A versatile approach to 6-substituted-5-methoxy-δ-lactam framework and application to the formal synthesis of (±)-homopumiliotoxin 223G

Article abstract of DOI:10.1016/j.tet.2004.09.001

Of the various 6-substituted-5-methoxy-δ-lactams 6 were synthesized from α-sulfonyl acetamide 9 in 4 steps in good yield. The key glutarimides 7 were obtained via facile [3+3] annulation. The method featured regioselective introduction of C-6 substituents in glutarimides 7. Synthesis of tribenzyl lactam 8 and the formal synthesis of (±)-homopumiliotoxin 223G were also reported. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.09.001

Tetrahedron 60 (2004) 10223–10231
A versatile approach to 6-substituted-5-methoxy-d-lactam
framework and application to the formal synthesis of
(G)-homopumiliotoxin 223G
*
Bo-Fong Chen, Min-Ruei Tasi, Cheng-Yu Yang, Jung-Kai Chang and Nein-Chen Chang
Department of Chemistry, National Sun Yat-Sen University, 70 Lien-hai Rd., Kaohsiung 804, Taiwan, ROC
Received 12 July 2004; revised 30 August 2004; accepted 1 September 2004
Abstract—Of the various 6-substituted-5-methoxy-d-lactams 6 were synthesized from a-sulfonyl acetamide 9 in 4 steps in good yield. The
key glutarimides 7 were obtained via facile [3C3] annulation. The method featured regioselective introduction of C-6 substituents in
glutarimides 7. Synthesis of tribenzyl lactam 8 and the formal synthesis of (G)-homopumiliotoxin 223G were also reported.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
lactam 8 was discussed (Fig. 2). Tribenzyl lactam 8 is a key
intermediate for the preparation of prosopinine 1, manno-
nolactam 2 and deoxymannojirimycin 3. The formal
synthesis of (G)-homopumiliotoxin 223G 4d was also
reported.
Naturally occurring 3-piperidinols and polyhydroxylated
piperidines such as prosopinine (1), mannonolactam (2),
deoxymannojirimycin (3) and homopumiliotoxins (4)
alkaloids (Fig. 1) have received much attention owing to a
variety of their biological activities.1 Numerous syntheses
of these classes of compounds have been reported.2,4
However, it is still desirable to develop a general synthetic
strategy that provides a common pivotal intermediate from
which 2,6-disubstituted piperidine-3-ol 5 can be derived. 6-
Substituted-5-hyrdoxy-d-lactams 6 have been reported as
precursors for the synthesis of 2,6-disubstituted piperidine-
3-ol 5.2c,k,r,u,3 In this paper, we described a new and versatile
approach to 6-substituted-5-methoxy-d-lactams 6 starting
from glutarimides 7 (Scheme 1). The synthesis of tribenzyl
2. Results and discussion
2.1. Synthesis of 5-methoxy-3-tolsyl glutarimides 7a and
7b
Glutarimide 7a was successfully prepared in just one step. It
was taken from a-sulfonyl acetamide 9a and ester 10 via
stepwise [3C3] cycloaddition5 in 80% yield. The stereo-
chemistry of 7a was established by X-ray analysis (Fig. 3).6
Figure 1.
Keywords: 3-Piperidinol; [3C3] Annulation; Regioselective reduction.
* Corresponding author. Tel.: C886 7 5252000 3914; fax: C886 7 5253913; e-mail: ncchang@mail.nsysu.edu.tw
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.001

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B.-F. Chen et al. / Tetrahedron 60 (2004) 10223–10231
was established by NMR spectra (Fig. 4). (3) Treatment of
13 with various nucleophiles in the presence of BF3–OEt2
furnished the corresponding N-benzyl-6-substituted-5-
methoxy-d-lactams 14a–14e as shown in Table 1.8 Attempts
Scheme 1.
Figure 2.
Figure 4. Meaningful NOE and coupling constants for 13.
to improve the stereoselectivity of the nucleophilic addition
with different substituent group at C-5 oxygen (i.e., Ac,
TBS) were failed. The stereochemical assignment of N-
benzyl-6-substituted-5-methoxy-d-lactams 14a–14e were
established by NOE studies and coupling constants. It is
noteworthy that the trans isomer 14b was obtained as the
only product when nucleophilic addition with propargyl
trimethylsilane was performed. The reason of not observing
cis-14b is not clear.
2.3. Preparation of tribenzyl lactam 8, a key
intermediate for the synthesis of prosopinine (1),
Figure 3. X-ray crystallography of 7a.
mannonolactam (2) and deoxymannojirimycin (3).2a,b
The reaction of propargyl trimethylsilane with dimethoxy d-
lactam 12 in the presence of BF3–OEt2 produced allene 15
as the only product. The stereochemistry of 15 was
established by NMR spectra (Fig. 5). Compound 15 was
transformed into hydroxymethyl product 16 by ozonolysis
followed by the reduction of the corresponding aldehyde
with NaBH4 in 76% yield in two steps. Subsequently, the
acetylation of primary alcohol with acetic anhydride
followed by demethylation of the resulting compound 17
with BBr3 and quenched with NaHCO3 provided alcohol 18.
After removing the sulfonyl group in compound 18 with
sodium amalgam, the resulting diol was subsequently
treated with sodium hydride and benzyl bromide. d-Lactam
8 was obtained from 18 in 51% yield (Scheme 4). The
spectroscopic data of 8 were identical with those reported in
the literature.2a,b
Scheme 2.
Following the same procedure, 7b was prepared from 9b in
73% yield (Scheme 2).
2.2. Regioselective introduction of C-6 substituents in 7a
With 7a in hand, the next step was to introduce substituent
regioselectively at C-6 position in 7a. Such introduction was
accomplished by the following procedures. (1) Reduction of
7a with LiAlH4 afforded hydroxy lactam 11.7 Without
purification, 11 was converted to 5,6-dimethoxy-d-lactam
12 in methanol solution in the presence of BF3–OEt2. (2)
Lactam 12 was desulfonated with sodium amalgam to
produce trans-5,6-dimethoxy-d-lactam 13 as N-acylimi-
nium ion precursor (Scheme 3). The stereochemistry of 13
2.4. Formal synthesis of (G)-homopumiliotoxin 223G
from 19
For the synthesis of homopumiliotoxin 223G, 7b was used
as starting material. Following the same procedures
described in Scheme 3, 19 was obtained in 61% yield
from 7b. In the presence of BF3–OEt2, 19 smoothly reacted
with allylsilane to yield the diallyl adduct 20 as a mixture of
1
three diastereomers (ca. 33:33:34 as judged by H NMR).
This unexpected result might due to part of the C-3
stereocenter epimerized under the reaction condition.
Therefore, three diastereoisomers were obtained instead of
two. Inasmuch as this mixture would converge to a single
compound 24, the diastereomers were not individually
isolated and characterized. The stage was thus set for
Scheme 3.

B.-F. Chen et al. / Tetrahedron 60 (2004) 10223–10231
Table 1. Treatment of 13 with various nucleophiles in the presence of BF3–OEt2
10225
Entry
1
Nucleophile
Product
(yield)a
cis 62%
trans 27%
2
3
71%
TMSCN
cis 26%
trans 55%
4
cis 41%
trans 43%
5
Et3SiH
96%
a
Isolated yields after column chromatography.
Figure 5. Meaningful NOE and coupling constants for 15.
hydroxy lactam 23 as a mixture of two isomers (ca. 30:70 as
judged by 1H NMR). After oxidation of 23 with Jones
reagent, the resulting ketone 24 underwent stereoselectively
1,2-addition with MeMgBr. The desired 25 was obtained as
the only product in the 74% yield (Scheme 5). The
spectroscopic data for 25 matched those reported in the
literature.4a The present work constitutes a formal synthesis
of (G)-homopumiliotoxin 223G.
Scheme 4. Preparation of d-lactam 8, a key intermediate for the synthesis of
prosopinine (1), mannonolactam (2) and deoxymannojirimycin (3).2a,b
3. Conclusion
In conclusion, the N-substituted-5-methoxy-3-tolsyl glutar-
imides 7 were synthesized in good yield. The glutarimides 7
are versatile intermediate for the preparation of 6-sub-
stituted-5-methoxy-d-lactam 6. These results were applied
to the preparation of d-lactam 8, which is a key intermediate
for the synthesis of prosopinine 1, mannonolactam 2 and
deoxymannojirimycin 3. Formal synthesis of (G)-homo-
pumiliotoxin 223G was also reported.
intramolecular metathesis. Exposure of mixture 20 to the
first-generation Grubbs’ catalyst at room temperature
cleanly provided a mixture of quinolizidinones 21 in 71%
yield. Subsequently, the hydrogenation of olefin followed
by demethylation of the resulting product with NaI and
TMSCl provided mixture 22. Removal of the sulfonyl
function was effected with sodium amalgam to afford

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B.-F. Chen et al. / Tetrahedron 60 (2004) 10223–10231
substituted-2-(toluene-4-sulfonyl)acetamide (2.0 mmol) 9a,
9b in THF (15 mL) was added to a rapidly stirred
suspension of sodium hydride (4.4 mmol, 60%) in THF
(10 mL). After the reaction mixture was stirred at room
temperature for 15 min, a,b-unsaturated ester 10
(6.0 mmol) was added. The resulting mixture was stirring
for 7 h at room temperature, quenched with NH4Cl (1 mL)
in an ice bath, and concentrated under reduced pressure. The
residue was diluted with water (5 mL) and extracted with
EtOAc (3!20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated. Purifi-
cation on silica gel chromatography (hexane/ethyl acetateZ
4/1–2/1) produced products.
For 7a. Yield 80%; white solid; mp 146.6 8C; IR (CHCl3,
cmK1) 1685; FAB-MS: C20H21NO5S m/z (%)Z91 (100),
137 (36), 154 (35), 388 (MCC1, 12); HRMS (FAB, MCC
1
1) Calcd for C20H22NO5S 388.1219, found 388.1216; H
NMR (500 MHz, CDCl3) d 7.65 (d, JZ8 Hz, 2H), 7.32 (d,
JZ8 Hz, 2H), 7.30–7.23 (m, 5H), 4.95 (d, JZ14.5 Hz, 1H),
4.88 (d, JZ14.5 Hz, 1H), 4.39 (dd, JZ4.5, 8.5 Hz, 1H),
4.31 (t, JZ6.5 Hz, 1H), 3.55 (S, 3H), 2.85 (ddd, JZ4.5, 6.5,
14.5 Hz, 1H), 2.52 (ddd, JZ6, 8.5, 14.5 Hz, 1H), 2.64 (S,
3H); 13C NMR (125 MHz, CDCl3) d 170.34, 164.22,
145.73, 136.00, 134.52, 129.77 (2C), 129.25 (2C), 128.52
(2C), 128.39 (2C), 127.61, 74.11, 64.30, 59.30, 43.74,
24.44, 21.77. Anal. Calcd for C20H21NO5S: C, 62.00; H,
5.46; N, 3.62; S, 8.28, found C, 61.98; H, 5.44; N, 3.58; S,
8.28. Compound 7a was recrystallized from ethyl acetate,
and as a colorless prism.
Scheme 5. Formal synthesis of (G)-homopumiliotoxin 223G.
4. Experimental
4.1. General
For 7b. Yield 73%; colorless oil; IR (CHCl3, cmK1) 1738,
1687; FAB-MS: C16H19NO5S m/z (%)Z91 (100), 151 (38),
155 (9), 182 (14), 337 (MC, 1); HRMS (FAB, MCC1)
Calcd for C16H20NO5S 337.0978, found 337.0980; 1H NMR
(500 MHz, CDCl3) d 7.78 (d, JZ8.0 Hz, 2H), 7.38 (d, JZ
8.0 Hz, 2H), 5.78–5.70 (m, 1H), 5.18 (dd, JZ1, 17.5 Hz,
1H), 5.14 (dd, JZ1, 10 Hz, 1H), 4.37–4.30 (m, 4H), 3.85 (s,
3H), 2.83 (ddd, JZ4, 7, 15 Hz, 1H), 2.55 (ddd, JZ6, 11.5,
15 Hz, 1H), 2.46 (s, 3H); 13C NMR (125 MHz, CDCl3) d
169.92, 164.00, 145.74, 134.86, 130.95, 129.79 (2C),
129.25 (2C), 117.75, 74.14, 64.02, 59.20, 42.41, 24.42,
21.74.
Before use, THF was distilled from a deep blue solution
resulting from sodium and benzophenone under nitrogen.
All reagents and solvents were obtained from commercial
sources and used without further purification. Thin layer
chromatography (TLC) analysis was performed with pre-
coated silica gel (60 f254 plates) and column chromato-
graphy was carried out on silica (70–230 mesh). All
reactions were performed under an atmosphere of nitrogen
in dried (except those concerned with aqueous solutions)
spherical flasks and stirred with magnetic bars. Organic
layers were dried with anhydrous magnesium sulfate before
concentration in vacuo.
4.1.1. Preparation of 2-methoxyacrylic acid ethyl ester
(10). A mixture of ethyl pyruvate (5 g, 43.06 mmol) and
trimethyl orthoformate (10.9 g, 103.34 mmol) was added
dropwise concentrated sulfuric acid (0.1 mL) at room
temperature. After being stirred for 6 h, the residue was
diluted with water (10 mL) and extracted with CH2Cl2 (3!
20 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated. Without purification, to
a solution of above crude product in dry DMF (5 mL), P2O5
(3.05 g, 21.52 mmol) was added under strong stirring. The
mixture was heated for 6 h at 100 8C, cooled to room
temperature, poured on to saturated aqueous NaHCO3
(15 mL) and extracted with Et2O (3!20 mL). The com-
bined organic layers were washed with water (30 mL),
dried, filtered and evaporated. Distillation gave 4.19 g of 10
(75%) as colorless oil.
4.1.3. Preparation of 1-substituted-5,6-dimethoxy-3-
(toluene-4-sulfonyl)piperidin-2-one (12), (19). A solution
of glutarimide 7 (2.0 mmol) in THF (20 mL) was added
lithium aluminum hydride (2.5 mmol) at K10 8C. The
resulting mixture was stirred for 3 h, quenched with
saturated aqueous NH4Cl (1 mL) at the same temperature,
filtered and then concentrated under reduced pressure. The
residue was diluted with water (10 mL) and extracted with
EtOAc (3!20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated. Without
purification, to a solution of above crude product in MeOH
(20 mL) was treated with BF3–OEt2 (0.24 mL, 2.0 mmol) at
room temperature. After 15 h, the resulting mixture was
diluted with saturated aqueous NaHCO3, concentrated
under reduce pressure and extracted with CH2Cl2 (3!
20 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated. Purification on silica
gel chromatography (hexane/ethyl acetateZ4/1–2/1) pro-
duced products.
4.1.2. Procedure of [3C3] cycloaddition to N-substi-
tuted-5-methoxy-3-tolsyl glutarimides 7. A solution of N-

B.-F. Chen et al. / Tetrahedron 60 (2004) 10223–10231
10227
For 12. Yield 67%; colorless oil; IR (CHCl3, cmK1) 1654;
FAB-MS: C21H25NO5S m/z (%)Z91 (100), 69 (61), 372
(8), 404 (MCC1, 9); HRMS (FAB, MCC1) Calcd for
C21H26NO5S 404.1532, found 404.1529; 1H NMR
(500 MHz, CDCl3) d 7.38 (d, JZ8 Hz, 2H), 7.33 (d, JZ
8 Hz, 2H), 7.27–7.18 (m, 5H), 5.24 (d, JZ15.5 Hz, 1H),
4.34 (dd, JZ1.5, 3 Hz, 1H), 4.22 (dd, JZ7, 11.5 Hz, 1H),
4.06 ((d, JZ15.5 Hz, 1H), 3.69 (dt, JZ4.5, 2.5 Hz, 1H),
3.35 (S, 3H), 3.20 (S, 3H), 2.76 (ddd, JZ2.5, 11.5, 14.5 Hz,
1H), 2.59–2.54 (m, 1H), 2.43 (S, 3H); 13C NMR (125 MHz,
CDCl3) d 162.51, 144.54, 136.67, 136.17, 129.36 (2C),
129.29 (2C), 128.48 (2C), 127.98 (2C), 127.42, 87.12,
72.52, 62.44, 56.98, 56.72, 48.51, 21.68, 21.42. Anal. Calcd
for C21H25NO5S: C, 62.51; H, 6.25; N, 3.47; S, 7.95, found
C, 62.52; H, 6.24; N, 3.45; S, 8.00.
filtered and evaporated. Purification on silica gel (hexane/
ethyl acetateZ2/1–1/1) produced products.
For cis-6-allyl-1-benzyl-5-methoxypiperidin-2-one (cis-
14a). Yield 62%; colorless oil; IR (CHCl3, cmK1) 3071,
1638; FAB-MS: C16H21NO2 m/z (%)Z91 (100), 117 (42),
218 (18), 260 (MCC1, 69); HRMS (FAB, MCC1) Calcd
for C16H22NO2 260.1650, found 260.1653; 1H NMR
(500 MHz, CDCl3) d 7.32–7.21 (m, 5H), 5.87–5.79 (m,
1H), 5.43 (d, JZ15 Hz, 1H), 5.13 (dd, JZ17.5, 3 Hz, 1H),
5.09 (d, JZ10 Hz, 1H), 3.94 (d, JZ15 Hz, 1H), 3.49–3.42
(m, 2H), 3.25 (s, 3H), 2.65 (dt, JZ18, 5.5 Hz, 1H), 2.59–
2.49 (m, 2H), 2.34–2.28 (m, 1H), 1.98–1.93 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 169.67, 137.22, 135.38, 128.59
(2C), 127.83 (2C), 127.32, 117.77, 75.72, 57.11, 56.36,
48.55, 33.76, 28.59, 22.12.
For 19. Yield 61%; colorless oil; IR (CHCl3, cmK1) 1740,
1689; FAB-MS: C17H23NO5S m/z (%)Z166 (100%), 91
(12), 168 (7), 354 (MCC1, 7); HRMS (FAB, MCC1)
Calcd for C17H24NO5S 354.1375, found 354.1374; 1H NMR
(500 MHz, CDCl3) d 7.77 (d, JZ8.5 Hz, 2H), 7.34 (d, JZ
8.5 Hz, 2H), 5.66–5.58 (m, 1H), 5.12 (dd, JZ17, 1.5 Hz,
1H), 5.08 (dd, JZ10, 1 Hz, 1H), 4.39 (dd, JZ15.5, 4 Hz,
1H), 4.37 (d, JZ1.5 Hz, 1H), 4.09 (dd, JZ11.5, 7 Hz, 1H),
3.68–3.66 (m, 1H), 3.51 (dd, JZ15.5, 7 Hz, 1H), 3.33 (s,
3H), 3.32 (s, 3H), 2.62 (ddd, JZ14, 12, 2 Hz, 1H), 2.53–
2.48 (m, 1H), 2.38 (s, 3H); 13C NMR (125 MHz, CDCl3) d
161.82, 144.29, 136.31, 131.96, 129.01 (2C), 128.96 (2C),
171.24, 87.38, 72.31, 61.99, 56.63, 56.53, 48.17, 21.39,
20.96. Anal. Calcd for C17H23NO5S: C, 57.77; H, 6.56; N,
3.96; S, 9.07, found C, 58.02; H, 6.68; N, 3.93; S, 9.39.
For
(trans-14a). Yield 27%; colorless oil; IR (CHCl3, cmK1
trans-6-allyl-1-benzyl-5-methoxypiperidin-2-one
)
3076, 1638; FAB-MS: C16H21NO2 m/z (%)Z91 (100), 133
(52), 260 (MCC1, 34); HRMS (FAB, MCC1) Calcd for
C16H22NO2 260.1650, found 260.1651; 1H NMR
(500 MHz, CDCl3) d 7.31–7.24 (m, 5H), 5.70–5.63 (m,
1H), 5.44 (d, JZ15.5 Hz, 1H), 5.12–5.08 (m, 2H), 3.94 (d,
JZ15.5 Hz, 1H), 3.44–3.43 (m, 2H), 3.12 (s, 3H), 2.64
(ddd, JZ8, 11, 18 Hz, 1H), 2.54–2.49 (m, 1H), 2.40 (ddd,
JZ3, 6.5, 18 Hz, 1H), 2.19–2.13 (m, 1H), 2.05–1.94 (m,
2H); 13C NMR (125 MHz, CDCl3) d 169.79, 137.14,
133.59, 128.47 (2C), 127.78 (2C), 127.16, 118.43, 74.28,
57.71, 55.58, 47.53, 36.67, 27.01, 21.07.
For trans-1-benzyl-5-methoxy-6-propa-1,2-dienyl-piperi-
din-2-one (trans-14b). Yield 71%; colorless oil; IR
(CHCl3, cmK1) 1960, 1648; FAB-MS: C16H19NO2 m/z
(%)Z91 (100), 133 (43), 258 (MCC1, 26); HRMS (FAB,
MCC1) Calcd for C16H20NO2 258.1494, found 258.1497;
1H NMR (500 MHz, CDCl3) d 7.31–7.24 (m, 5H), 5.32 (d,
JZ15 Hz, 1H), 5.03 (dd, JZ6, 13 Hz, 1H), 4.92–4.90 (m,
2H), 4.00–3.98 (m, 1H), 3.79 (d, JZ15 Hz, 1H), 3.43 (dt,
JZ4.5, 2 Hz, 1H), 3.15 (s, 3H), 2.61 (ddd, JZ7.5, 12,
18 Hz, 1H), 2.41 (ddd, JZ2, 6.5, 18 Hz, 1H), 2.17–2.20 (m,
1H), 2.00–1.95 (m, 1H); 13C NMR (125 MHz, CDCl3) d
208.56, 169.58, 137.07, 128.54 (2C), 127.95 (2C), 127.15,
90.19, 78.18, 76.31, 57.00, 55.91, 47.42, 27.01, 21.33.
4.1.4. 1-Benzyl-5,6-dimethoxypiperidin-2-one (13).
Sodium amalgam 6% (Na/Hg, 3.0 g) and sodium phosphate
(40 mg) were added to a stirred solution of 12 (806 mg,
2.0 mmol) in MeOH (5 mL), and vigorously stirred for 2 h
at room temperature The residue was filtered and washed
with MeOH (2!10 mL). The combined organic layers were
concentrated to obtain the crude product. The crude product
was purified by silica gel chromatography (hexane/ethyl
acetateZ2/1–1/1) to afford 13 (433 mg, 87%) as colorless
oil; IR (CHCl3, cmK1) 1654; FAB-MS: C14H19NO3 m/z
(%)Z91 (100), 69 (43), 218 (16), 250 (MCC1, 71); HRMS
(FAB, MCC1) Calcd for C14H20NO3 250.1443, found
1
250.1442; H NMR (500 MHz, CDCl3) d 7.32–7.25 (m,
For cis-1-benzyl-3-methoxy-6-oxopiperidine-2-carbonitrile
(cis-14c). Yield 26%; colorless oil; IR (CHCl3, cmK1) 2391,
1654; FAB-MS: C14H16N2O2 m/z (%)Z154 (100), 91 (70),
137 (72), 245 (MCC1, 65); HRMS (FAB, MCC1) Calcd
for C14H17N2O2 245.1290, found 245.1288; 1H NMR
(500 MHz, CDCl3) d 7.37–7.26 (m, 5H), 5.56 (d, JZ
15 Hz, 1H), 4.31 (dd, JZ1.5, 5 Hz, 1H), 3.91 (d, JZ15 Hz,
1H), 3.57 (dt, JZ11, 4.5 Hz, 1H), 3.38 (s, 3H), 2.77 (ddd,
JZ3.5, 6.5, 18.5 Hz, 1H), 2.52 (ddd, JZ7, 11, 18.5 Hz,
1H), 2.21–2.17 (m, 1H), 2.16–2.07 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 168.17, 135.00, 129.06 (2C), 128.46
(2C), 128.33, 115.42, 73.63, 57.00, 51.18, 48.53, 29.06,
23.82.
5H), 5.34 (d, JZ15 Hz, 1H), 4.34 (dd, JZ1.5, 2.5 Hz, 1H),
4.06 (d, JZ15 Hz, 1H), 3.52 (dt, JZ4.5, 2.5 Hz, 1H), 3.35
(s, 3H), 3.25 (s, 3H), 2.58 (ddd, JZ7, 12, 18.5 Hz, 1H), 2.41
(ddd, JZ3, 9.5, 17.5 Hz, 1H), 2.14–2.09 (m, 1H), 1.97–1.92
(m, 1H); 13C NMR (125 MHz, CDCl3) d 170.02, 137.14,
128.66, 128.09, 127.68, 127.15 (2C), 88.19, 73.31, 56.75,
56.27, 47.54, 27.20, 20.34.
4.1.5. Preparation of N-benzyl-6-substituted-5-methoxy-
d-lactams 14a–14e. To a solution of 13 (0.26 mmol) and
the nucleophiles (1.0 mmol) in dry CH2Cl2 (5 mL), BF3–
OEt2 (0.12 mL, 1.0 mmol) was added at 0 8C. The reaction
was allowed to warm to room temperature and was
monitored by TLC. When the reaction was finished,
saturated aqueous NaHCO3 (5 mL) was added and the
water layer was extracted with CH2Cl2 (3!10 mL). The
combined organic layers were washed with brine, dried,
For trans-1-benzyl-3-methoxy-6-oxopiperidine-2-carboni-
trile (trans-14c). Yield 55%; colorless oil; IR (CHCl3,
cmK1) 2303, 1658; FAB-MS: C14H16N2O2 m/z (%)Z91
(100), 136 (85), 145 (87), 245 (MCC1, 42); HRMS (FAB,

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B.-F. Chen et al. / Tetrahedron 60 (2004) 10223–10231
MCC1) Calcd for C14H17N2O2 245.1290, found 245.1291;
1H NMR (500 MHz, CDCl3) d 7.36–7.26 (m, 5H), 5.67 (d,
JZ15 Hz, 1H), 4.24 (t, JZ2.5 Hz, 1H), 3.86 (d, JZ15 Hz,
1H), 3.80 (dt, JZ4.5, 2.5 Hz, 1H), 3.17 (s, 3H), 2.70 (ddd,
JZ7, 12, 18.5 Hz, 1H), 2.54 (ddd, JZ2.5, 6.5, 18.5 Hz,
1H), 2.30–2.22 (m, 1H), 2.18–2.12 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 168.48, 134.98, 128.91 (2C), 128.25
(2C), 128.11, 116.36, 74.04, 56.61, 49.54, 47.96, 26.88,
23.23.
evaporated. The crude product was purified by silica gel
chromatography (hexane/ethyl acetateZ2/1–1/1) to afford
15 (386 mg, 67%) as colorless oil; IR (CHCl3, cmK1) 1963,
1654; EI-MS: C23H25NO4S m/z (%)Z91 (100), 411 (MC,
0.59); HRMS (FAB, MCC1) Calcd for C23H26NO4S
1
412.1583, found 412.1584; H NMR (500 MHz, CDCl3) d
7.85 (d, JZ8.5 Hz, 2H), 7.35 (d, JZ8.5 Hz, 2H), 7.32–7.18
(m, 5H), 5.39 (d, JZ15 Hz, 1H), 5.10 (dd, JZ6.5, 13 Hz,
1H), 5.00–4.91 (m, 2H), 4.28 (dd, JZ7.5, 12 Hz, 1H), 3.99
(m, 1H), 3.77 (d, JZ15 Hz, 1H), 3.58 (dt, JZ4.5, 2.5 Hz,
1H), 3.05 (s, 3H), 2.69 (ddd, JZ2, 12, 14 Hz, 1H), 2.59–
2.54 (m, 1H), 2.43 (s, 3H); 13C NMR (125 MHz, CDCl3) d
208.76, 161.98, 144.52, 136.84, 136.10, 129.37 (2C),
129.17 (2C), 128.44 (2C), 128.17 (2C), 127.43, 89.01,
78.51, 75.54, 62.36, 56.66, 56.19, 47.94, 22.67, 21.68.
For cis-1-benzyl-6-furan-2-yl-5-methoxypiperidin-2-one
(cis-14d). Yield 41%; colorless oil; IR (CHCl3, cmK1
)
3123, 3045, 1638; FAB-MS: C17H19NO3 m/z (%)Z91
(100), 154 (95), 286 (MCC1, 60); HRMS (FAB, MCC1)
Calcd for C17H20NO3 286.1443, found 286.1443; 1H NMR
(500 MHz, CDCl3) d 7.43 (d, JZ1 Hz, 1H), 7.34–7.18 (m,
5H), 6.39 (dd, JZ2, 3 Hz, 1H), 6.26 (d, JZ3.5 Hz, 1H),
5.46 (d, JZ15.5 Hz, 1H), 4.61 (d, JZ4.5 Hz, 1H), 3.61 (dt,
JZ11, 5 Hz, 1H), 3.51 (d, JZ15.5 Hz, 1H), 3.31 (s, 3H),
2.77 (ddd, JZ3, 7, 18 Hz, 1H), 2.58 (ddd, JZ8, 11, 18 Hz,
1H), 2.05–1.97 (m, 2H); 13C NMR (125 MHz, CDCl3) d
169.41, 150.08, 142.86, 136.74, 128.60 (2C), 128.08 (2C),
127.46, 110.31, 109.76, 76.02, 56.70, 55.29, 48.06, 29.62,
22.81.
4.1.7. 1-Benzyl-6-hydroxymethyl-5-methoxy-3-(toluene-
4-sulfonyl)piperidin-2-one (16). A stream of ozone was
bubbled through a solution of 15 (197 mg, 0.48 mmol) in
CH2Cl2 (5 mL) at K78 8C until a pale blue color developed
(5 min). Nitrogen was bubbled through the solution to
remove excess ozone and dimethyl sulfide (0.5 mL) was
added. The reaction mixture was allowed to warm to room
temperature, and stirring was continued for 5 h. The
solution was concentrated under reduce pressure followed
diluted with MeOH (10 mL), NaBH4 (22 mg, 0.58 mmol)
was added and monitored by TLC. When the reaction was
finished, water (10 mL) was added and then concentrated
under reduced pressure. The residue was extracted with
EtOAc (3!10 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated. The crude
product was purified by silica gel chromatography (hexane/
ethyl acetateZ2/1–1/1) to afford 16 (147 mg, 76%) as a
colorless oil; IR (CHCl3, cmK1) 3432, 1660; FAB-MS:
C21H25NO5S m/z (%)Z117 (100), 91 (43), 219 (12), 404
(MCC1, 2); HRMS (FAB, MCC1) Calcd for C21H26NO5S
For trans-1-benzyl-6-furan-2-yl-5-methoxypiperidin-2-one
(trans-14d). Yield 43%; colorless oil; IR (CHCl3, cmK1
)
3108, 3040, 1641; FAB-MS: C17H19NO3 m/z (%)Z91
(100), 136 (38), 154 (36), 286 (MCC1, 32); HRMS (FAB,
MCC1) Calcd for C17H20NO3 286.1443, found 286.1442;
1H NMR (500 MHz, CDCl3) d 7.38 (d, JZ2 Hz, 1H), 7.32–
7.21 (m, 5H), 6.36 (dd, JZ1.5, 3 Hz, 1H), 6.22 (d, JZ3 Hz,
1H), 5.60 (d, JZ15.5 Hz, 1H), 4.58 (s, 1H), 3.64 (dt, JZ4.5,
2.5 Hz, 1H), 3.58 (d, JZ15.5 Hz, 1H), 3.20 (s, 3H), 2.71
(ddd, JZ7.5, 12.5, 18.5 Hz, 1H), 2.50 (ddd, JZ2.5, 6.5,
18.5 Hz, 1H), 2.06–2.00 (m, 1H), 1.96–1.91 (m, 1H); 13C
NMR (125 MHz, CDCl3) d 169.89, 151.94, 142.58, 136.80,
128.49 (2C), 127.85 (2C), 127.24, 110.47, 108.06, 75.81,
56.86, 56.16, 47.55, 27.10, 21.84.
1
404.1532, found 404.1532; H NMR (500 MHz, CDCl3) d
7.82 (d, JZ8.5 Hz, 2H), 7.35 (d, JZ8.5 Hz, 2H), 7.28–7.21
(m, 5H), 5.11 (d, JZ15.5 Hz, 1H), 4.27 (dd, JZ8, 10.5 Hz,
1H), 4.21 (d, JZ15.5 Hz, 1H), 3.80–3.78 (m, 3H), 3.58–
3.55 (m, 1H), 3.05 (s, 3H), 2.79 (ddd, JZ3, 10.5, 15 Hz,
1H), 2.55–2.49 (m, 1H), 2.44 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 162.65, 144.76, 136.39, 136.35, 129.46 (2C),
129.10 (2C), 128.57 (2C), 127.94 (2C), 127.54, 73.09,
62.77, 62.00, 59.44, 56.09, 49.16, 23.57, 21.71.
For 1-benzyl-5-methoxypiperidin-2-one (14e). Yield 96%;
colorless oil; IR (CHCl3, cmK1) 1638; FAB-MS:
C13H17NO2 m/z (%)Z91 (59), 220 (MCC1, 100); HRMS
(FAB, MCC1) Calcd for C13H18NO2 220.1338, found
1
220.1338; H NMR (500 MHz, CDCl3) d 7.33–7.24 (m,
5H), 4.61 (d, JZ15 Hz, 1H), 4.56 (d, JZ15 Hz, 1H), 3.59–
3.56 (m, 1H), 3.30 (dd, JZ4, 13 Hz, 1H), 3.25 (s, 3H), 3.23
(ddd, JZ1, 4.5, 13 Hz, 1H), 2.62 (ddd, JZ6.5, 16, 17.5 Hz,
1H), 2.40 (dt, JZ6, 17.5 Hz, 1H), 2.02–1.89 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 169.21, 136.70, 128.40 (2C),
128.77 (2C), 127.17, 72.21, 55.80, 50.19, 49.71, 27.80,
25.08.
4.1.8. Acetic acid 1-benzyl-3-methoxy-6-oxo-5-(toluene-
4-sulfonyl)piperidin-2-ylmethyl ester (17). To a solution
of 16 (318 mg, 0.79 mmol) and 4-N,N-(dimethylamino)pyr-
idine (96 mg, 0.79 mmol) in triethylamine (0.5 mL) was
added acetic anhydride (2 mL) at room temperature. The
reaction mixture was stirred for 3 h. The reaction was
quenched with a saturated aqueous NaHCO3 (5 mL) at 0 8C
and extracted with EtOAc (3!10 mL). The combined
organic layers were washed with brine, dried, filtered and
evaporated. The crude product was purified by silica gel
chromatography (hexane/ethyl acetateZ2/1–1/1) to afford
17 (298 mg, 85%) as colorless oil; IR (CHCl3, cmK1) 1747,
1654; FAB-MS: C23H27NO6S m/z (%)Z91 (100), 133 (24),
290 (3), 446 (MCC1, 6); HRMS (FAB, MCC1) Calcd for
C23H28NO6S 446.1637, found 446.1637; 1H NMR
(500 MHz, CDCl3) d 7.83 (d, JZ8.5 Hz, 2H), 7.36 (d, JZ
8.5 Hz, 2H), 7.30–7.21 (m, 5H), 5.27 (d, JZ15 Hz, 1H),
4.1.6. 1-Benzyl-5-methoxy-6-propa-1,2-dienyl-3-(tolu-
ene-4-sulfonyl)piperidin-2-one (15). To a solution of 12
(564 mg, 1.4 mmol) and the propargyl trimethylsilane
(627 mg, 5.6 mmol) in dry CH2Cl2 (5 mL), BF3–OEt2
(0.7 mL, 5.6 mmol) was added at 0 8C. The reaction was
allowed to warm to room temperature and monitored by
TLC. When the reaction was finished, saturated aqueous
NaHCO3 (5 mL) was added and the water layer was
extracted with CH2Cl2 (3!10 mL). The combined organic
layers were washed with brine, dried, filtered and

B.-F. Chen et al. / Tetrahedron 60 (2004) 10223–10231
10229
4.28–4.23 (m, 3H), 4.06 (d, JZ15 Hz, 1H), 3.70 (dd, JZ3,
6.5 Hz, 1H), 3.66–3.63 (m, 1H), 3.03 (s, 3H), 2.68 (ddd, JZ
2.5, 10.5, 15 Hz, 1H), 2.62–2.57 (m, 1H), 2.45 (s, 3H), 2.11
(s, 3H); 13C NMR (125 MHz, CDCl3) d 170.43, 162.39,
144.75, 136.45, 136.01, 129.46 (2C), 129.13 (2C), 128.53
(2C), 128.14 (2C), 127.59, 73.02, 62.68, 62.42, 56.42,
56.15, 48.74, 23.19, 21.72, 20.76.
127.91, 127.78 (2C), 127.61 (2C), 127.54, 127.31 (2C),
127.12, 73.30, 71.98, 70.03, 69.36, 58.59, 47.96, 27.41,
22.38.
4.1.11. 1,6-Diallyl-5-methoxy-3-(toluene-4-sulfonyl)
piperidin-2-one (20). To a solution of 19 (1 g, 2.9 mmol)
and the allylsilane (1.32 g, 11.6 mmol) in dry CH2Cl2
(20 mL), BF3$OEt2 (1.46 mL, 11.6 mmol) was added at
0 8C. The reaction was allowed to warm to room
temperature and monitored by TLC. When the reaction
was finished, saturated aqueous NaHCO3 (5 mL) was added
and the water layer was extracted with CH2Cl2 (3!10 mL).
The combined organic layers were washed with brine, dried,
filtered and evaporated. The crude product was purified by
silica gel chromatography to afford 20 (897 mg, 85%) as
mixture (ca. 33:33:34) of three diastereomers and as
colorless oil. For spectroscopic characterization a mixture
4.1.9. 1-Benzyl-5-hydroxy-6-hydroxymethyl-3-(toluene-
4-sulfonyl)piperidin-2-one (18). To a solution of 17
(298 mg, 0.67 mmol) in dry CH2Cl2 (5 mL) at 0 8C was
added dropwise a 1.0 M solution of boron tribromide in
dichloromethane (4.0 mL, 4.0 mmol). After stirring the
solution for 10 h, the reaction contents was quenched with a
saturated aqueous NaHCO3 (10 mL) at 0 8C. The resulting
mixture was stirred for 20 min and extracted with CH2Cl2
(3!10 mL). The combined organic layers were washed
with brine, dried, filtered and evaporated. The crude product
was purified by silica gel chromatography (hexane/ethyl
acetateZ1/1–1/2) to afford 18 (188 mg, 72%) as colorless
oil; IR (CHCl3, cmK1) 3401, 1640; FAB-MS: C20H23NO5S
m/z (%)Z91 (100), 136 (74), 390 (MCC1, 30); HRMS
(FAB, MCC1) Calcd for C20H24NO5S 390.1375, found
390.1375; 1H NMR (500 MHz, CDCl3) d 7.82 (d, JZ
8.5 Hz, 2H), 7.36 (d, JZ8.5 Hz, 2H), 7.33–7.22 (m, 5H),
5.10 (d, JZ15 Hz, 1H), 4.41–4.39 (m, 1H), 4.33 (t, JZ9 Hz,
1H), 4.25 (d, JZ15 Hz, 1H), 3.81–3.79 (m, 2H), 3.40 (dd,
JZ4, 9 Hz, 1H), 2.84 (ddd, JZ2.5, 9, 14.5 Hz, 1H), 2.44 (s,
3H), 2.42–2.39 (m, 1H); 13C NMR (125 MHz, CDCl3) d
162.60, 144.91, 136.33, 136.22, 129.53 (2C), 129.23 (2C),
128.82 (2C), 127.85 (2C), 127.67, 64.31, 63.69, 63.02,
61.90, 49.16, 26.12, 21.73.
1
of the three isomers; H NMR (500 MHz, CDCl3) d 7.81–
7.77 (comp, 2H), 7.34–7.32 (comp, 2H), 5.88–5.58 (comp,
2H), 5.24–5.07 (comp, 4H), 4.60–4.12 (comp, 1H), 4.16 (t,
JZ10 Hz, 0.3H), 4.11 (t, JZ10 Hz, 0.3H), 4.06 (tt, JZ5,
8 Hz, 0.3H), 3.97 (dt, JZ9.5, 4 Hz, 0.3H), 3.65 (q, JZ3 Hz,
0.3H), 3.63 (q, JZ4.5 Hz, 0.3H), 3.57–3.34 (comp, 2.3H),
3.41 (s, 1H), 3.38 (s, 3H), 3.30 (s, 1H), 2.74 (dt, JZ15,
4.5 Hz, 0.3H), 2.64–2.23 (comp, 6.3H).
4.1.12. 1-Methoxy-3-(toluene-4-sulfonyl)-1,2,3,6,9,9a-
hexa hydroquinolizin-4-one (21). 1st Grubbs’ catalyst
(82 mg, 0.1 mmol) was added to a solution of mixture 20
(881 mg, 2.4 mmol) in CH2Cl2 (20 mL) and stirred for 12 h
at room temperature The resulting mixture was concentrated
and purified by silica gel chromatography (hexane/ethyl
acetateZ2/1–1/1) to afford 21 (570 mg, 71%) as a mixture
of three diastereomers. For spectroscopic characterization
the major isomer was isolated by chromatography; colorless
oil; IR (CHCl3, cmK1) 3045, 1639; FAB-MS: C17H21NO4S
m/z (%)Z154 (100), 136 (87), 219 (30), 336 (MCC1, 28);
HRMS (FAB, MCC1) Calcd for C17H22NO4S 336.1270,
found 336.1271; 1H NMR (500 MHz, CDCl3) d 7.83 (d, JZ
8 Hz, 2H), 7.34 (d, JZ8 Hz, 2H), 5.85–5.81 (m, 1H), 5.66–
5.63 (m, 1H), 4.55 (dd, JZ3.5, 18.5 Hz, 1H), 4.10 (t, JZ
7 Hz, 1H), 4.04 (ddd, JZ3, 5, 8 Hz, 1H), 3.57 (dt, JZ11.5,
4 Hz, 1H), 3.54 (d, br, JZ19 Hz, 1H), 3.46 (s, 3H), 2.64
(ddd, JZ3, 7, 14 Hz, 1H), 2.52 (ddd, JZ6, 9, 15 Hz, 1H),
2.44 (s, 3H), 2.36–2.32 (m, 1H), 2.12 (d, br, JZ17 Hz, 1H);
13C NMR (125 MHz, CDCl3) d 160.80, 144.63, 136.70,
129.39, 129.30, 129.20, 129.02, 124.31, 123.33, 72.82,
63.45, 57.19, 55.48, 43.14, 26.12, 22.83, 21.64.
4.1.10. 1-Benzyl-5-benzyloxy-6-benzyloxymethylpiperi-
din-2-one (8). Sodium amalgam 6% (Na/Hg, 3.0 g) and
sodium phosphate (40 mg) were added to a stirred solution
of lactam 18 (132 mg, 0.34 mmol) in methanol (5 mL), and
vigorously stirred for 2 h at room temperature The residue
was filtered and washed with methanol (2!10 mL). The
combined organic layers were concentrated to obtain the
crude product. Without purification, the solution of above
crude product in dry THF (5 mL) was added to a rapidly
stirred suspension of NaH (48 mg, 1.2 mmol, 60%) in dry
THF (5 mL) at room temperature. The mixture was stirred
for 5 min and then benzyl bromide (149 mg, 0.87 mmol)
was added. After stirring for 30 min, the reaction was
quenched with water (10 mL). The resulting mixture was
extracted with EtOAc (3!10 mL). The combined organic
layers were washed with brine, dried, filtered and evapor-
ated. The crude product was purified by silica gel
chromatography (hexane/ethyl acetateZ2/1–1/1) to afford
8 (72 mg, 51%) as colorless oil; IR (CHCl3, cmK1) 1640;
FAB-MS: C27H29NO3 m/z (%)Z91 (100), 154 (86), 416
(MCC1, 8); HRMS (FAB, MCC1) Calcd for C27H30NO3
4.1.13. 1-Hydroxy-3-(toluene-4-sulfonyl)octahydro-
quinolizin-4-one (22). Palladium on activated carbon 10%
(10 mg) was added to the solution of 21 (577 mg, 1.7 mmol)
in MeOH (20 mL) The hydrogen was bubbled into the
mixture for 10 min, and the reaction mixture was continued
to stir for 3 h at room temperature. The catalyst was filtered
through a short plug of celite and washing with MeOH
(2!5 mL). The combined organic layers were evaporated.
Without purification, sodium iodide (1.27 g, 8.5 mmol) was
added to a solution of above crude product in MeCN
(10 mL), followed by 8.5 mmol (1.1 mL) of distilled
Me3SiCl added dropwise. The mixture was refluxed for
15 h. After cooling to room temperature, few drops of
aqueous 10% NH4Cl were added, follow by CH2Cl2
1
416.2226, found 416.2224; H NMR (500 MHz, CDCl3) d
7.36–7.19 (m, 15), 5.36 (d, JZ15 Hz, 1H), 4.45 (d, JZ
12 Hz, 1H), 4.41 (d, JZ12 Hz, 1H), 4.38 (d, JZ12 Hz, 1H),
4.30 (d, JZ12 Hz, 1H), 3.97 (d, JZ15 Hz, 1H), 3.86 (dd,
JZ2.5, 6.5 Hz, 1H), 3.68–3.66 (m, 1H), 3.55 (dd, JZ4,
10 Hz, 1H), 3.45 (dd, JZ7, 9.5 Hz, 1H), 2.70 (ddd, JZ8,
10, 18 Hz, 1H), 2.43 (ddd, JZ4, 6.5, 18 Hz, 1H), 2.04–2.00
(m, 2H); 13C NMR (125 MHz, CDCl3) d 170.31, 138.03,
137.52, 137.18, 128.50 (2C), 128.45 (2C), 128.29 (2C),

10230
B.-F. Chen et al. / Tetrahedron 60 (2004) 10223–10231
(2!10 mL) extraction. The organic layer was sequentially
washed with aqueous 20% Na2S2O3 and brine, dried,
filtered and evaporated. The crude product was purified by
silica gel chromatography (hexane/ethyl acetateZ2/1–1/1)
to afford 22 (65%) as a mixture of three diastereomers. For
spectroscopic characterization the major isomer was
isolated by chromatography; white solid; mp 184.6 8C; IR
(CHCl3, cmK1) 3447, 1640; FAB-MS: C16H21NO4S m/z
(%)Z136 (100), 77 (93), 154 (88), 324 (MCC1, 23);
HRMS (FAB, MCC1) Calcd for C16H22NO4S 324.1269,
found 324.1270; 1H NMR (500 MHz, CDCl3) d 7.84 (d, JZ
8 Hz, 2H), 7.33 (d, JZ8 Hz, 2H), 4.59 (d, br, JZ13.5 Hz,
1H), 4.32–4.29 (m, 2H), 3.35 (d, JZ11.5 Hz, 1H), 2.59 (dt,
JZ13, 6.5 Hz, 1H), 2.49–2.40 (m, 5H), 1.91–1.81 (m, 1H),
1.68–1.63 (m, 2H), 1.52 (ddt, JZ13, 3 Hz, 1H), 1.46–1.39
(m, 1H), 1.30 (dtt, JZ13, 4 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 161.22, 144.92, 137.06, 129.31 (2C),128.96 (2C),
64.17, 62.42, 60.50, 43.05, 27.26 (2C), 25.21, 23.73, 21.63.
Anal. Calcd for C16H21NO4S: C, 59.42; H, 6.54; N, 4.33; S,
9.92, found C, 59.25; H, 6.58; N, 4.32; S, 9.97.
The combined organic layers were washed with brine, dried,
filtered and evaporated. Purification on silica gel (hexane/
ethyl acetateZ1/1) produced 25 (74 mg, 76%). The 1H, 13
NMR data was in accordance with the reported in the
C
literature.4a
Acknowledgements
Financial support from the National Science Council of the
Republic of China is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.09.
001
4.1.14. 1-Hydroxyoctahydroquinolizin-4-one (23).
Sodium amalgam 6% (Na/Hg, 3 g) and sodium phosphate
(40 mg) were added to a stirred solution of 22 (286 mg,
0.9 mmol) in MeOH (5 mL), and vigorously srirred for 2 h
at room temperature The residue was filtered and washed
with MeOH (2!10 mL). The combined organic layers were
concentrated to obtain the crude product. The crude product
was purified by silica gel chromatography (hexane/ethyl
acetateZ1/1–1/2) to afford 23 (132 mg, 88%) as a mixture
of two diastereomers (ca. 70:30) and as colorless oil. For
spectroscopic characterization an inseparable mixture of the
two isomers; 1H NMR (500 MHz, CDCl3) d 4.62–4.59
(comp, 1H), 3.95–3.94 (m, 0.7H), 3.65–3.62 (m, 0.3H), 3.22
(ddd, JZ3, 4, 12 Hz, 0.7H), 3.10 (ddd, JZ2.5, 4.5, 12 Hz,
0.3H), 2.58–2.46 (comp, 1H), 2.37–2.31 (comp, 1H) 2.27–
2.20 (comp, 1H), 1.91–1.09 (comp, 8H).
References and notes
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741. (q) Yuasa, Y.; Ando, J.; Shibuya, S. J. Chem. Soc., Perkin
Trans. 1 1996, 793. (r) Toyooka, N.; Yotsui, Y.; Yoshida, Y.;
Momose, T. J. Org. Chem. 1996, 61, 4882. (s) Yuasa, Y.; Ando, J.;
Shibuya, S. Tetrahedron: Asymmetry 1995, 6, 1525. (t) Johnson,
C. R.; Golebiowski, A.; Schoffers, E.; Sundram, H.; Braun, M. P.
4.1.15. Hexahydroquinolizine-1,4-dione (24). To an ice-
cold solution of 23 (132 mg, 0.8 mmol) in acetone (10 mL)
was added dropwise Jones reagent (0.5 mL). After being
stirred for 10 min, isopropanol (1 mL) was added and the
mixture was concentrated to a residue that was partitioned in
CH2Cl2 (20 mL) and water (5 mL). The organic layer was
separated, washed with brine, dried, filtered and evaporated.
The crude product was purified by silica gel chromato-
graphy (hexane/ethyl acetateZ1/1) to afford 24 (89 mg,
68%) as colorless oil; IR (CHCl3, cmK1) 1731, 1638; EI-
MS: C9H13NO2 m/z (%)Z83 (100), 167 (MC, 21); HRMS
(EI, MC) Calcd for C9H13NO2 167.0946, found 167.0943;
1H NMR (500 MHz, CDCl3) d 4.67 (d, br, JZ13 Hz, 1H),
3.69 (dd, JZ12, 3 Hz, 1H), 2.77–2.64 (m, 4H), 2.48 (dt, JZ
12.5, 3 Hz, 1H), 2.15 (d, br, JZ13 Hz, 1H), 1.79 (d, br, JZ
13 Hz, 1H), 1.74–1.72 (m, 1H), 1.58–1.34 (m, 3H); 13C
NMR (125 MHz, CDCl3) d 205.42, 168.06, 64.82, 42.82,
35.37, 30.26, 29.60, 24.55, 24.17.
4.1.16. 1-Hydroxy-1-methyloctahydroquinolizin-4-one
(25). To a solution of 24 (89 mg, 0.5 mmol) in THF
(5 mL) was added MeMgBr (3 M in THF, 0.27 mL,
0.8 mmol) at room temperature, and the mixture was stirred
for 10 min. Water (10 mL) was added to the mixture and the
aqueous solution was extracted with EtOAc (3!20 mL).

B.-F. Chen et al. / Tetrahedron 60 (2004) 10223–10231
10231
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