Concise enantioselective synthesis of (-)-lasubine II

Article abstract of DOI:10.1016/j.tet.2004.06.145

An enantioselective synthesis of the quinolizidine alkaloid (-)-lasubine II 1 is reported. Two different pathways to the key intermediate 2 are described. The first case involving a sequence of ring rearrangement metathesis (RRM), simple functional group interconversion operations, followed by a stereoselective cross metathesis (CM) and in the second case a domino ring opening-/ring closing-/cross metathesis step is involved. In both cases, following the metathesis reactions, exclusively the E-isomer was obtained. The final cyclisation towards the quinolizidine skeleton is achieved by an intramolecular Michael reaction. This concept represents the first example of a highly stereoselective RRM-CM combination in the synthesis of a natural product. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.06.145

Tetrahedron 60 (2004) 9629–9634
Concise enantioselective synthesis of (K)-lasubine II
*
Mirko Zaja and Siegfried Blechert
¨
Institu fur Organische Chemie, Technische Universitat Berlin, Strasse des 17. Juni 135, Sekr.TC 2, D-10623 Berlin, Germany
Received 4 May 2004; revised 8 June 2004; accepted 10 June 2004
Available online 25 August 2004
Abstract—An enantioselective synthesis of the quinolizidine alkaloid (K)-lasubine II 1 is reported. Two different pathways to the key
intermediate 2 are described. The first case involving a sequence of ring rearrangement metathesis (RRM), simple functional group
interconversion operations, followed by a stereoselective cross metathesis (CM) and in the second case a domino ring opening-/ring closing-/
cross metathesis step is involved. In both cases, following the metathesis reactions, exclusively the E-isomer was obtained. The final
cyclisation towards the quinolizidine skeleton is achieved by an intramolecular Michael reaction. This concept represents the first example of
a highly stereoselective RRM-CM combination in the synthesis of a natural product.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
N-heterocyclic carbene ligands such as the second gener-
ation Grubbs catalyst [Ru-2]7 and its phosphine-free variant
[Ru-3],8 have proved to be efficient catalysts to afford CM
products in good to excellent yields and high E/Z
selectivities.
Several biologically important and structurally interesting
quinolizidine alkaloids possessing both cis and trans
junctures have been isolated from plants of the Lythraceae
family. Two of these alkaloids, 1 and its 3,4-dimethoxy-
cinnamate ester (C)-subcosine II bearing a trans C-4, C-10
hydrogen relationship, were isolated in 1978 by Fuji et al.
from the leaves of Lagerstroemia subcostata Koehne
(Fig. 1).1 Whereas numerous syntheses of 1 in racemic
form have been described, only a few asymmetric syntheses
have been reported since the first enantioselective synthesis
in 1998 by Remuson et al.2
A ruthenium-catalysed ring rearrangement metathesis and a
stereoselective cross metathesis were planned as key steps
of the synthesis for the key intermediate 2 (Scheme 1). The
quinolizidine skeleton could be built upon N-deprotection
and intramolecular Michael addition. The alkaloid would be
available after stereoselective reduction of the ketone and
hydrogenation of the endocyclic double bond. The enone 2
could be derived from piperidine derivative 3 after
deprotection of the alcohol, oxidation to the corresponding
a,b-unsaturated ketone and stereoselective CM with 1,2-
dimethoxy-4-vinylbenzene 6. From our previous studies, it
was foreseen that 3 could be obtained after RRM of 4. The
RRM precursor 4 is readily available by asymmetric
palladium-catalysed allylic amination of monoacetate 7.
Olefin metathesis has become a useful method for the
preparation of chiral heterocyclic ring systems in natural
product synthesis.3 Besides the most widely used ring-
closing metathesis (RCM) combinations of RCM and ring-
opening metathesis (ROM), such as the RRM, are also
suitable for natural product synthesis, thereby a chiral
carbocycle is transformed into a heterocyclic product,
without loss of stereochemical information.4 The first
generation Grubbs catalyst [Ru-1]5 was found to efficiently
catalyse these transformations (Fig. 2). In addition to these
well established reactions CM is gaining importance as a
powerful tool for the formation of carbon–carbon bonds.6
The problem of arised E/Z selectivities can be evaded by
CM reactions between terminal alkyl-substituted and
electron-deficient olefins. Ruthenium complexes bearing
2. Results and discussion
2.1. Synthesis of the key intermediate 10
Initial studies towards the key intermediate 10 considered
the monoacetate 7 as starting material (Scheme 2), which
could be prepared easily on a multi gram scale in high
enantiomeric purity (O99% ee) by enzymatic hydrolysis of
the racemic meso diacetate.9 The cyclopentene derivative
8a was obtained by h3-allyl-Pd(0) substitution with but-3-
enylamine10 in the presence of catalytic amounts of
Pd(PPh3)4, followed by the protection of the nitrogen with
Keywords: Ring rearrangement metathesis; Cross metathesis; Ruthenium;
Alkaloids.
* Corresponding author. Tel.: C49-30-314-222-55; fax: C49-30-314-
23619; e-mail: blechert@chem.tu-berlin.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.145

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M. Zaja, S. Blechert / Tetrahedron 60 (2004) 9629–9634
Figure 1. Lythraceae alkaloids.
with high E-selectivities.12 To obtain an acceptor substi-
tuted olefin for the following CM step the TBDMS-group
was removed with TBAF in THF to give the alcohol 9b in
96% yield. After oxidation with Dess–Martin periodinane
and filtration over silica gel the corresponding a,b-
unsaturated ketone could be coupled, without any further
purification, with 6,13 utilising 5 mol% of [Ru-3] in boiling
DCM, to give exclusively the E-isomer of the key
intermediate 10 after 6 h in gratifying 85% yield (2 steps).
Figure 2. Ruthenium based olefin metathesis catalysts.
(Boc)2O in 65% yield (2 steps).11 Protection of the alcohol
with TBDMSCl gave the metathesis precursor 8b. In the
following RRM 8b was converted to the piperidine
derivative 9a in 98% yield, utilising 2 mol% of [Ru-1] in
DCM at room temperature after 57 h. For the introduction of
the aryl unit a separate stereoselective CM step with 6 was
envisaged. [Ru-3] is known to be a versatile catalyst for CM
with high E-selectivities involving acceptor substituted
alkenes, and styrenes are known to give also CM products
The question arose if it was possible to reduce the number of
synthetic operations by combining the previously separate
RRM and CM steps into one domino metathesis step.
Scheme 3 shows the assumed mechanism of the ruthenium
catalysed ring rearrangement of A, via B and C, to give the
RRM product D. Initially the catalyst reacts with the most
accessible terminal double bond of the cyclopentene
derivative A to form the ruthenium carbene complex B. If
the intramolecular formation of a metallacyclobutane with
Scheme 1. Retrosynthetic approach to 1.
Scheme 2. Synthesis of 10 via sequential RRM and CM. Reagents and conditions: (a) (i) but-3-enylamine, NEt3, THF, rt, 1 h, (ii) 5 mol% Pd(PPh3)4, 40 8C,
15 h, (iii) Boc2O, NEt3, MeOH, 70 8C, 4 h (65%); (b) TBDMSCl, imidazole, DMF, rt, 48 h (99%); (c) 2 mol% [Ru-1], DCM, reflux, 57 h (98%); (d) (i) TBAF,
THF, rt, 1 h (96%); (e) (i) DMP, DCM, rt, 30 min, (ii) 6, 5 mol% [Ru-3], DCM, reflux, 6 h (85%).

M. Zaja, S. Blechert / Tetrahedron 60 (2004) 9629–9634
9631
Scheme 3. Proposed mechanism for RRM-CM.
the endocyclic double bond in B, followed by [2C2]-
cycloreversion is fast, the ruthenium carbene complex C
should be obtained. The catalytic cycle is closed by the
reaction of C with a molecule ethylene leading to D and
reformation of the propagating ruthenium species.
boiling DCM and 5 mol% of [Ru-1], yielded none of the
desired product after 12 h. The reaction resulted only in
traces of CM of the terminal double bond of 11 with 6.
However under the same reaction conditions and utilisation
of 5 mol% [Ru-2] or [Ru-3] product 10 was obtained in a
gratifying yield of 48% respectively 44%. In both cases the
main byproduct being the CM of the terminal double bond
of 11 with 6.
If a CM partner E is added, we suppose that after the RCM/
ROM sequence C could react with E to give the desired
RRM/CM product G. Our earlier attempts to use cyclo-
pentene derivatives like A as starting materials and [Ru-1]
for this type domino metathesis have shown that after the
RRM the final CM step occurs yielding only small amounts
of G.3d These investigations have shown that introduction of
a bulky group R, for example a TBDMS group, has a
favourable effect on the equilibrium of the ring rearrange-
ment but it was supposed that the steric effects account for
the failing final CM step. The use of Schrock’s highly
reactive molybdenum complex [PhMe2CCH]Mo]N(2,6-
(iPr2C6H3)(OCMe(CF3)2)2]14 resulted mainly in the CM
product F.
2.2. Synthesis of (K)-lasubine II from key intermediate
10
Following the deprotection of the carbamate 10 in DCM
with TFA at room temperature the quinolizidone derivative
was obtained as a 3:2 mixture of diastereomers 12a and 12b
by treatment with DBU at room temperature, through an
intramolecular Michael reaction.15 Treatment of 12a with
2 N NaOH in methanol afforded the thermodynamically
more stable 12b in 98% yield, presumably through a retro
Michael fragmentation–recyclisation step.16 Unfortunately
the direct reduction of 12b with NaBH4 in MeOH gave the
undesired S-configurated quinolizin-2-ol in 99% yield, also
the reduction of 12b with L-selectride in THF at K78 8C
resulted in a unsatisfactory 1:1 mixture of the two
diastereomeric quinolizin-2-ols in 82% yield. For this
reason the double bond was removed by hydrogenation in
the presence of catalytic amounts of Pd/C in ethyl acetate to
obtain the quinolizidin-2-one. Final stereoselective reduc-
tion2e with L-selectride in THF at K78 8C provided (K)-
lasubine II in 74% yield in excellent agreement with
Our synthesis began by investigating the one pot domino
metathesis of the cyclopentenone derivative 11, which can
be obtained in 98% yield after oxidation of 8a with MnO2 in
acetone, with 6 as CM partner. The absence of the bulky
TBDMS-group could prevent the RRM step, however it
should allow the final CM step to proceed. The acceptor
substituted endocyclic double bond in 11 should lead solely
to the E-configurated CM product (Scheme 4). Utilisation of
1.0 equiv cyclopentenone 11 and a excess of 3.0 equiv 6 in
Scheme 4. Synthesis of 1 via one pot domino metathesis. Reagents and conditions: (a) (i) MnO2, acetone, rt, 15 h (98%); (b) 6, 5 mol% [Ru], DCM, reflux,
12 h; (c) (i) TFA, DCM, 0 8C, 1h, (ii) DBU, DCM, rt, 24 h (77%, 12a/12b 3:2); (d) NaOH, MeOH, rt, 48 h (98%); (e) (i) H2, Pd/C, ethyl acetate, 12 h,
(ii) L-selectride, THF, K78 8C (74%).

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M. Zaja, S. Blechert / Tetrahedron 60 (2004) 9629–9634
previously reported values ([a]2D0ZK48 (c 0.79, MeOH);
lit.1 [a]2D0ZK34.7 (c 0.32, MeOH); lit.2a [a]2D0ZK41
(c 3.7, MeOH); lit.2b [a]D20ZK50 (c 0.37, MeOH); lit.2c
[a]D20ZK47.5 (c 3.7, MeOH); lit.2d [a]2D0ZK46.0 (c 2.1,
MeOH); lit.2e [a]2D0ZK53 (c 0.13, MeOH).
4.46 (m, 1H), 3.13 (m, 2H), 2.53 (m, 1H), 2.27 (m, 2H),
1.46–1.36 (bs, 10H). 13C NMR (125 MHz, DMSO-d6,
100 8C) d 154.1 (Cq), 136.5 (CH), 135.3 (CH), 131.6 (CH),
115.0 (CH2), 78.1 (Cq), 72.6 (CH), 59.2 (CH), 41.7 (CH2),
38.7 (CH2), 33.4 (CH2), 27.6 (3!CH3). IR n 3421, 2976,
2933, 1691, 1669, 1410, 1366, 1169, 1145 cmK1. MS m/z
(%) 253 (1), 212 (10), 112 (78), 94 (90), 83 (33), 57 (100);
HR-MS Calcd for C14H23NO3 [MC] 253.1678, found
253.1676. [a]2D0ZC89 (c 0.77, CHCl3). Anal. Calcd for
C14H23NO3: C, 66.37; H, 9.15; N, 5.53. Found: C, 66.24; H,
8.84; N, 5.56.
3. Conclusion
In summary, we have demonstrated that a sequence of RRM
and stereoselective CM can be combined to a one pot
domino metathesis step and applied this concept success-
fully in the concise enantioselective synthesis of the
quinolizidine alkaloid (K)-lasubine II. The variability of
the side chain length of the cyclopentenone derivative and
the possible free choice of CM partner makes this strategy a
powerful method for synthesis of quionolizidine, indolizi-
dine and pyrrolizidine alkaloids. Further investigations and
syntheses based on this concept are currently under study in
our laboratories and the results will be reported in due
course.
4.1.2. But-3-enyl-[(1R,4S)4-(tert-butyl-dimethyl-silanyl-
oxy)-cyclopent-2-enyl]-carbamic acid tert-butylester
(8b). The mixture of alcohol 8a (1.51 g, 5.96 mmol),
TBDMSCl (898 mg, 5.96 mmol) and imidazole (609 mg,
8.94 mmol) in DMF (7 mL) was stirred for 48 h at room
temperature, after this time TBDMSCl (45 mg, 0.30 mmol)
was added and the solution was stirred for a further 2 h.
DCM (50 mL) was added and the solution was washed with
saturated NH4Cl solution (30 mL), the organic layers were
dried over MgSO4, and concentated in vacuo. The residue
was purified by flash chromatography (hexane/MTBE 5:1),
1
4. Experimental
4.1. General
affording 8b (2.19 g, 99%) as a colourless oil. H NMR
(500 MHz, CDCl3, 50 8C): d 5.86 (d, JZ5.2 Hz, 1H), 5.80–
5.69 (m, 2H), 5.08 (bs, 1H), 5.03 (d, JZ17.3 Hz, 1H), 4.98
(d, JZ10.2 Hz, 1H), 4.69 (bs, 1H), 3.14 (m, 2H), 2.61 (dt,
JZ14.5, 7.8 Hz, 1H), 2.33 (m, 1H), 2.24 (m, 1H), 1.48 (bs,
10H), 0.91 (s, 9H), 0.09 (s, 6H). 13C NMR (125 MHz,
CDCl3, 50 8C) d 155.6 (Cq), 136.7 (CH), 135.9 (CH), 133.2
(CH), 115.9 (CH2), 79.5 (CH), 75.3 (CH), 59.6 (Cq), 42.4
(CH2), 39.8 (CH2), 34.9 (CH2), 28.6 (3!CH3), 25.9
(3!CH3), 18.13 (Cq), K4.66 (2!CH3). IR n 3077, 2956,
2930, 2857, 1693, 1408, 1366, 1253, 1170, 1145, 1085, 903,
836, 775 cmK1. MS m/z (%) 367 (3), 326 (13), 254 (68), 226
(80), 172 (22), 94 (100), 75 (38), 73 (35), 57 (96); HR-MS
Calcd for C20H37NO3Si [MC] 367.2543, found 367.2550.
[a]2D0ZC12 (c 0.92, CHCl3). Anal. Calcd for
C20H37NO3Si: C, 65.35; H, 10.15; N, 3.81. Found: C,
65.36; H, 10.17; N, 3.71.
Each reaction with air- and moisture-sensitive components
was carried out under a nitrogen atmosphere unless
otherwise indicated. Tetrahydrofuran was distilled from
sodium/benzophenone, and dichloromethane was distilled
1
from calcium hydride. H NMR (500 MHz) and 13C NMR
(125 MHz) were recorded on Bruker DRX 500 in the
solvent and at temperatures indicated. NMR chemical shifts
are expressed in ppm upfield, relative to the internal solvent
peak. Mass spectra were recorded using a Finnegan MAT 95
SQ at an ionizing potential of 70 eV. IR spectra were
recorded on a Nicolet FT-750 spectrometer by attenuated
total reflectance (ATR). Optical rotations were determined
on a Perkin–Elmer polarimeter 341 as solutions in a 10 cm
unit cell at 589 nm. Microanalysis were determined on a
Elementar Varion EI. Flash chromatography was carried out
using standard commercially available silica gel. Those
chemicals which were purchased were used without further
purification.
4.1.3. (R)-6-[(S)-2-(tert-Butyl-dimethyl-silanyloxy)-but-
3-enyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-
butylester (9a). Compound 8b (6.44 g, 17.52 mmol) was
dissolved in DCM (360 mL), and ethylene gas (50 mL) was
bubbled slowly through the solution. [Ru-1] (288 mg,
0.35 mmol) was added, and the mixture was stirred for
57 h at room temperature under N2 atmosphere. The solvent
was removed in vacuo, and the residue was chromato-
graphed on silica gel (hexane/MTBE 5:1) to give 9a (6.31 g,
98%) as a colourless oil. 1H NMR (500 MHz, CDCl3,
50 8C): d 5.93 (ddd, JZ17.1, 10.4, 5.8 Hz, 1H), 5.76 (m,
1H), 5.72 (m, 1H), 5.23 (d, JZ17.1 Hz, 1H), 5.06 (d, JZ
10.4 Hz, 1H), 4.48 (bs, 1H), 4.23 (dt, JZ6.1, 6.1 Hz, 1H),
4.10 (bs, 1H), 2.85 (t, J 10.7 Hz, 1H), 2.20 (bs, 1H), 1.90 (dt,
JZ17.3, 4.1 Hz, 1H), 1.83 (dt, JZ13.4, 6.8 Hz, 1H), 1.65
(dt, JZ13.4, 6.8 Hz, 1H), 1.46 (s, 9H), 0.90 (s, 9H), 0.06 (s,
3H), 0.04 (s, 3H). 13C NMR (125 MHz, CDCl3, 50 8C) d
154.6 (Cq), 141.2 (CH), 129.0 (CH), 125.0 (CH), 114.0
(CH2), 79.4 (Cq), 71.3 (CH), 49.1 (CH), 42.8 (CH2), 36.7
(CH2), 28.6 (3!CH3), 25.9 (3!CH3), 25.1 (CH2), 18.22
(Cq), K4.3 (CH3), K4.9 (CH3). IR n 2957, 2929, 2857,
1695, 1417, 1364, 1251, 1173, 1106, 836, 775 cmK1. MS
4.1.1. But-3-enyl-((1R,4S)-4-hydroxy-cyclopent-2-enyl)-
carbamic acid tert-butylester (8a). To a mixture of 79
(2.63 g, 18.50 mmol) and but-3-enylamine10 (3.29 g,
46.25 mmol) in THF (70 mL) was added triethylamine
(7.7 mL) and the solution was stirred for 1 h at room
temperature. Then Pd(PPh3)4 (1.07 g, 0.93 mmol) was
added in ten portions over 60 min, and the mixture was
stirred for 15 h at 40 8C. The solution was concentrated in
vacuo and the residue was taken up in methanol (40 mL),
triethylamine (2.54 mL, 18.3 mmol) and Boc2O (4.04 g,
18.5 mmol) were added and the mixture stirred at 70 8C for
4 h. The solution was concentrated in vacuo. Purification of
the residue by flash chromatography (hexane/MTBE 1:1)
1
afforded 8a as a colourless oil (3.05 g, 65%). H NMR
(500 MHz, DMSO-d6, 100 8C): d 5.90 (d, JZ5.1 Hz, 1H),
5.77 (m, 1H), 5.71 (d, JZ5.1 Hz, 1H), 5.04 (d, JZ17.2 Hz,
1H), 4.99 (d, JZ10.3 Hz, 1H), 4.85 (bs, 1H), 4.56 (bs, 1H),

M. Zaja, S. Blechert / Tetrahedron 60 (2004) 9629–9634
9633
m/z (%) 367 (2), 254 (100), 126 (52), 82 (28), 57 (28); HR-
MS Calcd for C20H37NO3Si [MC] 367.2543, found
367.2551. [a]2D0ZK144 (c 0.67, CHCl3). Anal. Calcd for
C20H37NO3Si: C, 65.35; H, 10.15; N, 3.81. Found: C, 65.38;
H, 9.68; N, 3.66.
1023 cmK1. MS m/z (%) 387 (13), 331 (25), 286 (24), 191
(100), 126 (58), 95 (21), 82 (46), 57 (61); HR-MS Calcd for
C22H29NO5 [MC] 387.2046, found 387.2030. [a]2D0ZK129
(c 0.61, CHCl3). Anal. Calcd for C22H29NO5: C, 68.20; H,
7.54; N, 3.62. Found: C, 68.38; H, 7.63; N, 3.52.
4.1.4. (R)-6-((S)-2-Hydroxy-but-3-enyl)-3,6-dihydro-2H-
pyridine-1-carboxylic acid tert-butylester (9b). To a
solution of 9a (2.00 g, 5.44 mmol) in THF (80 mL) was
added 1.0 M solution of TBAF in THF (6.0 mL,
5.98 mmol). The mixture was stirred for 1 h at room
temperature, concentrated in vacuo and the resulting yellow
oil was chromatographed on silica gel (hexane/MTBE 5:1)
4.1.6. But-3-enyl((R)-4-oxo-cyclopent-2-enyl)-carbamic
acid tert-butylester (11). To a solution of alcohol 8a
(1.30 g, 5.13 mmol) in acetone (70 mL) was added MnO2
(17.85 g, 205 mmol), and the mixture was stirred for 15 h at
room temperature. Then the mixture was filtered through a
small pad of silica. The filtrate was concentrated in vacuo,
and the residue was purified by flash chromatography
(hexane/MTBE 4:1) to give 11 (1.26 g, 98%) as a light
yellow oil. 1H NMR (500 MHz, DMSO-d6, 100 8C): d 7.60
(dd, JZ5.7, 2.3 Hz, 1H), 6.19 (dd, JZ5.7, 2.3 Hz, 1H), 5.78
(m, 1H), 5.07 (d, JZ17.2 Hz, 1H), 5.03 (d, JZ10.3 Hz,
1H), 4.93 (bs, 1H), 3.24 (dt, JZ14.2, 6.9 Hz, 1H), 3.16 (dt,
JZ14.2, 6.9 Hz, 1H), 2.64 (dd, JZ18.2, 6.7 Hz, 1H), 2.31–
2.22 (m, 3H), 1.42 (s, 9H). 13C NMR (125 MHz, DMSO-d6,
100 8C) d 204.9 (Cq), 162.6 (CH), 153.7 (Cq), 135.0 (CH),
133.4 (CH), 115.5 (CH2), 78.9 (Cq), 56.8 (CH), 44.9 (CH2),
39.4 (CH2), 32.9 (CH2), 27.4 (3!CH3). IR n 3077, 2976,
2932, 1719, 1691, 1459, 1401, 1366, 1173, 1157 cmK1. MS
m/z (%) 251 (2), 210 (8), 195 (14), 154 (13), 110 (94), 81
(38), 57 (100), 53 (17); HR-MS Calcd for C14H21NO3 [MC]
251.1521, found 251.1519. [a]2D0ZC101 (c 1.19, CHCl3).
Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57.
Found: C, 66.63; H, 8.30; N, 5.36.
1
to achieve 9b (1.32 g, 96%) as a colourless oil. H NMR
(500 MHz, CDCl3, 50 8C): d 5.88 (ddd, JZ17.2, 10.4,
5.1 Hz, 1H), 5.78 (m, 1H), 5.67 (m, 1H), 5.23 (d, JZ
17.2 Hz, 1H), 5.03 (d, JZ10.4 Hz, 1H), 4.53 (bs, 1H), 4.25
(bs, 1H), 4.00 (bs, 1H), 2.85 (dt, JZ13.1, 3.1 Hz, 1H), 2.18
(t, JZ10.9 Hz, 1H), 1.90 (dt, JZ17.2, 3.1 Hz, 1H), 1.76 (t,
JZ6.3 Hz, 2H), 1.44 (s, 9H). 13C NMR (125 MHz, CDCl3,
50 8C) d 155.0 (Cq), 141.1 (CH), 129.0 (CH), 125.2 (CH),
113.6 (CH2), 79.9 (Cq), 70.4 (CH), 49.5 (CH), 41.0 (CH2),
37.1 (CH2), 28.5 (3!CH3), 24.9 (CH2). IR n 3429, 2977,
2931, 2919, 1692, 1670, 1420, 1365, 1251, 1171, 1110,
1056 cmK1. MS m/z (%) 253 (1), 182 (16), 126 (100), 82
(49), 57 (47); HR-MS Calcd for C14H23NO3 [MC]
253.1678, found 253.1689. [a]2D0ZK202 (c 0.58, CHCl3).
Anal. Calcd for C14H23NO3: C, 66.37; H, 9.15; N, 5.53.
Found: C, 66.12; H, 9.22; N, 5.10.
4.1.5. (R)-6-[(E)-4-(3,4-Dimethoxy-phenyl)-2-oxo-but-3-
enyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-
butylester (10). (a) From alcohol 9b. Alcohol 9b (1.27 g,
5.01 mmol) was dissolved in DCM (30 mL) and Dess–
Martin periodinane (2.34 g, 5.51 mmol) was added. After
stirring at room temperature for 30 min, the suspension was
filtered over a short pad of silica, 70 mL DCM and 6 (1.65 g,
10.03 mmol) were added to the solution. The mixture was
heated to reflux under a N2 atmosphere and [Ru-3] (126 mg,
4 mol%) was added, and stirring was continued for 14 h.
The solution was concentrated in vacuo, and the residue was
purified by flash chromatography (hexane/MTBE 3:1/1:1)
to afford 10 (1.65 g, 85%) as a light yellow oil.
4.2. 4-(3,4-Dimethoxy-phenyl)-1,3,4,6,7,10-hexahydro-
quinolizin-2-ones (12a, 12b)
To a solution of 10 (322 mg, 0.83 mmol) in DCM (2.5 mL)
was added TFA (3.3 mL) at 0 8C. After 1 h at 0 8C the
mixture was concentrated in vacuo and the residue was
taken up in DCM (3 mL), DBU (0.21 mL, 1.40 mmol) was
then added, and the reaction mixture stirred for 24 h at room
temperature. The solvent was removed in vacuo and the
residue was chromatographed on silica gel (hexane/MTBE
1:1) to give a mixture of 12a (107 mg, 45%) and 12b
(76 mg, 32%) as yellow oils.
(b) From cyclopentenone 11. Compound 11 (1.16 g,
4.62 mmol) and 6 (2.27 g, 13.85 mmol) were refluxed in
DCM (90 mL) under a N2 atmosphere. [Ru-2] (196 mg,
5 mol%) was added and the solution was stirred for further
12 h. The solution was concentrated in vacuo, and the
residue was purified by flash chromatography (hexane/
MTBE 3:1/1:1) to give 10 (859 mg, 48%) as a light
yellow oil. 1H NMR (500 MHz, CDCl3, 50 8C): d 7.53
(d, JZ16.1 Hz, 1H), 7.13 (dd, JZ8.3, 1.6 Hz, 1H), 7.08
(s, 1H), 6.88 (d, JZ8.3 Hz, 1H), 6.64 (d, JZ16.1 Hz, 1H),
5.85 (m, 1H), 5.75 (m, 1H), 4.88 (bs, 1H), 4.15 (bs, 1H),
3.91 (s, 6H), 2.93 (m, 2H), 2.85 (dd, JZ14.3, 8.4 Hz, 1H),
2.23 (m, 1H), 1.98 (dt, JZ17.3, 3.8 Hz, 1H), 1.47 (s, 9H).
13C NMR (125 MHz, CDCl3, 50 8C) d 197.4 (Cq), 154.2
(Cq), 151.6 (Cq), 149.5 (Cq), 142.9 (CH), 127.9 (CH), 127.6
(Cq), 125.6 (CH), 124.6 (CH), 122.9 (CH), 111.5 (CH),
110.5 (CH), 79.7 (Cq), 55.9 (2!CH3), 49.4 (CH), 45.0
(CH2), 36.9 (CH2), 28.3 (3!CH3), 24.9 (CH2). IR n 2972,
2932, 1688, 1595, 1512, 1418, 1264, 1162, 1140, 1107,
4.2.1. (4R,10R)-4-(3,4-Dimethoxy-phenyl)-1,3,4,6,7,10-
hexahydroquinolizin-2-one (12a). 1H NMR (500 MHz,
CDCl3, 25 8C): d 6.80 (d, JZ8.3 Hz, 1H), 6.75 (s, 1H),
6.73 (d, JZ8.3 Hz, 1H), 5.77 (m, 1H), 5.43 (d, JZ9.5 Hz,
1H), 4.28 (dd, JZ6.1, 4.4 Hz, 1H), 3.86 (s, 6H), 3.54 (bs,
1H), 2.97 (m, 1H), 2.88 (dd, JZ14.7, 6.1 Hz, 1H), 2.72 (d,
JZ14.7 Hz, 1H), 2.53 (m, 2H), 2.39 (dd, JZ14.5, 10.5 Hz,
1H), 2.33 (m, 1H), 2.03 (d, JZ16.6 Hz, 1H). 13C NMR
(125 MHz, CDCl3, 25 8C) d 209.6 (Cq), 148.6 (Cq), 148.4
(Cq), 131.4 (Cq), 128.5 (CH), 125.5 (CH), 120.6 (CH),
111.5 (CH), 110.6 (CH), 63.3 (CH), 55.9 (CH3), 55.8
(CH3), 52.2 (CH), 47.2 (CH2), 46.5 (CH2), 46.3 (CH2),
25.0 (CH2). IR n 2930, 2907, 2833, 1710, 1515, 1257,
1145, 1025 cmK1. MS m/z (%) 287 (34), 206 (16), 191
(16), 175 (18), 164 (100), 149 (20), 108 (22), 95 (40), 82
(52), 77 (24); HR-MS Calcd for C17H21NO3 [MC]
287.1521, found 287.1527. [a]2D0ZC25 (c 1.19, CHCl3).
Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.88.
Found: C, 71.49; H, 7.43; N, 4.75.

9634
M. Zaja, S. Blechert / Tetrahedron 60 (2004) 9629–9634
4.2.2. (4S,10R)-4-(3,4-Dimethoxy-phenyl)-1,3,4,6,7,10-
hexahydroquinolizin-2-one (12b). To a solution of 12a
(94 mg, 0.33 mmol) in MeOH (0.6 mL) was added 2 N
NaOH (0.6 mL), and the mixture was stirred for 48 h at
room temperature. MTBE (40 mL) was added and the
solution was washed with water (15 mL), the organic layers
were dried over MgSO4, and concentated in vacuo. The
residue was purified by flash chromatography (hexane/
MTBE 1:1), affording 12b (92 mg, 98%) as a yellow oil. 1H
NMR (500 MHz, CDCl3, 25 8C): d 6.93 (d, JZ1.4 Hz, 1H),
6.84 (m, 2H), 5.83 (m, 1H), 5.44 (d, JZ9.8 Hz, 1H), 3.88 (s,
3H), 3.87 (s, 3H), 3.38 (dd, JZ11.6, 3.4 Hz, 1H), 3.09 (d,
JZ12.7 Hz, 1H), 2.83 (dd, JZ11.3, 5.6 Hz, 1H), 2.69 (dd,
JZ14.3, 11.6 Hz, 1H), 2.51 (m, 2H), 2.40 (dt, JZ11.6,
2.5 Hz, 1H), 2.26 (m, 1H), 2.01 (dt, JZ11.3, 3.7 Hz, 1H),
1.94 (m, 1H). 13C NMR (125 MHz, CDCl3, 25 8C) d 207.4
(Cq), 149.5 (Cq), 148.5 (Cq), 134.6 (Cq), 128.7 (CH), 126.4
(CH), 119.7 (CH), 111.1 (CH), 109.5 (CH), 68.4 (CH), 60.5
(CH), 56.0 (CH3), 55.9 (CH3), 50.9 (CH2), 47.5 (CH2), 47.4
(CH2), 26.5 (CH2). IR n 2957, 2929, 2833, 1720, 1515,
1258, 1236, 1135, 1027 cmK1. MS m/z (%) 287 (20), 206
(24), 191 (25), 164 (100), 91 (56), 82 (42); HR-MS Calcd
for C17H21NO3 [MC] 287.1521, found 287.1527.
[a]2D0ZK69 (c 0.71, CHCl3). Anal. Calcd for C17H21NO3:
C, 71.06; H, 7.37; N, 4.88. Found: C, 71.20; H, 7.48; N,
4.62.
Acknowledgements
We would like to thank the Fonds der Chemischen Industrie
for financial support.
References and notes
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quinolizin-2-ol ((K)-lasubine II (1)). A solution of 12b
(62 mg, 0.21 mmol) in absolute ethyl acetate (2 mL)
containing palladium on charcoal (10%) was hydrogenated
at room temperature for 12 h. The catalyst was removed by
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organic solvent was removed under reduced pressure. The
aqueous phase was extracted with MTBE (2!25 mL) and
the combined organic extracts were dried over MgSO4, and
concentrated in vacuo. Purification of the residue by flash
chromatography (DCM/MeOH 30:1) afforded 1 (46 mg,
74%) as white crystals. 1H NMR (500 MHz, CDCl3, 25 8C):
d 6.96–6.75 (m, 3H), 4.14 (bs, 1H), 3.88 (s, 3H), 3.86 (s,
3H), 3.31 (dd, JZ11.8, 2.8 Hz, 1H), 2.69 (d, JZ11.3 Hz,
1H), 2.39 (m, 1H), 1.92–1.23 (m, 12H). 13C NMR (125 MHz,
CDCl3, 25 8C) d 149.0 (Cq), 147.8 (Cq), 137.2 (Cq), 119.7
(CH), 110.9 (CH), 110.5 (CH), 65.1 (CH), 63.4 (CH), 56.4
(CH), 56.0 (CH3), 55.9 (CH3), 53.2 (CH2), 42.8 (CH2), 40.4
(CH2), 33.7 (CH2), 26.2 (CH2), 24.9 (CH2). IR n 3406, 2931,
2835, 1516, 1507, 1261, 1230, 1134, 1029 cmK1. MS m/z
(%) 291 (100), 246 (20), 191 (20), 164 (70), 154 (70), 126
(20), 110 (23), 84 (22); HR-MS Calcd for C17H25NO3 [MC]
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