Asymmetric synthesis of quinolizidine alkaloids (-)-lasubine I, (-)- lasubine II and (+)-subcosine II

Article abstract of DOI:10.1016/S0957-4166(98)00468-6

The enantioselective synthesis of (-)-lasubine I 1 and the first asymmetric synthesis of (-)-lasubine II 2 and (+)-subcosine II 3 is described. The key step is the intramolecular cyclization of N-acyliminium ion 4 which is derived from (S)-aminoester 6.

Full text of DOI:10.1016/S0957-4166(98)00468-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4361–4368
Asymmetric synthesis of quinolizidine alkaloids (−)-lasubine I,
(−)-lasubine II and (+)-subcosine II
Pierre Chalard, Roland Remuson,∗ Yvonne Gelas-Mialhe and Jean-Claude Gramain
Laboratoire de Chimie des Substances Naturelles, UMR 6504, Université Blaise Pascal (Clermont-Ferrand),
63177 Aubière Cedex, France
Received 6 October 1998; accepted 17 November 1998
Abstract
The enantioselective synthesis of (−)-lasubine I 1 and the first asymmetric synthesis of (−)-lasubine II 2 and
(+)-subcosine II 3 is described. The key step is the intramolecular cyclization of N-acyliminium ion 4 which is
derived from (S)-aminoester 6. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The quinolizidine skeleton constitutes the backbone of many structurally interesting alkaloids.1
Several quinolizidine alkaloids have been isolated from plants of the Lythraceae family. (−)-Lasubine
I, (−)-lasubine II, (+)-subcosine I and (+)-subcosine II were isolated by Fuji et al. from the leaves of
Lagerstroemia subcostata Koehne.2 Numerous syntheses of these compounds in racemic form were
described;3 the first asymmetric syntheses of (−)-lasubine I 1 and (+)-subcosine I have recently been
reported;4 (−)-lasubine II 2 and (+)-subcosine II 3 have never been synthesized.
We have found that intramolecular cyclization of acyliminium ions substituted by an allylsilyl side
chain as an internal π-nucleophile provided an excellent route to these structures.5 By using this reaction,
we have achieved the total synthesis of a variety of racemic quinolizidine alkaloids: (ꢀ)-myrtine and
∗
Corresponding author. E-mail: remuson@chisg1.univ-bpclermont.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00468-6

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(ꢀ)-epimyrtine,6 (ꢀ)-lasubine I and (ꢀ)-lasubine II.3n We have recently utilized this strategy for the
synthesis of (+)-myrtine and (−)-epimyrtine starting from (S)-2-(2-hydroxypropyl)allyltrimethylsilane.
In this paper, we describe a new approach to the quinolizidine alkaloids (−)-lasubine I 1, (−)-lasubine II
2 and (+)-subcosine II 3. Our synthetic sequence is illustrated in Scheme 1.
Scheme 1.
The key step is the intramolecular acyliminium ion–allylsilane cyclization of intermediate 4 generated
from ethoxylactam 5. Chirality is introduced with β-aminoester 6.
2. Results and discussion
(S)-β-Aminoester 6 was prepared according to Davies’ procedure (Scheme 2).7
Scheme 2.
Conjugate addition of lithium (R)-N-benzyl-N-α-methylbenzylamide to methyl 3,4-dimethoxyphenyl-
cinnamate afforded the tertiary amine 7 with excellent diastereoselectivity (>92%). Debenzylation
of 7 with Pearlman’s catalyst and hydrogen gave the aminoester 6 in 90% yield. The enantiomeric
excess of 6 was determined by deuterium NMR of its N-trideuteroacetyl derivative in a chiral solvent
[dichloromethane solution of γ-benzyl L-glutamate (PBLG)] as described previously by Courtieu et al.8
and was found to be 92%. The absolute configuration of 6 was assigned as S by analogy with related
experiments of Davies et al.7
The synthesis of the quinolizidine skeleton is illustrated in Scheme 3. Reaction of 6 with glutaric
anhydride then with acetyl chloride9 in refluxing toluene gave imide 8 in 86% yield. Its enantiomeric
purity was determined to be >90% by chiral column HPLC analysis. Imide 8 was reduced10 into
ethoxylactam 5 which was isolated as a mixture of two diastereomers. The reduction had to be performed
at −10°C to prevent formation of ring opening products.11 In the next step, ethoxylactam 5 was treated
with the cerium reagent12 derived from CeCl3 and trimethylsilylmethylmagnesium chloride. The mixture
was then hydrolyzed with 1 N HCl, to give methylenequinolizidinones 9a and 9b in a 1:5 ratio and 60%
yield. These isomers were separated by flash column chromatography. The enantiomeric excess of 9b
was found to be >90%.
This reaction involved formation of acyliminium ion (S)-4 which cyclized spontaneously. The structure
and 4,10-stereochemistry of 9a and 9b were established by comparison of their NMR data with literature
values of the racemic compounds.3n
Lasubine I and lasubine II were synthesized from methylenequinolizidinones 9a and 9b as outlined in
Scheme 4.

P. Chalard et al. / Tetrahedron: Asymmetry 9 (1998) 4361–4368
4363
Scheme 3.
Scheme 4.
This route began with the reduction of lactams 9a and 9b with lithium aluminium hydride in refluxing
THF for 12 h to give methylenequinolizidines 10a and 10b in 83% and 92% yields, respectively. Osmium
tetroxide catalyzed periodate oxidation of the olefinic bond of 10a and 10b under carefully controlled
conditions led to quinolizidin-2-ones 11a {[α]D +9.5 (c 3.1, CHCl3); lit.4 [α]D +10.8 (c 1.31,
CHCl3)} and 11b in 70 and 90% yields. The final step is a reduction of the carbonyl group. Stereoselective
25
23
25
reduction of 11a with L-Selectride provided (−)-lasubine I 1 in 62% yield {[α]D −6.5 (c 2.6, MeOH);
lit.2 [α]D −8.8 (c 0.34, MeOH); lit.4 [α]D −7.03 (c 0.37, MeOH)}. Quinolizidin-2-one 11b was
22
23
25
selectively converted to (−)-lasubine II (2) with LS-Selectride in 65% yield {ee >90%; [α]D −41.0 (c
3.7, MeOH); lit.2 [α]D22 −34.7 (c 0.32, MeOH)}. Acylation of 2 with 3,4-dimethoxycinnamic anhydride
25
22
gave (+)-subcosine II 3 in 60% yield {[α]D +121 (c 3.5, MeOH); lit.2 [α]D +85.3 (c 0.64, MeOH)}.
These three alkaloids exhibited IR, 1H and 13C NMR spectral data in agreement with the reported values
for the natural products.2
In conclusion, we describe the total synthesis of (−)-lasubine I 1, (−)-lasubine II 2 and (+)-subcosine
II (3) using intramolecular cyclization of N-acyliminium ion (S)-4. Alkaloids 1 and 2 were obtained in
six steps with overall yields of 7 and 14%, respectively. Subcosine 3 was prepared in seven steps with
an overall yield of 9%. These three compounds were obtained with a high enantiomeric purity. These
results constitute the first total synthesis of naturally occurring (−)-lasubine II and (+)-subcosine II and
unambiguously establish their absolute configuration as 2S,4S,10S.

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3. Experimental section
3.1. General methods
NMR spectra were recorded on a Bruker AC 400 spectrometer operating at 400.13 MHz for 1H NMR,
2
at 46.07 MHz for H NMR and 100.61 MHz for 13C NMR. Chemical shifts are recorded as δ values
(ppm). A Perkin–Elmer 377 instrument was used to determine IR spectra. TLC analyses were performed
on Merck 60 F254 silica gel plates and were visualized using iodine. Column chromatography was carried
out using Merck silica gel (grade 60, 70–230 mesh) and Merck silica gel (grade 60, 230–400 mesh) for
flash column chromatography. The enantiomeric purity was determined by HPLC using a Chiracel OJ
column (J. T. Baker, Inc., Phillipsburg, NJ).
3.2. Methyl 3-(N-methylbenzyl-N0-benzylamino)-3-(3,4-dimethoxyphenyl)propanoate 7
To a stirred solution of (+)-(R)-N-benzyl-N-α-methylbenzylamine (7.7 g, 36.5 mmol) in dry THF (160
ml) at 0°C under argon was slowly added n-BuLi (1.6 M, 22.8 ml, 36.5 mmol). After 1 h, methyl 3,4-
dimethoxycinnamate (7 g, 31.4 mmol) in dry THF (60 ml) was added. The mixture was stirred for 3 h
at 0°C then ammonium chloride (60 ml) was added. The aqueous layer was extracted with diethyl ether
(3×60 ml). The combined organic phases were dried over MgSO4 and the solvent removed in vacuo. The
resulting crude product was purified by flash column chromatography (ethyl acetate:hexane 1:1) to give
7 (11.0 g, 81% yield) as a yellow oil: [α]D +2 (c 5.3, CHCl3); de >92%; 1H NMR (CDCl3) δ 1.25 (d,
25
3H, J=7.0 Hz), 2.62 (ABX system, 2H, JAB=14.8, JAX=5.4, JBX=9.5 Hz), 3.50 (s, 3H), 3.75 (s, 2H), 3.88
(s, 3H) 3.94 (s, 3H), 4.05 (q, 1H, J=7.0 Hz), 4.40 (dd, 1H, JAX=5.4, JBX=9.5 Hz), 6.80–7.04 (m, 3H),
7.15–7.50 (m, 10H); 13C NMR (CDCl3) δ 16.6, 37.2, 50.7, 51.5, 55.9, 56.1, 57.1, 59.0, 110.7, 111.7,
119.7, 126.6, 126.9, 127.8, 127.9, 128.1, 128.2, 134.3, 141.5, 144.2, 148.1, 148.7, 172.3; IR (NaCl neat)
1743, 1601, 1593 cm−1. Anal. calcd for C28H33NO4: C, 74.31; H, 7.35; N, 3.23. Found: C, 74.79; H,
7.21, N, 3.35.
3.3. Methyl (3S)-3-amino-3-(3,4-dimethoxyphenyl)propanoate 6
A mixture of 7 (11.3 g, 26.1 mmol) in methanol (120 ml), acetic acid (3.1 ml) and water (12 ml)
was treated with 20% palladium hydroxide on activated carbon (2.7 g). The mixture was stirred under a
hydrogen atmosphere (4 bar) for 3 days. The reaction mixture was filtered through Celite, then washed
with methanol and the filtrate was concentrated under reduced pressure to give a residue which was
treated with saturated aqueous bicarbonate solution (200 ml) and then extracted with dichloromethane
(3×200 ml). The combined organic extracts were dried over anhydrous K2CO3. Evaporation under
25
1
reduced pressure provided 6 (5.6 g, 90% yield) as a clear oil: [α]D −9.8 (c 1.2, MeOH); H NMR
(CDCl3) δ 1.95 (br s, 2H), 2.65 (d, 2H, J=6.8 Hz), 3.65 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 4.40 (t, 1H,
J=6.8 Hz), 6.78–6.93 (m, 3H); 13C NMR (CDCl3) δ 44.1, 51.7, 52.3, 55.8, 55.9, 109.2, 111.1, 118.2,
137.2, 148.2, 149.0, 172.5; IR (NaCl neat) 3391, 1737, 1609–1590 cm−1. Anal. calcd for C12H17NO4: C,
60.22; H, 7.16; N, 5.86. Found: C, 59.89; H, 7.28; N, 5.79.
3.4. Methyl (3S)-3-amino-3-(3,4-dimethoxyphenyl)-N-trideuteroacetyl)propanoate
To a stirred solution of 6 (196 mg, 0.82 mmol) and triethylamine (0.137 ml, 0.98 mmol) in anhydrous
diethyl ether (6 ml), was added trideuteroacetyl chloride (73 mg, 0.9 mmol) and the mixture stirred for 10

P. Chalard et al. / Tetrahedron: Asymmetry 9 (1998) 4361–4368
4365
min. The solvent was removed in vacuo and the resulting mixture was dissolved with ethyl acetate:hexane
7:3 (10 ml). The mixture was filtered and concentrated. The crude product was chromatographed over
silica gel (eluted with ethyl acetate:hexane 7:3) to give the N-trideuteroacetyl compound (148 mg, 63%
yield) as a pale yellow oil: ee >92%; 1H NMR (CDCl3) δ 2.80 (ABX system, 2H, JAB=15.2 Hz, JAX=6.2,
J
BX=6.25 Hz), 3.70 (s, 3H), 3.85 (s, 3H), 3.90 (s, 3H), 5.30 (m, 1H), 6.75 (m, 3H); 13C NMR (CDCl3) δ
39.9, 49.4, 51.7, 55.7, 110.0, 111.1, 118.2, 133.2, 148.3, 148.9, 169.3, 171.7; IR (NaCl neat) 3435, 1740,
1680 cm−1.
3.5. (S)-N-[1-(3,4-Dimethoxyphenyl)-2-methoxycarbonylethyl]glutarimide 8
A solution of 5 (4.0 g, 16.7 mmol) and glutaric anhydride (2.1 g, 18.4 mmol) in toluene (160 ml) was
refluxed for 12 h. The solvent was removed and the mixture was refluxed with acetyl chloride (5.4 ml,
75.3 mmol) in toluene (160 ml) for 3 h. The solvent was removed in vacuo and the resulting mixture was
taken up with 50 ml of dichloromethane and washed with 10% HCl (20 ml) then with water (20 ml). The
organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was chromatographed
over silica gel (eluted with ethyl acetate:hexane 9:1) to afford 8 (4.8 g, 86% yield) as a white solid: mp
113°C; [α]D25 −84 (c 1.46, CHCl3); ee >90% (HPLC, eluted with hexane:ethanol 1:9); 1H NMR (CDCl3)
δ 1.60 (q, 2H, J=6.5 Hz), 2.61 (t, 4H, J=6.5 Hz), 3.15 (dd, 1H, J=16.0, 5.9 Hz), 3.60 (dd, 1H, J=16.0, 9.8
Hz), 3.65 (s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 6.27 (dd, 1H, J=9.8, 5.9 Hz), 6.74–7.04 (m, 3H); 13C NMR
(CDCl3) δ 17.1, 33.6 (×2), 35.4, 50.6, 51.9, 55.9, 56.0, 110.7, 111.8, 120.8, 131.3, 148.6, 148.7, 171.6
(×2), 172.8; IR (NaCl neat) 1741, 1688, 1680 cm−1. Anal. calcd for C17H21NO6: C, 60.87; H, 6.31; N,
4.18. Found: C, 61.03; H, 6.45; N, 4.08.
3.6. 6-Ethoxy-N-[1-(3,4-dimethoxyphenyl)-2-methoxycarbonylethyl]piperidin-2-one 5
NaBH4 (3.2 g, 84.8 mmol) was slowly added to a solution of 8 (4 g, 11.9 mmol) in anhydrous ethanol
(90 ml) at −10°C under argon. After stirring for 15 min, 10 drops of a 4 N solution of H2SO4 in ethanol
were added every 15 min during 2 h. The NaBH4 excess was destroyed by adding a 12 N solution of
H2SO4 in ethanol until pH 2. The solution was then poured into 300 ml of saturated aqueous NaHCO3
and extracted with CHCl3. The organic layers were dried over K2CO3 and concentrated in vacuo. The
resulting pale yellow oil was purified by column chromatography on silica gel (ethyl acetate:hexane 8:2)
to give 5 (3.4 g, 77% yield) as a pale yellow oil which was isolated as a mixture of two diastereomers in a
4:1 ratio: 1H NMR (CDCl3) δ 0.92 (t, 0.6H, J=6.9 Hz), 1.19 (t, 2.4H, J=7.0 Hz), 1.33 (tt, 1H, J=13.7, 3.0
Hz), 1.55 (m, 1H), 1.85–2.00 (m, 2H), 2.20–2.35 (m, 1H), 2.43–2.53 (m, 1H), 3.08–3.35 (m, 4H), 3.56
(s, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 4.22 (br s, 0.8H), 4.57 (br s, 0.2H), 5.87 (t, 0.8H, J=7.7 Hz), 6.15 (t,
0.2H, J=7.7 Hz), 6.72–6.86 (m, 3H); 13C NMR (CDCl3) δ 14.9, 15.1, 15.4, 19.8, 26.1, 26.8, 31.6, 32.5,
32.6, 36.7, 37.5, 51.3, 51.6, 53.9, 55.7, 56.1, 62.1, 62.9, 83.7, 85.1, 110.3, 110.8, 111.6, 111.9, 130.5,
130.7, 148.4, 148.6, 148.9, 149.0, 169.1, 170.0, 170.7, 171.6; IR (NaCl neat) 1737, 1658 cm−1. Anal.
calcd for C19H27NO6: C, 62.44; H, 7.45; N, 3.83. Found: C, 62.31; H, 7.63; N, 3.73.
3.7. 2-Methylene-4-(3,4-dimethoxyphenyl)quinolizidin-6-ones 9a and 9b
CeCl3·7H2O (20 g, 53 mmol) was dried by stirring under 0.01 mbar, for 4 h at 150°C, then overnight
at room temperature. The flask was flushed with argon, then dry THF (60 ml) was added and the white
suspension was stirred at room temperature for 2 h. This slurry was cooled to −78°C under argon and
trimethylsilylmethylmagnesium chloride in THF [prepared from chloromethyltrimethylsilane (7.4 ml, 53

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P. Chalard et al. / Tetrahedron: Asymmetry 9 (1998) 4361–4368
mmol) and magnesium pellets (1.3 g, 54 mmol) in dry THF (20 ml)] was added dropwise over a period
of 40–60 min. The cold mixture was stirred for 2 h and a solution of 7 (4.3 g, 12 mmol) in 50 ml of dry
THF was added. The resulting mixture was allowed to warm to room temperature and stirred for 3 days.
The reaction mixture was then cooled to 0°C and a 1 N HCl solution (200 ml) was added. The aqueous
layer was extracted with CHCl3 (3×150 ml). The combined organic layers were dried over MgSO4 and
concentrated. The resulting crude mixture was purified by column chromatography on silica gel (ethyl
acetate:hexane 1:1) to give 9a (0.6 g, 16% yield) and 9b (1.7 g, 44% yield) as pale yellow oils.
25
1
9a: [α]D −118 (c 1.25, CHCl3); H NMR (CDCl3) δ 1.45–1.70 (m, 2H), 1.75–2.00 (m, 2H),
2.10–2.35 (m, 2H), 2.40–2.50 (m, 2H), 2.54 (dd, 1H, J=15.5, 6.5 Hz), 2.86 (d, 1H, J=14.5 Hz), 3.25–3.33
(m, 1H), 3.78 (s, 3H), 3.81 (s, 3H), 4.87 (d, 1H, J=1.5 Hz), 4.91 (d, 1H, J=1.5 Hz), 6.70–6.95 (m, 3H);
13C NMR (CDCl3) δ 18.4, 29.8, 33.3, 35.7, 42.0, 50.0, 51.2, 55.8, 110.8, 111.2, 111.7, 120.1, 133.1,
142.7, 147.9, 148.8, 169.8; IR (NaCl neat) 1640, 1517 cm−1.
25
1
9b: [α]D +49 (c 1.6, CHCl3); ee >90% (HPLC, hexane:2-propanol 8:2, 0.1% Et3N); H NMR
(CDCl3) δ 1.45–1.65 (m, 1H), 1.75–2.00 (m, 3H), 2.30–2.55 (m, 4H), 2.75 (dd, 1H, J=15.9, 2.4 Hz),
2.95 (br d, 1H, J=15.9 Hz), 3.73 (m, 1H), 3.79 (s, 3H), 3.83 (s, 3H), 4.71 (br s, 1H), 4.74 (br s, 1H), 5.50
(m, 1H), 6.65–6.80 (m, 3H); 13C NMR (CDCl3) δ 20.4, 31.0, 32.3, 36.3, 37.1, 53.4, 55.7, 55.8, 109.6,
110.9, 111.4, 117.6, 135.2, 139.8, 147.5, 148.6, 170.3; IR (NaCl neat) 1649, 1517 cm−1.
These spectral data are in agreement with reported values.3n
3.8. (4S,10R)-4-(3,4-Dimethoxyphenyl)-2-methylenequinolizidine 10a
A mixture of 9a (64 mg, 0.21 mmol) and LiAlH4 (16 mg, 0.43 mmol) in dry THF (5 ml) was refluxed
for 12 h. Ether was added, followed by water (0.05 ml), 15% NaOH (0.05 ml) and water (0.250 ml).The
aqueous layer was extracted with CH2Cl2 (3×2 ml) and the combined organic layers were dried over
25
MgSO4 and evaporated in vacuo to give 10a (50 mg, 83% yield) as a clear oil: [α]D +57 (c 3.4,
CHCl3); 1H NMR (CDCl3) δ 1.15–1.37 (m, 2H), 1.39–1.62 (m, 3H), 1.66–1.75 (m, 1H), 2.02–2.17 (m,
2H), 2.42 (ABX system, 2H, JAB=13.4, JAX=4.0, JBX=5.4 Hz), 2.62–2.73 (m, 2H), 2.79 (m, 1H), 3.80
(s, 3H), 3.85 (s, 3H), 3.90 (t, 1H, J=5.4 Hz), 4.70 (br s, 1H), 4.75 (br s, 1H), 4.75 (br s, 1H), 6.70–6.95
(m, 3H); 13C NMR (CDCl3) δ 23.0, 24.5, 30.2, 41.4, 41.5, 51.7, 55.5, 55.7, 55.9, 62.3, 109.1, 110.3,
111.9, 121.2, 134.6, 144.4, 147.9, 148.4; IR (NaCl neat) 1650, 1604, 1592 cm−1. These spectral data are
in agreement with reported values.3n
3.9. (4S,10S)-4-(3,4-Dimethoxyphenyl)-2-methylenequinolizidine 10b
25
Using the above procedure, 9b (0.93 g, 3.1 mmol) gave 10b (0.79 g, 89% yield) as a clear oil: [α]D
1
−15 (c 2.4, CHCl3); H NMR (CDCl3) δ 1.15–1.35 (m, 2H), 1.35–1.55 (m, 3H), 1.62–1.75 (m, 2H),
1.85–2.00 (m, 1H); 2.10–2.40 (m, 4H), 2.70 (d, 1H, J=11.3 Hz), 2.85 (dd, 1H, J=11.3, 3.2 Hz), 3.85 (s,
3H), 3.90 (s, 3H); 4.63 (br s, 1H), 4.66 (br s, 1H), 6.80–6.95 (m, 3H); 13C NMR (CDCl3) δ 24.7, 26.2,
34.0, 42.3, 44.8, 53.3, 55.9, 56.0, 64.2, 71.3, 106.9, 110.3, 110.9, 119.7, 137.2, 146.3, 147.8, 148.7; IR
(NaCl neat) 1655, 1604, 1592 cm−1. These spectral data are in agreement with reported values.3n
3.10. (4S,10R)-4-(3,4-Dimethoxyphenyl)quinolizidin-2-one 11a
To a stirred solution of 10a (0.2 g, 0.70 mmol) in 80% acetic acid (15 ml) at 0°C was added sodium
paraperiodate (0.45 g, 1.54 mmol) and osmium tetroxide (0.006 g, 0.024 mmol). The reaction mixture
was stirred for 18 h at 10°C. Acetic acid was evaporated to give a residue which was partitioned

P. Chalard et al. / Tetrahedron: Asymmetry 9 (1998) 4361–4368
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between CH2Cl2 (10 ml) and saturated sodium bicarbonate solution (10 ml). The aqueous layer was
extracted with CH2Cl2 (15 ml). The combined organic layers were dried over MgSO4, concentrated and
chromatographed over silica gel (eluted with ethyl acetate) to afford 11a (140 mg, 70% yield) as a yellow
oil: [α]D25 +9.5 (c 3.1, CHCl3) {lit.4 [α]D25 +10.8 (c 1.31, CHCl3)}; 1H NMR (CDCl3) δ 1.10–1.24 (m,
1H), 1.34–1.70 (m, 5H), 2.17 (td, 1H, J=11.8, 3.0 Hz), 2.35 (dd, 1H, J=14.9, 8.7 Hz), 2.58 (m, 2H), 2.87
(m, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.25 (dd, 1H, J=6.1, 3.9 Hz), 6.64–6.68 (m, 2H), 6.79 (d, 1H, J=8.7
Hz); 13C NMR (CDCl3) δ 23.2, 23.9, 31.7, 46.7, 47.4, 51.2, 54.0, 55.6, 55.7, 63.7, 110.4, 111.5, 120.7,
131.3, 148.2, 148.5, 209.6; IR (NaCl neat) 1715 cm−1. These spectral data are in agreement with reported
values.3n
3.11. (4S,10S)-4-(3,4-Dimethoxyphenyl)quinolizidin-2-one 11b
Using the above procedure, 10b (147 mg, 0.51 mmol) gave 11b (130 mg, 90% yield) as a yellow oil:
[α]D −63 (c 1.38, CHCl3); 1H NMR (CDCl3) δ 1.24 (m, 1H), 1.35–1.70 (m, 6H), 2.19–2.50 (m, 4H),
25
2.64 (t, 1H, J=12.8 Hz), 2.73 (d, 1H, J=11.4 Hz), 3.15 (dd, 1H, J=12.1, 3.1 Hz), 3.82 (s, 3H), 3.85 (s, 3H),
6.75 (m, 2H), 6.93 (br s, 1H); 13C NMR (CDCl3) δ 24.1, 25.7, 34.2, 48.6, 50.7, 52.7, 55.8, 55.9, 62.3,
69.8, 109.7, 110.9, 119.4, 135.0, 148.2, 149.2, 207.7; IR (NaCl neat): 2793, 2755 (Bohlmann bands),
1725 cm−1. These spectral data are in agreement with reported values.3n
3.11.1. (−)-Lasubine I 1
To a solution of 11a (47 mg, 0.16 mmol) in anhydrous THF (5 ml) at −78°C under argon was added
L-Selectride (1 M solution in THF, 0.244 ml, 0.244 mmol). The reaction mixture was stirred for 2 h at
−78°C, then it was warmed to 0°C and water (3.1 ml) was added. The mixture was concentrated and
saturated sodium bicarbonate (5 ml) was added. The aqueous layer was extracted with CHCl3 (3×5
ml). The organic layer was dried over MgSO4, concentrated and chromatographed over alumina (eluted
25
with ethyl acetate:hexane 1:1) to give (−)-lasubine I 1 (29 mg, 62% yield) as a pale yellow oil: [α]D
−6.5 (c 2.6, MeOH) {lit.2 [α]D −8.8 (c 0.34, MeOH), lit.4 [α]D −7.03 (c 0.37, MeOH)}; 1H NMR
(CDCl3) δ 1.18–2.12 (m, 11H), 2.24 (td, 1H, J=11.7, 2.6 Hz), 2.69 (br d, 1H, J=4.7 Hz), 2.96 (m, 1H),
3.86 (s, 3H), 3.87 (s, 3H), 4.08 (t, 1H, J=4.7 Hz), 4.18 (heptuplet, 1H, J=4.4 Hz), 6.77–6.89 (m, 3H);
13C NMR (CDCl3) δ 24.1, 24.5, 32.4, 40.2, 40.3, 51.2, 54.0, 55.8, 55.9, 61.9, 65.0, 110.7, 111.9, 120.6,
135.3, 147.8, 148.7; IR (NaCl neat): 3382, 1513 cm−1. These spectral data are in agreement with reported
values.3n
22
23
3.11.2. (−)-Lasubine II 2
To a solution of 12b (241 mg, 0.83 mmol) in dry THF (7 ml) at −78°C under argon was added LS-
Selectride (1 M solution in THF, 1.24 ml, 1.24 mmol). The reaction mixture was stirred for 12 h at
−78°C, then it was warmed to 0°C and water (5 ml) was added. The mixture was concentrated and
saturated aqueous sodium bicarbonate (7 ml) was added. The aqueous layer was extracted with CHCl3
(3×15 ml). The organic layer was dried over MgSO4, concentrated and chromatographed over silica gel
(eluted with ethyl acetate:methanol 9:1) to give (−)-lasubine II 2 (140 mg, 60% yield) as a pale yellow oil:
25
22
[α]D −41.0 (c 3.7, MeOH) {lit.2 [α]D −34.7 (c 0.32, MeOH)}; ee >90% (HPLC, hexane:2-propanol
1
8:2, 0.1% Et3N); H NMR (CDCl3) δ 1.20–1.43 (m, 2H), 1.48 (m, 2H), 1.53 (m, 1H), 1.61–1.73 (m,
4H), 1.74–1.92 (m, 3H), 2.38 (m, 1H), 2.67 (d, 1H, J=10.9 Hz), 3.32 (br d, 1H, J=10.5 Hz), 3.84 (s, 3H),
3.87 (s, 3H), 4.12 (br s, 1H), 6.74–6.95 (m, 3H); 13C NMR (CDCl3) δ 24.9, 26.1, 33.6, 40.3, 42.8, 53.2,
55.8, 55.9, 56.5, 63.5, 64.9, 110.8, 119.5, 119.7, 137.2, 147.8, 148.9; IR (NaCl): 3620, 2797, 2762 cm−1.
These spectral data are in agreement with reported values.3n

4368
P. Chalard et al. / Tetrahedron: Asymmetry 9 (1998) 4361–4368
3.11.3. (+)-Subcosine II 3
trans-3,4-Dimethoxycinnamic anhydride (0.100 g, 0.25 mmol) was added to a solution of (−)-lasubine
II (68 mg, 0.23 mmol) and DMAP (2.5 g, 0.023 mmol) in pyridine (10 ml) under argon. The mixture
was refluxed for 3 h, then cooled to room temperature. The solvent was removed in vacuo and saturated
aqueous sodium bicarbonate (10 ml) was added. The aqueous layer was extracted with CH2Cl2 (3×15
ml). The combined organic layers were dried over K2CO3 and concentrated. The resulting crude product
was chromatographed over silica gel (eluted with ethyl acetate) to give (+)-subcosine II 3 (65 mg, 60%
yield) as a pale yellow oil: [α]D +121 (c 3.5, MeOH) {lit.2 [α]D +85.3 (c 0.64, MeOH)}; 1H NMR
(CDCl3) δ 1.20–1.80 (m, 8H), 1.85–2.20 (m, 3H), 2.36 (t, 1H, J=10.5 Hz), 2.72 (t, 1H, J=11.4 Hz),
3.28 (d, 1H, J=8.4 Hz), 3.85 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 5.20 (m, 1H), 6.40 (d, 1H,
J=15.9 Hz), 6.75–6.93 (m, 4H), 7.08–7.18 (m, 2H), 7.67 (d, 1H, J=15.9 Hz); 13C NMR (CDCl3) δ 24.9,
26.2, 33.6, 37.4, 39.8, 53.2, 55.8, 55.9, 56.0, 56.1, 57.2, 64.2, 68.4, 109.6 (×2), 111.0 (×2), 116.3 (×2),
122.8, 127.5, 137.0, 147.9, 149.2 (×2), 151.1 (×2), 166.7; IR (NaCl neat) 1709, 1634, 1599 cm−1. These
spectral data are in agreement with reported values.2
25
22
Acknowledgements
We thank Mrs. I. Canet for determination of enantiomeric purity of 5 by deuterium NMR in a chiral
solvent (PBLG).
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