Stereoselective synthesis of quinolizidine alkaloids: (-)-Lasubin II

Article abstract of DOI:10.1515/znb-2008-0409

Based on a higly diastereoselective Mannich reaction of N-(3,4-dimethoxybenzylidene) 2,3,4,6-tetra-O-pivaloyl-β-D- galactopyranosylamine 3 with the Danishefsky diene the quinolizidine alkaloid lasubin II was synthesized in enantiomerically pure form in six steps.

Full text of DOI:10.1515/znb-2008-0409

Stereoselective Synthesis of Quinolizidine Alkaloids: (–)-Lasubin II
Markus Weymann and Horst Kunz
Institut fu¨r Organische Chemie, Universita¨t Mainz, Duesbergweg 10 – 14, D-55128 Mainz, Germany
Reprint requests to Prof. Dr. Horst Kunz. E-mail: hokunz@uni-mainz.de
Z. Naturforsch. 2008, 63b, 425 – 430; received January 15, 2008
Based on a higly diastereoselective Mannich reaction of N-(3,4-dimethoxybenzylidene) 2,3,4,6-
tetra-O-pivaloyl-β-D-galactopyranosylamine 3 with the Danishefsky diene the quinolizidine alkaloid
lasubin II was synthesized in enantiomerically pure form in six steps.
Key words: Quinolizidine Alkaloids, Carbohydrate Auxiliaries, Domino Mannich-Michael
Reactions, Cuprate Addition, Lasubin II
Introduction
Michael condensation reaction sequence [8] start-
ing from 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranos-
ylamine (1) and veratrum aldehyde (2). The imine 3
formed from these components reacts with the Dan-
ishefsky diene [9] 4 promoted by ZnCl2 to give the de-
hydro-piperidinone5 with high yield and excellent dia-
stereoselectivity (> 15 : 1 according to 1H NMR spec-
troscopy, Scheme 1).
A number of biologically and structurally interest-
ing alkaloids have the quinolizidine framework [1].
(–)-Lasubin I and (–)-lasubin II isolated from Lager-
stroemia subcostata Koehne [2] recently received in-
creasing attention as target compounds for the valida-
tion of stereoselective syntheses of quinolizidine alka-
loids.
Dehydropiperidinoneslike 5 are vinylogous carbox-
amides and, therefore, of low electrophilic reactivity.
They do not react with Grignard compounds or organo-
lithium reagents at low temperature. However, once
subjected to a stress between a soft nucleophile, e. g.
a cuprate, and a hard electrophile the conjugate addi-
tion of the cuprate smoothly proceeds. Reaction with
the 4-chlorobutyl-magnesiocuprate obtained from 4-
chloro-butylbromide via the Grignard reagent and sub-
sequent addition of CuI furnished the 2,6-cis-disub-
stituted piperidinones 6 with high diastereoselectivity.
However, a byproduct 7 obviously resulting from a β-
elimination was also formed (Scheme 2). The chro-
matographic separation of the mixture turned out to be
difficult. By changing the Lewis acid from BF3 ether-
ate to trimethylchlorosilane (TMS-Cl), the formation
of 7 could be prevented, but the 1,4-addition now pro-
ceeded more slowly and with almost no diastereoselec-
tivity.
Initially, lasubin II was synthesized diastereoselec-
tively in racemic form [3]. Asymmetric syntheses of
lasubin II were achieved based on stereoselective trans-
formations of enantiomerically pure substrates [4] or,
for example, via a diastereoselective aza-Diels-Alder
reaction using a resolved chiral arylaldehyde tricar-
bonylchromium complex [5]. Recently, an enantios-
electively catalyzed aza-Diels-Alder reaction [6] and
a [2+2+2] cycloaddition reaction [7] were success-
fully used for the synthesis of enantiomerically pure
lasubin II.
The conjugate addition of the (1-ethoxy)ethyl-
(EE)-protected 4-hydroxybutylmagnesiocuprate to de-
hydropiperidinone 5 promoted by BF3· Et2O pro-
ceeded with high yield to give the 2,6-disubstituted
piperidinones 8 (Scheme 2). No byproduct analogous
to 7 was observed. The 2,6-cis-disubstituted compound
Stereoselective Synthesis of the Quinolizidine Alka-
loid Lasubin II
We here describe a short stereoselective synthe-
sis of (–)-lasubin II based on a domino Mannich-
c
0932–0776 / 08 / 0400–0425 $ 06.00 ꢀ 2008 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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426
M. Weymann – H. Kunz · Stereoselective Synthesis of Quinolizidine Alkaloids: (–)-Lasubin II
Scheme 1.
Scheme 2.
was preferentially formed, but with only moderate di- lated (69 %) besides the minor diastereomer trans-9
astereoselectivity of 5 : 2. Probably, the 1-ethoxy-eth- (27 %).
oxy functionality participates in the coordination of the
Lewis acid and of the metal ions. This could prevent
an elimination to give byproducts like 7, but also could
Reaction of cis-9 with triphenylphosphine/carbon
tetrachloride [10] in the presence of triethylamine
in acetonitrile resulted in a sequence of nucle-
interfere with the coordination phenomena responsible ophilic substitution of the hydroxyl group and sub-
for the stereodifferentiation.
sequent ring-closing N-alkylation to furnish the
Simultaneous mildly acidic cleavage of the eth- cis-disubstituted piperidinone 10. The stereoselec-
oxyethyl group and of the N-glycosidic bond with tive reduction of the carbonyl group of 10 to
1N HCl in methanol gave the hydrochloride of the give the thermodynamically less favored trans-con-
piperidinones. The pivaloylated galactose auxiliary figured compound lasubin II 11 is best accom-
was quantitatively recollected by extraction with di- plished using lithium tris-siamylborohydride (LS-
R
ethyl ether. Treatment of the piperidinone hydrochlo- Selectrideꢀ) [3c] as the sterically demanding hydride
ride with Na2CO3 solution (pH = 10 – 11) and ex- transfer reagent. After hydrolytic work up and chro-
traction with CH2Cl2 gave the free piperidinone 9 matography (–)-lasubin II was isolated in a not op-
as a mixture of the diastereomers cis-9 and trans-9 timized yield of 51 %. Its IR-spectroscopic [3c] and
(65%, d. r. 2.5: 1, Scheme 3). After separation by col- NMR-spectroscopic data [3a, b, d] as well as its optical
umn chromatography on silica in CH2Cl2 (15 : 1), the rotation value [2] are in agreement with those reported
pure 2,6-cis-disubstituted piperidinone cis-9 was iso- in the literature.
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M. Weymann – H. Kunz · Stereoselective Synthesis of Quinolizidine Alkaloids: (–)-Lasubin II
427
Scheme 3.
Conclusion
on silica gel MN 60 (0.04 – 0.063 mm), Macherey und Nagel,
for chromatography under atmospheric pressure, silica gel 60
(0.06 – 0.2 mm) (Baker) was used. Analytical HPLC was car-
ried out in MeOH/H2O mixtures using a LKB (Pharmacia)
2150 unit equipped with diode array detection (LKB 2140).
1H and 13C NMR spectra were recorded on Bruker AC-200
and Bruker AC-400 NMR instruments. Optical rotation val-
ues were measured with a Perkin-Elmer 241 polarimeter.
FAB-MS spectra were recorded on a Finnigan-MAT-95 spec-
trometer.
2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosylamine (1)
was prepared as reported in the literature [11], however,
applying a varied procedure via penta-O-acetyl-galactopyr-
anose as described for the corresponding D-arabinopyranos-
ylamine [12].
Owing to the stereodifferentiating potential of
the carbohydrate framework [10] in the O-pivalo-
ylated galactosylamine 1, the enantiomerically pure
Lythraceae alkaloid lasubin II is accessible from vera-
trum aldehyde (2) in six steps. A separation of diastere-
omers was only necessary on the stage of the cis/trans-
diastereomeric 2,6-disubstituted piperidinones 9. Al-
though inexpensive, the carbohydrate auxiliary can be
recollected almost quantitatively and after conversion
to the glycosylamine re-used for the same process.
Experimental Section
General procedures
N-(3,4-Dimethoxybenzylidene)-2,3,4,6-tetra-O-pivaloyl-β-
D-galactopyranosylamine (3)
Reagents and solvents were distilled before use: Tetrahy-
drofuran, dioxane, and Et2O were distilled from potassium/
benzophenone ketyl. CH2Cl2 was distilled from CaH2. Light
petroleum refers to b. p. 60 – 80 ◦C. All reactions and distilla-
tions were carried out in flame-dried glassware under argon
atmosphere.
To a solution of tetra-O-pivaloyl-galactosylamine (1)
(5.2 g, 10 mmol) and 3,4-dimethoxybenzaldehyde (2.0 g,
12 mmol) in isopropanol (20 mL) 10 drops of glacial ◦acidic
acid were added, and the solution was heated to 80 C for
TLC was performed on silica gel 60 F254 (E. Merck, 30 min. After removal of the solvent in vacuo the crude
Darmstadt, Germany). Flash chromatography was carried out N-galactosyl imine remained as an amorphous solid. Further
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M. Weymann – H. Kunz · Stereoselective Synthesis of Quinolizidine Alkaloids: (–)-Lasubin II
purification was not necessary. Characterization of the com- 5 mmol) was added. After 3 h, the magnesium has been dis-
pound was carried out via its subsequent products.
solved, and the Grignard solution was given via a steel sy-
ringe to a cooled (−78 ◦C) suspension of CuI (0.9 g, 5 mmol)
in tetrahydrofuran (15 mL). The clear brown solution was
warmed up to −50 ◦C within 2 h and was cooled again
N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
2-(3,4-dimethoxyphenyl)-5,6-dehydropiperidin-4-one (5)
◦
to −78 C. BF3· Et2O (0.6 mL, 5 mmol) was added. Af-
In analogy to a reported procedure [8], imine 3 (7.3 g,
10 mmol) was dissolved in dry tetrahydrofuran (50 mL) and
cooled to −78 ◦C. A 1 M solution (11 mL) of ZnCl2 in
THF/CH2Cl2 (1 : 1, v/v) was added. After 10 min Danishefky
diene 4 [9] (2.5 mL, 12.5 mmol) was added. After stirring for
30 min at −78 ◦C, the solution was stirred at −20 ◦C for 36 h
(monitoring by TLC). Aqueous 1 N HCl (10 mL) was added,
and the solvent evaporated in vacuo. Diethyl ether (200 mL)
was added, the acidic aqueous solution separated, and the or-
ganic solution extracted three times with aq. NaHCO3 solu-
tion. Remaining zinc salts were removed by extraction with
◦
ter 15 min (temperature < −55 C) a solution of dehydro-
piperidinone 5 (0.73 g, 1 mmol) in tetrahydrofuran (10 mL)
was added and the mixture stirred for 18 h. The mixture was
diluted with diethyl ether (50 mL) and treated with conc.
aq. NH4OH/NH4Cl 1 : 1 (v/v). The aqueous layers were ex-
tracted twice with diethyl ether, the combined ether solutions
were washed with brine and dried with MgSO4. After evap-
oration of the solvent the remainder was purified by chro-
matography on silica (15 × 3 cm) in light petroleum/ethyl
acetate (4 : 1). Yield: 0.46 g (56 %) of a mixture of 6 and 7.
The composition was determined by 1H NMR spectroscopy,
ratio of 6/7 4 : 1. Diastereomeric ratio for 6: > 10 : 1. – NMR
data for 6: 1H NMR (400 MHz, CDCl3): δ = 1.06, 1.15, 1.20
and 1.23 (4s, each 9H, piv-CH3), 1.48 (m, 2-3H, CH2), 1.74
(m, 2H, CH2), 2.08 (m, 1H, CH2), 2.44 (m, 3H, CH2C=O,
CH2C=Oꢀ), 2.57 (dd, 1H, Jvic = 11.0 Hz, Jgem = 14.6 Hz,
CH2C=O), 3.29 (dd, 1H, J1 = 7.0 Hz, J2 = 7.5 Hz, alkyl-
CHN), 3.50 (m, 2H, CH2Cl), 3.77 – 3.94 (m, 8H, H-5ꢀ, H-6aꢀ,
R
10 % TitriplexꢀIII solution (2×50 mL). After washing with
brine and drying with MgSO4, the solvent was evaporated in
vacuo, and the product was purified by chromatography on
silica (20×5 cm) in light petroleum/ethyl acetate 2 : 1.
Yield: 5.26 g (72 %, based on glycosylamine 1); pale
yellow crystalline solid; m. p. 148 ◦C; [α]D22 = 33.7 (c =
1.0, CHCl3); Rf = 0.08 (light petroleum/ethyl acetate 3 : 1).
Diastereomeric ratio: > 15 : 1 (1H NMR). – 1H NMR
(200 MHz, CDCl3): δ = 1.08, 1.15, 1.16 and 1.25 (4s, each
9H, piv-CH3), 2.66 – 2.75 (m, 2H, CH2C=O), 3.68 (m, 1H,
H-5ꢀ), 3.85 (s, 3H, OCH3), 3.86 (m, 1H, H-6aꢀ), 3.90 (s, 3H,
OCH3, OCHꢀ ), 3.97 (d, 1H, J1 ,2 = 9.6 Hz, H-1), 4.08 (dd,
ꢀ
ꢀ
1H, J6b ,5 =36.4 Hz, J6b ,6a = 11.0 Hz, H-6bꢀ), 4.38 (dd,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1H, Jvic = 3.6 Hz, Jvic = 11.0 Hz, aryl-CHN), 4.84 (dd,
1H, J3 ,4 = 3.2 Hz, J3 ,2 = 9.8 Hz, H-3ꢀ), 5.23 (d, 1H,
ꢀ
ꢀ
ꢀ
ꢀ
OCH3), 4.02 (m, 1H, H-6bꢀ), 4.28 (d, 1H, J1 ,2 = 9.5 Hz,
J4 ,3 = 3.0 Hz, H-4ꢀ), 5.48 (t, 1H, J = 9.7 Hz, H-2ꢀ), 6.76 –
6.84 (m, 3H, arom.). – 13C NMR (100.6 MHz, CDCl3):
δ = 24.95 (CH2), 27.09, 27.22 and 27.42 (piv-CH3), 31.05
and 32.87 (CH2), 38.71, 38.83 and 39.03 (piv-Cquart), 44.68
(CH2C=O), 45.76 (CH2C=Oꢀ), 49.27 (CH2Cl), 54.15 (alkyl-
CHN), 55.91 and 56.10 (OCH3, OCHꢀ3), 58.09 (aryl-CHN),
61.06 (C-6ꢀ), 65.27, 67.07, 71.56 and 72.53 (C-2ꢀ, C-3ꢀ,
C-4ꢀ, C-5ꢀ), 88.53 (C-1ꢀ), 111.22, 111.46, 120.98, 131.72,
149.32 and 149.53 (arom.), 176.52, 176.98 and 177.11
(pivC=O), 208.37 (C=O). – NMR data for 7: 13C NMR
(100.6 MHz, CDCl3): δ = 25.24, 31.53 and 31.88 (CH2),
44.45 (CH2C=O), 48.74 (CH2Cl), 54.15 and 55.91 (OCH3,
OCHꢀ3), 56.02 (aryl-CHN), 61.53 (C-6ꢀ), 65.82, 67.37 and
68.83 (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 110.89 (C-1ꢀ), 110.89 and
120.12 (arom.), 130.90 (alkene), 133.88 (arom.), 146.86
(alkene), 197.95 (C=O).
ꢀ
ꢀ
ꢀ
ꢀ
H-1ꢀ), 4.72 (dd, 1H, Jvic = 5.7 Hz, Jvic = 11.1 Hz, aryl-CHN),
ꢀ
4.95 (dd, 1H, J3 ,4 = 3.1 Hz, J3 ,2 = 9.9 Hz, H-3ꢀ), 5.26
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(d, 1H, J = 8.1 Hz, =CHCO), 5.31 (d, 1H, J4 ,3 = 2.7 Hz,
H-4ꢀ), 5.66 (t, 1H, J = 9.8 Hz, H-2ꢀ), 6.79 – 6.91 (m, 3H,
arom.), 7.29 (d, 1H, J = 8.0 Hz, NCH=C). – 13C NMR
(100.6 MHz, CDCl3): δ = 27.07, 27.09 and 27.15 (piv-CH3),
38.65, 38.72, 28.81 und 39.04 (piv-Cquart), 43.94 (CH2C=O),
55.89 and 56.05 (OCH3), 60.90 (arylCHN), 60.94 (C-6ꢀ),
65.00, 66.75, 71.64 and 72.53 (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 87.15
(C-1ꢀ), 103.79 (=CHCO), 110.64, 111.44, 120.45 and 130.15
(arom.), 149.29 (NCH=), 149.47 and 149.56 (arom.), 176.44,
176.79, 177.03 and 177.64 (pivC=O), 192.04 (C=O). –
C39H57NO12 (731.87): calcd. C 64.00, H 7.85, N 1.91; found
C 63.97, H 7.82, N 2.10.
(2S,6S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyrano-
syl)-2-(3,4-dimethoxyphenyl)-6-(4-chlor-butyl)-piperidin-4-
one (6) and N-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-
pyranosyl)-1-amino-1-(3,4-dimethoxyphenyl)-9-chloro-4-
nonen-3-one (7)
(2S,6S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranos-
yl)-2-(3,4-dimethoxyphenyl)-6-(4-(1-ethoxyethyloxy)-butyl)-
piperidin-4-one (8)
Dibromomethane (5 – 10 drops) was added to a stirred
To stirred magnesium cuttings (0.39 g, 16 mmol) in
suspension of magnesium cuttings (0.12 g, 10 mmol) in tetrahydrofuran (12 mL) 4-chlorobutyl-(1-ethoxy)ethyl ether
diethyl ether (10 mL). After opacity occurred the mixture (2.17 g, 12 mmol) was given. After addition of a few drops
◦
was cooled to 0 C, and 1-bromo-4-chlorobutane (0.58 mL, of dibromomethane the mixture was heated under reflux
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M. Weymann – H. Kunz · Stereoselective Synthesis of Quinolizidine Alkaloids: (–)-Lasubin II
429
for 5 h. The resulting Grignard solution was added drop- (TLC monitoring). The solvent was evaporated in vacuo and
wise via a steel syringe to a cooled (−60 ◦C) and vigorously the residue dissolved in diethyl ether (100 mL). The ether
stirred suspension of CuBr (1.72 g, 12 mmol) in tetrahy- solution was washed with water (5×20 mL). The combined
drofuran (60 mL). Within 1 h the mixture was warmed up aqueous solutions were concentrated in vacuo to a volume
◦
to −40 C thereby changing the color from greyish brown of 30 mL. Na2CO3 was added until a pH of 10 – 11 was
to grey black. After cooling again to −78 ◦C, BF3· OEt2 reached and the mixture stirred for 20 min. Extraction with
(2.8 mL, 22.5 mmol) was added dropwise. Via a steel sy- CH2Cl2 (3 × 50 mL), drying with Na2SO4 and evaporation
ringe and under exclusion of moisture, a solution of the of the solvent in vacuo gave the crude piperidinone 9 as a
dehydropiperidone 5 (2.2 g, 3.0 mmol) in tetrahydrofuran brown oil. Purification was carried out by chromatography
was added within 25 min. The color changed to ochre- on silica (13×3 cm) in CH2Cl2/MeOH 15 : 1. Yield: 0.76 g
yellow. After completion of the reaction (1.5 h, TLC mon- (65 %), yellow amorphous solid. – C17H25NO4 (307.39):
itoring), conc. NH4OH/sat. NH4Cl (50 mL, 1 : 1 v/v) was calcd. C 66.43, H 8.20, N 4.56; found C 66.06, H 8.10,
added. After warming up to r. t., the mixture was diluted N 4.65.
with diethyl ether (300 mL), the organic layer was ex-
tracted with conc. NH4OH/sat. NH4Cl (50 mL, 1 : 1 v/v).
The combined aqueous solutions were washed with di-
ethyl ether (2 × 100 mL) and the combined organic solu-
tions dried with MgSO4. The solvent was evaporated in
vacuo and the remaining crude product 8 purified by chro-
matography on silica (17 × 4.5 cm) in light petroleum/ethyl
acetate (2 : 1). Yield 2.35 g (89 %), colorless amorphous
solid; [α]2D2 = −13.3 (c = 1.7, CHCl3), Rf = 0.48 (light
petroleum/ethyl acetate 2 : 1), diastereomeric ratio: 2.5 : 1
(according to 1H NMR spectroscopy). – 1H NMR (400 MHz,
CDCl3): δ = 1.01 (s, 9H, piv-CH3), 1.04 – 1.51 (m, 38H,
piv-CH3, EEO-CH3, CH2), 2.02 (m, 1H, CH2), 2.39 (m, 3H,
Separation of the diastereomers was achieved by repeated
chromatography:
Major diastereomer (cis-9): Yield: 0.53 g (45 %), [α]D22
=
−26.0 (c = 1.0, CHCl3), Rf = 0.48 (CH2Cl2/MeOH 9 : 1). –
1H NMR (200 MHz, CDCl3): δ = 1.32 – 1.54 (m, 6H, CH2),
2.15 (dd, 1H, Jvic = 11.6 Hz, Jgem = 13.5 Hz, CH2C=O),
2.34 – 2.45 (m, 4H, CH2C=O, CH2C=Oꢀ, OH), 2.89 (m, 1H,
alkyl-CHN), 3.55 (dd, 1H, J1 = 5.8 Hz, J2 = 6.2 Hz, CH2OH),
3.80 (m, 7H, OCH3, OCHꢀ3, aryl-CHN), 6.75 – 6.89 (m, 3H,
arom.). – 13C NMR (100.6 MHz, CDCl3): δ = 21.93, 32.52
and 36.61 (CH2), 48.03 and 50.48 (CH2C=O, CH2C=Oꢀ),
55.87 and 55.91 (OCH3, OCHꢀ3), 56.69 and 60.81 (alkyl-
CHN, aryl-CHN), 62.38 (CH2OH), 109.76, 111.29, 118.58
and 135.34 (arom.), 208.75 (C=O).
CH2C=O, CH2C=Oꢀ), 2.51 (dd, 1H, Jvic = 11.1 Hz, Jgem
=
14.6 Hz, CH2C=O), 3.22 – 3.59 (m, 4H, EEO-CH2, alkyl-
Minor diastereomer (trans-9): Yield: 0.21 g, 18 %),
[α]2D2 = 23.3 (c = 2.0, CHCl3), Rf = 0.41 (CH2Cl2/MeOH
9 : 1). – 1H NMR (200 MHz, CDCl3): δ = 1.10 – 1.56 (m,
CHN), 3.70 – 3.81 (m, 5H, OCH3, H-5ꢀ, H-6aꢀ), 3.85 (s, 3H,
OCH3), 3.92 (d, 1H, J1 ,2 = 9.6 Hz, H-1ꢀ), 4.01 (dd, 1H,
ꢀ
ꢀ
J6b ,5 = 6.3 Hz, J6b ,6a = 11.0 Hz, H-6bꢀ), 4.35 (dd, 1H,
ꢀ
ꢀ
ꢀ
ꢀ
6H, CH2), 2.06 (sbroad, 2H, NH, OH), 2.22 (dd, 1H, Jvic
5.4 Hz, Jgem = 14.3 Hz, CH2C=O), 2.56 (m, 3H, CH2C=O,
CH2C=Oꢀ), 3.21 (m, 1H, alkyl-CHN), 3.59 (dd, 1H, J1
=
ꢀ
Jvic = 3.4 Hz, Jvic = 10.9 Hz, aryl-CHN), 4.60 (q, 1H, J =
ꢀ
ꢀ
ꢀ
ꢀ
5.3 Hz, OCHOCH3), 4.79 (dd, 1H, J3 ,4 = 3.0 Hz, J3 ,2 =
=
9.7 Hz, H-3ꢀ), 5.18 (d, 1H, J4 ,3 = 3.0 Hz, H-4ꢀ), 5.44 (t,
1H, J = 9.6 Hz, H-2ꢀ), 6.72 (s, 1H, arom.), 6.80 (s, 2H,
arom.). – 13C NMR (100.6 MHz, CDCl3): δ = 15.26 and
19.78 (EEO-CH3), 24.36 (CH2), 27.01, 27.12 and 27.34 (piv-
CH3), 30.29 and 31.64 (CH2), 38.63, 38.74 and 38.92 (piv-
Cquart), 45.69 (CH2C=O), 49.15 (CH2C=Oꢀ), 54.23 (alkyl-
CHN), 55.82 and 56.01 (OCH3), 57.93 (aryl-CHN), 60.44
and 60.50 (EEO-CH2), 60.98, 64.98 (C-6ꢀ), 65.22, 67.01,
71.40 and 72.30 (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 88.48 (C-1), 99.41,
99.46 (OCHOCH3), 111.17, 111.37, 120.93, 131.79, 149.20
and 149.43 (arom.), 176.41, 176.87, 177.02 and 177.60
(pivC=O), 208.35 (C=O). – C47H75NO14 (878.10): calcd.
C 64.29, H 8.61, N 1.60; found C 64.40, H 8.64, N 1.59.
ꢀ
ꢀ
4.8 Hz, J2 = 6.2 Hz, CH2OH), 3.84 and 3.86 (2s, each 3H,
OCH3, OCHꢀ3), 4.29 (dd, 1H, J1 = 5.9 Hz, J2 = 6.3 Hz, aryl-
CHN), 6.80 – 6.91 (m, 3H, arom.). – 13C NMR (100.6 MHz,
CDCl3): δ = 22.18, 32.27 and 33.79 (CH2), 47.35 and 48.46
(CH2C=O, CH2C=Oꢀ), 52.37 and 55.07 (alkyl-CHN, aryl-
CHN), 55.87 and 55.91 (OCH3, OCHꢀ ), 62.34 (CH2OH),
110.05, 111.12, 118.87, 135.13, 148.443and 149.16 (arom.),
209.33 (C=O).
(4S,9aS)-4-(3,4-Dimethoxyphenyl)-decahydroquinolizidin-
2-one (10)
To a solution of piperidone cis-9 (0.51 g, 1.66 mmol)
in 5 mL of acetonitrile, triethylamine (0.22 mL, 1.6 mmol)
and CCl4 (0.24 mL, 2.5 mmol) were given. After cooling
◦
(2S,6S)-2-(3,4-Dimethoxyphenyl)-6-(4-hydroxy-butyl)-
piperidin-4-one (9)
to 0 C triphenylphosphine (0.52 g, 2.0 mmol) was added.
The mixture was stirred at 0 ◦C for 30 min and allowed to
warm up to r. t. After 48 h (montoring by TLC) sat. NaHCO3
To a stirred solution of the N-galactosyl piperidinone 8 solution (10 mL) and diethyl ether (60 mL) were added.
(2.3 g, 2.6 mmol) in methanol (50 mL) at r. t. was added The organic solution was washed with brine. The aque-
1N HCl (9 mL). After 36 h the hydrolysis was completed ous layer was extracted twice with diethyl ether (50 mL).
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430
M. Weymann – H. Kunz · Stereoselective Synthesis of Quinolizidine Alkaloids: (–)-Lasubin II
The combined organic solutions were dried with Na2SO4, added and the tetrahydrofuran removed in vacuo. The residue
and the solvent was evaporated in vacuo. Purification of the was dissolved in CH2Cl2 (20 mL), washed with sat. NaCl so-
crude quinolizidinone 10 was carried out by chromatogra- lution (10 mL) and dried over Na2SO4. After evaporation of
phy on silica (19 × 3 cm) in light petroleum/ethyl acetate the solvent, the crude lasubin II was purified by chromatog-
(1 : 2.5). The NMR spectroscopic data of 10 are in agree- raphy on silica (8 × 2.5 cm) in CH2Cl2/MeOH 9 : 1, subse-
ment with those given in the literature [3c]. Yield: 0.38 g quently in 100 % MeOH. The spectroscopic data (IR [3c],
(76 %), pale yellow, amorphous solid; [α]2D2 = −41.9 (c = NMR [3b]) of 11 are in agreement with those given in the
1.5, CHCl3), Rf = 0.22 (light petroleum/ethyl acetate 1 : 2). – literature. Yield: 0.17 g (51 %), yellow, amorphous solid; di-
FT-IR (CDCl3): 1719 cm−1. – 1H NMR (200 MHz, CDCl3): astereomeric ratio: ꢁ 10 : 1 (1H NMR), [α]2D2 = −34.2 (c =
δ = 1.18 – 1.66 (m, 7H, CH2), 2.25 – 2.78 (m, 6H, NCH2, 0.57, CHCl3), [α]22 = −30.8 (c = 0.34, MeOH); lit.: [2]
NCHR2, CH2C=O, CH2C=Oꢀ), 3.17 (dd, 1H, Jvic = 2.3 Hz, [α]D22 = −34.7 (c D= 0.32, MeOH). – FT-IR (CDCl3): ν =
ꢀ
Jvic = 11.7 Hz, aryl-CHN), 3.83 und 3.86 (2s, each 3H, 3614, 3456, 3155, 3007, 2973, 2839, 2798, 2254, 1818,
OCH3, OCHꢀ3), 6.79 (s, 1H, arom.), 6.87 (m, 2H, arom.). – 1794, 1709, 1641, 1606, 1694, 1563, 1516, 1465, 1443,
13C NMR (50.3 MHz, CDCl3): δ = 24.10, 25.75 and 1421, 1386, 1341, 1314, 1300, 1261, 1232, 1197, 1179,
34.26 (CH2), 48.65 and 50.78 (CH2C=O, CH2C=Oꢀ), 52.71 1152, 1133, 1094, 1076, 1047, 1029, 1014, 986, 908, 810,
1
(NCH2), 55.80 and 55.91 (OCH3, OCHꢀ3), 62.39 (NCHR2), 732 cm−1. – H NMR (400 MHz, CDCl3): δ = 1.20 – 1.27
69.90 (aryl-CHN), 109.71, 110.99, 119.45, 135.10, 148.28 (m, 4H, CH2), 1.28 – 1.35 (m, 2H, CH2), 1.40 – 1.62 (m, 4H,
and 149.28 (arom.), 207.75 (C=O).
CH2), 1.72 (d, 1H, Jgem = 14.0 Hz, NCH2), 1.82 (dt, 1H,
Jvic = 2.6 Hz, Jgem = 14.2 Hz, NCH2), 2.34 (m, 1H, NCHR2),
2.61 (d, 1H, J = 11.5 Hz, CHOH), 3.27 (dd, 1H, Jvic
=
(–)-(2S,4S,9aS)-2-Hydroxy-4-(3,4-dimethoxyphenyl)-
decahydroquinolizidine (11) (Lasubin II)
ꢀ
3.0 Hz, Jvic = 11.8 Hz, aryl-CHN), 3.77 and 3.88 (2s, each
3H, OCH3, OCHꢀ3), 4.07 (t, 1H, J = 2.6 Hz, OH), 6.70 – 6.86
(m, 3H, arom.). – 13C NMR (100.6 MHz, CDCl3): δ = 24.84,
26.10, 33.59, 40.32 and 42.72 (CH2), 53.18 (NCH2), 55.83,
55.92 and 56.50 (OCH3, OCHꢀ3, R2CHOH), 63.45 (NCHR2),
64.77 (aryl-CHN), 110.63, 111.06, 119.77, 137.22, 147.83
and 149.04 (arom.).
To a solution of quinolizidinone 10 (0.33 g, 1.14 mmol) in
dry tetrahydrofuran (10 mL) at −78 ◦C 1.5 mL of a 1 M so-
lution (1.5 mmol) of lithium tris-siamylborohydride (LS-
R
Selectrideꢀ) in tetrahydrofuran were given, and the solution
was stirred for 2.5 h [3c]. Sat. NaHCO3 solution (3 mL) was
[1] J. P. Michael, Nat. Prod. Rep. 1997, 14, 21.
[2] K. Fuji, T. Yamada, E. Fujita, H. Murata, Chem. Pham.
Bull. 1978, 26, 2515.
60, 9629; h) J. Lim, G. Kim, Tetrahedron Lett. 2008,
49, 88.
[5] H. Ratni, E. P. Ku¨ndig, Org. Lett. 1999, 1, 1997.
[3] a) K. Narasaka, S. Yamazaki, Y. Ukaj, Chem. Lett.
1985, 1177; b) R. W. Hoffmann, A. Endersfelder,
Liebigs Ann. Chem. 1986, 1823; c) J. D. Brown, M. A.
Foley, D. L. Comins, J. Am. Chem. Soc. 1988, 110,
7445; d) R. A. Pilli, L. C. Dias, A. O. Maldaner, J. Org.
Chem. 1995, 60, 717.
[4] a) P. Chalard, R. Remuson, Y. Gelas-Mialhe, J.-
C. Gramain, Tetrahedron: Asymmetry 1998, 9, 4361;
b) Y. Ukaji, M. Ima, T. Yamada, K. Inomata, Hetero-
cycles, 2000, 52, 563; c) F. A. Davies, B. Chao, Org.
Lett. 2000, 2, 2623; d) D. Ma, W. Zhu, Org. Lett. 2001,
3, 3927; e) T. B. Back, M. D. Hamilton, Org. Lett.
2002, 4, 1779; f) P. Desai, J. Aube´, Org. Lett. 2003,
5, 4999; g) M. Zaja, S. Blechert, Tetrahedron 2004,
[6] O. Garcia Mancheno, R. Gomes Arrayas, J. Adrio, J. C.
Carretero, J. Org. Chem. 2007, 72, 10294.
[7] R. T. Yu, T. Rovis, J. Am. Chem. Soc. 2006, 128, 12370.
[8] a) H. Kunz, W. Pfrengle, Angew. Chem. 1989,
101, 1041; Angew. Chem., Int. Ed. Engl. 1989, 28,
1067; b) M. Weymann, W. Pfrengle, D. Schollmeyer,
H. Kunz, Synthesis 1997, 1151.
[9] S. Danishefsky, J. Am. Chem. Soc. 1974, 96, 7807.
[10] S. Knauer, B. Kranke, L. Krause, H. Kunz, Curr. Org.
Chem. 2004, 8, 1739.
[11] H. Kunz, W. Sager, D. Schanzenbach, M. Decker,
Liebigs Ann. Chem. 1991, 649.
[12] H. Kunz, W. Pfrengle, K. Ru¨ck, W. Sager, Synthesis
1991, 1039.
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