, JZ14.5 Hz, 1H, NCH2), 3.80 (s, 3H, OCH3), 3.78–
3.73 (m, 1H, CH2O), 3.37 (ddd, JZ3.4, 4.2, 7.8 Hz, 1H,
H-6), 2.91 (br s, 1H, OH), 2.64 (ddd, JZ3.9, 7.7, 18.2 Hz,
1H, H-3), 2.48 (ddd, JZ8.0, 8.8, 18.2 Hz, 1H, H-3), 2.14–
2.06 (m, 1H, H-4), 1.91–1.85 (m, 1H, H-4), 0.88 (s, 9H,
Major diastereomer of 14b. Colorless oil. [a]2D0K5.6 (c 1.0,
CHCl3). IR (film) n: 3528, 3364, 2952, 2929, 1651, 1513,
1
1402, 1246, 1101 cmK1. H NMR (500 MHz, CD3CN) d:
7.42–7.20 (m, 7H, Ar-H), 6.82–6.78 (m, 2H, Ar-H), 4.64 (d,
JZ15.5 Hz, 1H, NCH2), 4.49 (d, JZ15.5 Hz, 1H, NCH2),
4.44 (d, JZ11.7 Hz, 1H, OCH2), 4.26–4.24 (m, 1H, H-5),
4.25 (d, JZ11.7 Hz, 1H, OCH2), 3.76 (s, 3H, OCH3), 3.82
(s, 1H, OH, exchangeable), 3.58 (s, 2H, BnCH2O), 2.56
(ddd, JZ6.6, 9.5, 17.7 Hz, 1H, H-3), 2.29 (ddd, JZ5.2, 6.2,
17.7 Hz, 1H, H-3), 2.16–2.10 (m, 1H, H-4), 1.98–1.92 (m,
1H, H-4), 0.96 (s, 9H, t-Bu–H), K0.32 (s, 3H, SiCH3),
K0.41 (s, 3H, SiCH3). 13C NMR (125 MHz, CD3CN) d:
171.2 (C]O), 159.2 (Ar), 139.2 (Ar), 133.4 (Ar), 129.4
(Ar), 129.0 (Ar), 128.7 (Ar), 128.6 (Ar), 118.4 (4C, Ar),
114.3 (Ar), 88.0 (C-6), 73.7 (C-5), 71.9 (CH2O), 70.6
(CH2O), 55.8 (OCH3), 44.2 (NCH2), 28.4 (C-3), 26.2 (C-4),
24.8 (3C, t-BuC), 18.7 (SiC), K4.09 (SiCH3), K4.86
(SiCH3). MS (ESI): 486 (MCHC, 100). HRESIMS calcd
for (C27H39NO5SiCNa): 508.2495, found: 508.2491.
t-Bu–H), K0.23 (s, 3H, SiCH3), K0.36 (s, 3H, SiCH3). 13
C
NMR (125 MHz, CDCl3) d: 169.5 (C]O), 159.1 (Ar),
129.3 (3C, Ar), 114.1 (2C, Ar), 69.7 (OCH2), 60.7 (C-5),
59.0 (C-6), 55.3 (OCH3), 47.8 (NCH2), 28.8 (C-3), 26.2
(C-4), 25.7 (3C, t-BuC), 17.9 (SiC), K4.8 (SiCH3), K5.3
(SiCH3). MS (ESI): 380 (MCHC, 100). HRESIMS calcd
for (C20H34NO4SiCH): 380.2257, found: 380.2249.
4.1.2. (5S,6S)-5-(tert-Butyldimethylsilyloxy)-6-[(tert-
butyldimethylsilyloxy)methyl]-1-(4-methoxybenzyl)
piperidin-2-one (12a). To a mixture of cis-20 (1.960 g,
5.17 mmol), imidazole (703 mg, 10.34 mmol) and a
catalytic amount of DMAP in anhydrous DMF (15 mL)
was added a solution of tert-butyldimethylchlorosilane
(930 mg, 6.20 mmol) in anhydrous DMF (5 mL). After
being stirred at rt for 12 h, water (20 mL) was added, and
the mixture was extracted with Et2O (30 mL!3). The
combined organic layers were washed with brine (10 mL!3),
dried over anhydrous Na2SO4, filtered, and concentrated.
The residue was purified by chromatography on silica gel
(EtOAc/PE) to give 12a (2.341 g, yield:92%) as a colorless
oil. [a]2D0K51.9 (c 1.0, CHCl3). IR (film) n: 2954, 2929,
To a suspension of 10% Pd/C (1.1 g, 30%) in EtOH (5 mL)
was added a solution of diastereomeric 14b (3.811 g,
7.86 mmol) in EtOH (30 mL) under a H2 atmosphere at rt.
After stirring for 8 h, the mixture was filtered and
concentrated. The residue was purified by chromatography
on silica gel (EtOAc/PE) to give 19 as an inseparable
mixture (2.794 g, yield: 90%).
Major diastereomer of 19. Colorless solid. Mp 111–112 8C
(CH3OH). [a]2D0K71.4 (c 1.0, CH3OH). IR (film) n: 3410,
2857, 1650, 1512, 1462, 1250, 1116 cmK1 1H NMR
.
2956, 2929, 2855, 1625, 1512, 1463, 1246, 1105, 1034 cmK1
.
(500 MHz, CDCl3) d: 7.18 (d, JZ8.6 Hz, 2H, Ar-H), 6.85
(d, JZ8.7 Hz, 2H, Ar-H), 5.35 (d, JZ14.7 Hz, 1H, NCH2),
3.98 (d, JZ14.7 Hz, 1H, NCH2), 3.90 (dd, JZ4.6, 10.5 Hz,
1H, CH2O), 3.87–3.84 (m, 2H, H-6 and CH2O), 3.80 (s, 3H,
OCH3), 3.19 (m, 1H, H-5), 2.62 (ddd, JZ2.6, 8.2, 18.3 Hz,
1H, H-3), 2.47 (ddd, JZ8.5, 9.1, 18.3 Hz, 1H, H-3), 2.09–
2.01 (m, 1H, H-4), 1.82–1.74 (m, 1H, H-4), 0.92 (s, 9H,
t-Bu), 0.84 (s, 9H, t-Bu), 0.38 (s, 6H, SiCH3), 0.16 (s, 6H,
SiCH3). 13C NMR (125 MHz, CDCl3) d: 169.8 (C]O),
158.9 (Ar), 129.8 (Ar), 129.3 (2C, Ar), 113.9 (2C, Ar), 67.7
(C-5), 60.4 (CH2O), 55.3 (OCH3), 47.9 (NCH2), 29.4 (C-5),
27.0 (C-4), 25.8 (3C, t-Bu), 25.6 (3C, t-Bu), 18.1 (SiCMe3),
17.9 (SiCMe3), K4.9 (SiCH3), K5.2 (SiCH3), K5.6 (2C,
1H NMR (500 MHz, CDCl3) d: 7.30–7.20 (m, 2H, Ar-H),
6.84–6.78 (m, 2H, Ar-H), 4.71 (d, JZ15.5 Hz, 1H, NCH2),
4.62 (d, JZ15.5 Hz, 1H, NCH2), 4.23–4.22 (m, 1H, H-5),
3.80 (s, 3H, OCH3), 3.61–3.52 (m, 3H, CH2O and OH),
2.73–2.66 (m, 1H, H-3), 2.47–2.40 (m, 1H, H-3), 2.12–2.07
(m, 1H, H-4), 1.99–1.94 (m, 1H, H-4), 1.92 (br s, 1H, OH),
0.86 (s, 9H, t-Bu–H), K0.35 (s, 3H, SiCH3), K0.47 (s, 3H,
SiCH3). 13C NMR (125 MHz, CD3CN) d: 170.9 (C]O),
158.5 (Ar), 131.8 (Ar), 128.1 (2C, Ar), 114.0 (2C, Ar), 87.5
(C-6), 68.2 (CH2O), 63.7 (C-5), 55.2 (OCH3), 43.2 (NCH2),
27.1 (C-3), 25.6 (C-4), 23.9 (3C, t-BuC), 17.9 (SiC), K4.4
(SiCH3), K5.3 (SiCH3). MS (ESI): 396 (MCHC, 100).

B.-G. Wei et al. / Tetrahedron 62 (2006) 190–198
195
SiCH3). MS (ESI): 494 (MCHC, 100). HRESIMS calcd for
(C26H47NO4Si2CNa): 516.2941, found: 516.2939.
4.1.5. tert-Butyl [(2S,3S)-1,3-bis(tert-butyldimethylsilyl-
oxy)-6-oxo-octadecan]-2-yl carbamate (23). To a solution
of 22 (105 mg, 0.22 mmol) in anhydrous THF (10 mL) was
added n-C12H25MgBr (0.289 mmol) at K78 8C. After being
stirred for 3 h at K78 8C, the reaction was allowed to warm
to K40 8C and stirred for 40 min. The mixture was
quenched with a saturated aqueous NH4Cl (2 mL), diluted
with EtOAc (10 mL) and brine (5 mL). The organic layer
was separated and the aqueous phase was extracted with
EtOAc (10 mL!3). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated.
The residue was purified by chromatography on silica gel
(EtOAc/PE) to give 23 (81 mg) in 70% yield based on the
recovered starting 22 (20 mg). Compound 23: colorless oil.
[a]2D0C8.2 (c 0.9, CHCl3). IR (film) n: 3450, 2927, 2855,
1718, 1491, 1471, 1365, 1254, 1171, 1101 cmK1. 1H NMR
(500 MHz, CDCl3) d: 4.70 (d, JZ8.5 Hz, 1H, NH), 3.93
(dd, JZ5.7, 7.8 Hz, 1H, CH2O), 3.55–3.53 (m, 2H,
CHOTBS and CH2O), 3.45–3.41 (m, 1H, NCHCH2O),
2.46–2.33 (m, 4H, CH2COCH2), 1.77–1.69 (m, 2H), 1.56
(m, 4H), 1.42 (s, 9H, t-Bu–H), 1.24 (m, 20H), 0.96 (s, 18H,
t-Bu–H), 0.40 (s, 6H, SiCH3), K0.2 (s, 6H, SiCH3). 13C
NMR (125 MHz, CDCl3) d: 204.6 (C]O) 155.9 (C]O),
79.2 (Boc t-C), 69.0 (C–TBS), 61.8 (CH2O), 53.7 (C–HCH),
43.0 (COCH2), 38.4 (COCH2), 31.9 (COCH2CH2
CHOTBS), 29.6 (2C), 29.5 (2C), 29.4, 29.3, 29.2, 28.4
(3C, t-BuC), 28.0, 25.9 (3C, t-BuC), 25.8 (3C, t-BuC), 23.9,
22.7, 18.1 (2C, SiCMe3), 14.1 (CH3), K4.3 (SiCH3), K4.9
(SiCH3), K5.3 (SiCH3), K5.4 (SiCH3). MS (ESI): 644
(MCHC). HRESIMS calcd for (C35H74NO5Si2CH):
644.5106, found: 644.5094, calcd for (MCNa): 666.4925,
found: 666.4903.
4.1.3. (5S,6S)-5-(tert-Butyldimethylsilyloxy)-6-[(tert-
butyldimethylsilyloxy)methyl]piperidin-2-one (21). To a
solution of 12a (1.228 g, 2.49 mmol) in CH3CN (90 mL,
0.025 M) and H2O (10 mL) was added CAN (6.822 g,
12.45 mmol) in one portion. The mixture was stirred at 0 8C
to rt for 4 h. To the resulting mixture was added H2O
(30 mL) and the mixture was extracted with EtOAc
(40 mL!3). The combined organic layers were succes-
sively washed with saturated aqueous NaHCO3 (20 mL!3)
and brine (20 mL!2). The organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated. The residue
was purified by chromatography on silica gel (EtOAc/PE) to
give 21 (594 mg, yield: 64%) as a colorless oil. [a]2D0K23.8
(c 0.9, CHCl3). IR (film) n: 3231, 2947, 1652, 1504, 1458,
1
1246, 1107 cmK1. H NMR (500 MHz, CDCl3) d: 5.96 (br
s, 1H, N-H), 4.06–4.00 (m, 1H, H-5), 3.66–3.59 (m, 2H,
OCH2), 3.43 (ddd, JZ3.2, 4.0, 8.4 Hz, 1H, H-6), 2.56 (ddd,
JZ6.4, 12.5, 18.1 Hz, 1H, H-3), 2.29 (ddd, JZ2.1, 5.8,
18.1 Hz, 1H, H-3), 1.94–1.88 (m, 1H, H-4), 1.83–1.77 (m,
1H, H-4), 0.86 (s, 18H, t-Bu), 0.32 (s, 12H, SiCH3). 13C
NMR (125 MHz, CDCl3) d: 171.3 (C]O), 64.3 (C-5), 64.1
(CH2O), 58.8 (C-6), 28.1 (C-3), 26.4 (C-4), 25.8 (3C, t-Bu),
25.6 (3C, t-Bu), 18.2 (SiCMe3), 18.0 (SiCMe3), K4.5
(SiCH3), K5.2 (SiCH3), K5.5 (2C, SiCH3). MS (ESI): 374
(MCHC). HRESIMS calcd for (C18H40NO3Si2CH):
374.2547, found: 374.2538.
4.1.4. tert-Butyl [(2S,3S)-3-(tert-butyldimethylsilyloxy)-
2-[(tert-butyldimethylsilyloxy)methyl]-6-oxo-piperidin-
1-yl] carboxylate (22). To a solution of 21 (242 mg,
0.65 mmol) in anhydrous THF (8 mL) was added n-BuLi
(1.6 M in hexane, 0.40 mL, 0.63 mmol) at K78 8C. After
being stirred at K78 8C for 10 min, a solution of Boc2O
(0.23 mL, 0.97 mmol) in anhydrous THF (2 mL) was added
dropwise. After being stirred for 30 min at the same
temperature, the mixture was quenched with saturated
aqueous NH4Cl (2 mL), diluted with EtOAc (10 mL) and
brine (5 mL). The organic layer was separated and the
aqueous phase was extracted with EtOAc (10 mL!3). The
combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified
by chromatography on silica gel (EtOAc/PE) to give 22
(275 mg, yield:90%) as a colorless oil. [a]2D0C25.8 (c 0.9,
CHCl3). IR (film) n: 2954, 2930, 2858, 1775, 1720, 1471,
4.1.6. (C)-2-epi-Deoxoprosopinine (11). Trifluoroacetic
acid (1 mL) was added dropwise to 23 (120 mg,
0.187 mmol) at 0 8C, and the resulting solution was stirred
at rt for 3 h. To the reaction mixture was added, at 0 8C, a
30% aqueous sodium hydroxide until pH was 11–12. The
resulting mixture was extracted with ether (20 mL!3),
washed with brine, dried over anhydrous Na2SO4, filtered,
and concentrated. The crude product, without further
purification, was dissolved in EtOH (4 mL), to which was
added 20% Pd(OH)2/C (60 mg) under H2 atmosphere
(1 atm). After being stirred for 2 h, concd HCl (0.4 mL)
was added and the mixture was stirred for 28 h. The reaction
mixture was filtered, washed with MeOH, and concentrated
in vacuum. The residue was dissolved in water (5 mL) and
extracted with ether (6 mL). The aqueous layer was basified
by addition of 1 N NaOH solution and extracted thoroughly
with CHCl3 (10 mL!5). The combined extracts were dried
over anhydrous Na2SO4, filtered, and concentrated in
vacuum. The residue was purified by chromatography on
silica gel (CHCl3/MeOH/NH3$H2O 100:15:2) to give 11
(28 mg, yield:51%) as a colorless solid. Mp 56–57 8C (Et2O/
MeOH) [lit.18mp 59 8C (acetone/pentane)]. [a]2D0C3.0 (c
0.6, CH3OH) {lit.18 [a]D26C2.7 (c 1.0, CH3OH)}. IR (film) n:
1
1367, 1294, 1253, 1160, 1115 cmK1. H NMR (500 MHz,
CDCl3) d: 4.08 (dd, JZ5.2, 10.4 Hz, 1H, CH2O), 4.06–4.04
(m, 1H, H-5), 3.90–3.89 (m, 1H, H-6), 3.83 (dd, JZ4.2,
10.4 Hz, 1H, CH2O), 2.54–2.42 (m, 2H, H-3), 2.28–2.22
(m, 1H, H-4), 1.77–1.73 (m, 1H, H-4), 1.52 (s, 9H, t-Bu–H),
0.96 (s, 9H, t-Bu–H), 0.87 (s, 9H, t-Bu–H), 0.40 (s, 6H,
SiCH3), K0.20 (s, 6H, SiCH3). 13C NMR (125 MHz,
CDCl3) d: 171.2 (C]O), 153.1 (C]O), 82.6 (Boc t-C),
67.6 (C-5), 59.7 (CH2O), 59.0 (C-6), 33.0 (C-4), 28.0 (C-3),
25.9 (3C, t-Bu–C), 25.7 (3C, t-BuC), 25.7 (3C, t-BuC), 18.2
(SiCMe3), 18.0 (SiCMe3), K4.6 (SiCH3), K4.9 (SiCH3),
K5.8 (SiCH3), K5.9 (SiCH3). MS (ESI): 496 (MCNaC,
100). HRESIMS calcd for (C23H47NO5Si2CNa): 496.2890,
found: 496.2891.
1
3341, 3239 cmK1. H NMR (500 MHz, CD3OD) d: 3.84–
3.82 (m, 1H, H-3), 3.67–3.60 (m, 2H, CH2OH), 2.76–2.74
(m, 1H, H-2), 2.62–2.58 (m, 1H, H-6), 1.91–1.86 (m, 1H, H-
4), 1.64–1.38 (m, 3H, H-4 and H-5), 1.39–1.22 (m, 22H),
0.89 (t, JZ6.7 Hz, 3H, CH3). 13C NMR (125 MHz,
CD3OD) d: 66.2 (C-3), 64.7 (CH2OH), 61.1 (C-2), 56.9
(C-6), 36.8, 31.9, 31.8, 29.7–29.4 (7C), 26.2, 25.8, 22.7,

196
B.-G. Wei et al. / Tetrahedron 62 (2006) 190–198
14.1. MS (ESI): (MCHC, 100). HRESIMS calcd for
(C18H37NO2CH): 300.2903, found: 300.2922.
CH2O), 3.80–3.75 (m, 1H, H-6), 3.57 (dd, JZ5.5, 10.7 Hz,
1H, CH2O), 0.90 (s, 9H, t-Bu–H), 0.86 (s, 9H, t-Bu–H),
0.22 (s, 6H, SiCH3), K0.20 (s, 6H, SiCH3). 13C NMR
(125 MHz, CDCl3) d: 172.0 (C]O), 158.9 (Ar), 128.8 (2C,
Ar), 128.4 (Ar), 114.0 (2C, Ar), 70.9, 70.3, 67.1, 60.9, 59.3,
55.3, 47.9, 25.8 (3C, t-Bu), 25.7 (3C, t-Bu), 18.2 (SiCMe3),
17.9 (SiCMe3), K4.7 (SiCH3), K5.4 (SiCH3), K5.5
(SiCH3), K5.5 (SiCH3). HRESIMS calcd for (C26H48NO6-
Si2CH): 526.3020, found: 526.3010.
4.1.7. (5S,6S)-5-(tert-Butyldimethylsilyloxy)-6-[(tert-
butyldimethylsilyloxy)methyl]-1-(4-methoxybenzyl)-5,6-
dihydropyridin-2(1H)-one (26). To a freshly prepared
solution of LDA (0.34 mmol, 1.4 mL THF) was added
dropwise a solution of 12a (80 mg, 0.23 mmol) in THF
(0.8 mL) at K78 8C, and the mixture was stirred at the same
temperature for 1.5 h. To the resulting mixture was added a
THF solution (0.8 mL) of PhSeBr (76 mg, 0.32 mmol), and
the mixture was stirred at K78 8C for 5 h. The mixture was
poured into a saturated aqueous NaHCO3 (2 mL) and
extracted with EtOAc (4 mL!3). The combined organic
layers were washed successively with water (3 mL!2) and
brine (3 mL!2), dried over Na2SO4, filtered and concen-
trated in vacuum. To a solution of the residue in wet CH2Cl2
(4 mL containing 0.01 mL of H2O) was added a solution of
30% H2O2 (0.06 mL, 0.49 mmol). After stirred for 1 h, a
second portion of H2O2 (0.45 mL, 3.69 mmol) was added
and the stirring was continued for another 1 h. The resulting
mixture was quenched with water (2 mL). The organic
phase was separated, and the aqueous layer was extracted
with CH2Cl2 (4 mL!3). The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuum.
The residue was purified by chromatography on silica gel
(EtOAc/PE) to give 26 (45 mg, yield: 58%) as a colorless
oil. [a]2D0C4.5 (c 1.1, CHCl3). IR (film) n: 2957, 2926, 2854,
1677, 1607, 1506, 1252 cmK1. 1H NMR (500 MHz, CDCl3)
d: 7.20–6.80 (m, 5H, Ar-H), 6.15 (d, JZ10.0 Hz, 1H, H-3),
5.76 (dd, JZ2.2, 10.0 Hz, 1H, H-4), 5.41 (d, JZ14.8 Hz,
1H, NCH2), 4.60–4.56 (m, 1H, H-5), 3.98 (d, JZ14.8 Hz,
1H, NCH2), 3.97–3.89 (m, 2H, CH2O), 3.76 (s, 3H, OCH3),
3.38–3.33 (m, 1H, H-6), 0.87 (s, 9H, t-Bu), 0.78 (s, 9H,
t-Bu), 0.01 (s, 6H, SiCH3), K0.09 (s, 6H, SiCH3). 13C NMR
(125 MHz, CDCl3) d: 163.0 (C]O), 158.9 (Ar), 143.2
(C-4), 130.6 (Ar), 129.4 (2C), 123.7 (C-3), 113.9 (Ar) 67.7
(C-5), 61.5 (CH2O), 60.8 (C-6), 55.3 (OCH3), 48.7 (NCH2),
25.9 (3C, t-Bu), 25.6 (3C, t-Bu), 18.2 (SiCMe3), 18.0
(SiCMe3), K5.2 (SiCH3), K5.4 (SiCH3), K5.6 (2C, SiCH3).
HRESIMS calcd for (C26H46NO4Si2CH): 492.2965, found:
492.2962.
Acknowledgements
The authors are grateful to the NSF of China (20272048;
203900505) and the Ministry of Education (Key Project
104201) for financial support.
References and notes
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