An enantioselective organocatalytic approach to both enantiomers of lasubine II

Article abstract of DOI:10.1021/jo900141f

A concise stereoselective route providing access to both enantiomers of the bioactive quinolizidine alkaloid lasubine II has been developed. The enantioselectivity was introduced by taking advantage of a proline-catalyzed asymmetric Mannich reaction. Next, the bicyclic system was constructed via a diastereoselective Mannich cyclization and subsequent ring-closing metathesis as the key steps.

Full text of DOI:10.1021/jo900141f

SCHEME 1. Structures of Lasubine I (1a) and Lasubine II
(1b)
An Enantioselective Organocatalytic Approach to
Both Enantiomers of Lasubine II
Jorge M. M. Verkade,† Ferdi van der Pijl,†
Marian M. J. H. P. Willems,† Peter J. L. M. Quaedflieg,‡
Floris L. van Delft,† and Floris P. J. T. Rutjes*,†
Radboud UniVersity Nijmegen, Institute for Molecules and
Materials, Heyendaalseweg 135, NL-6525 AJ Nijmegen,
The Netherlands, and DSM Pharmaceutical
Products-InnoVatiVe Synthesis and Catalysis,
P.O. Box 18, NL-6160 MD Geleen, The Netherlands
f.rutjes@science.ru.nl
ReceiVed January 22, 2009
products,4 and in view of the potentially interesting properties
of the lasubines, we set out to develop a new pathway to lasubine
II based on the asymmetric proline-catalyzed Mannich reaction.
We reasoned that the commercial availability of both the D-
and L-forms of the catalyst would provide an entry to both
enantiomers of lasubine II.
Retrosynthetic analysis of lasubine II (1b) leads to the bicyclic
lactam 2 as a suitable precursor, of which the unsaturated ring
can be retrosynthetically cleaved by using ring-closing metath-
esis, giving rise to piperidinone 3. We envisioned that the latter
compound may be formed via a Mannich cyclization of imine
4, which in turn would be accessible via an asymmetric proline-
catalyzed Mannich reaction involving acetone, veratryl aldehyde
(5), and p-anisidine (6).5
A concise stereoselective route providing access to both
enantiomers of the bioactive quinolizidine alkaloid lasubine
II has been developed. The enantioselectivity was introduced
by taking advantage of a proline-catalyzed asymmetric
Mannich reaction. Next, the bicyclic system was constructed
via a diastereoselective Mannich cyclization and subsequent
ring-closing metathesis as the key steps.
With this plan in mind, we set out to study the asymmetric
three-component Mannich reaction, employing D-proline leading
to unnatural (+)-lasubine (Scheme 2). This reaction was studied
previously by the group of Hayashi, who were unable to isolate
the desired aminoketone with proline as the catalyst.6 Instead,
they used a more expensive protected 4-hydroxyproline deriva-
tive. In our hands, careful analysis of the D-proline-catalyzed
Mannich reaction (20 mol % D-proline, DMSO, rt) revealed that
the product was formed, but accompanied by the formation of
enone 9. We showed that this was formed under the reaction
conditions via elimination of p-anisidine from the desired
product 7. Gratifyingly, by employing D-proline as the catalyst
and careful monitoring of the reaction progress by HPLC and
stopping the reaction at ca. 50% conversion, we were able to
The quinolizidine skeleton is widely encountered in druglike
compounds and natural products, displaying a large array of
biological activities.1 Quinolizidine-based natural products have
been mostly isolated from plants, trees, and herbs.1 Lasubine I
(1a) and II (1b, Scheme 1) represent two of these alkaloids and
were isolated from the leaves of the Lagerstroemia subcostata
Koehne by Fuji et al. in 1978.2 Synthetic efforts by various
groups have resulted in a number of racemic and enantioselec-
tive routes to lasubine II.3 In conjunction with recent work from
our group on the total synthesis of quinolizidine-based natural
† Radboud University Nijmegen.
‡ DSM Pharmaceutical Products.
(1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139–165, and previous issues
of this annual review.
(2) Fuji, K.; Yamada, T.; Fujita, E.; Murata, H. Chem. Pharm. Bull. 1978,
26, 2515–2521.
(4) (a) Kinderman, S. S.; de Gelder, R.; van Maarseveen, J. H.; Schoemaker,
H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Am. Chem. Soc. 2004, 126, 4100–
4101. (b) Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.; Schoemaker, H. E.;
Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett. 2005, 7, 4005–4007. (c) Wijdeven,
M. A.; Wijtmans, R.; van den Berg, R. J. F.; Noorduin, W.; Schoemaker, H. E.;
Sonke, T.; van Delft, F. L.; Blaauw, R. H.; Fitch, R. W.; Spande, T. F.; Daly,
J. W.; Rutjes, F. P. J. T. Org. Lett. 2008, 10, 4001–4003.
(5) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336–9337. For recent reviews
on the organocatalyzed Mannich reaction, see: (b) Verkade, J. M. M.; van Hemert,
L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. ReV. 2008, 37,
29–41. (c) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797–5815.
(6) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.; Shoji,
M.; Hashizume, D.; Koshino, H. AdV. Synth. Catal. 2004, 346, 1435–1439.
(3) For enantioselective routes see: (a) Davis, F. A.; Chao, B. Org. Lett.
2000, 2, 2623–2625. (b) Ukaji, Y.; Ima, M.; Yamada, T.; Inomata, K.
Heterocycles 2000, 52, 563–566. (c) Ma, D.; Zhu, W. Org. Lett. 2001, 3, 3927–
3929. (d) Gracias, V.; Zeng, Y.; Desai, P.; Aube´, J. Org. Lett. 2003, 5, 4999–
5001. (e) Back, T. G.; Hamilton, M. D. Org. Lett. 2002, 4, 1779–1781. (f) Zaja,
M.; Blechert, S. Tetrahedron 2004, 60, 9629–9634. (g) Yu, R. T.; Rovis, T.
J. Am. Chem. Soc. 2006, 128, 12370–12371. (h) Chalard, P.; Remuson, R.; Gelas-
Mialhe, Y.; Gramain, J.-C. Tetrahedron: Asymmetry 1998, 9, 4361–4368. (i)
Weymann, M.; Kunz, H. Z. Naturforsch. 2008, 63, 425–430. (j) Lim, J.; Kim,
G. Tetrahedron Lett. 2008, 49, 88–89. (k) Garcia Mancheno, O.; Gomez Arrayas,
R.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2007, 72, 10294–10297.
10.1021/jo900141f CCC: $40.75
Published on Web 03/13/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3207–3210 3207

SCHEME 2. Formation of 1,3-Aminoketone 8
SCHEME 3. Mannich Cyclization
isolate the (R)-aminoketone 7 by precipitation from the reaction
mixture as a crystalline solid in 50% yield and >99% ee. This
crystallization protocol allowed us to scale up the reaction to
10 g scale, furnishing the product in the same yield and
selectivity. The (S)-enantiomer was also prepared in comparable
yield and selectivity by using L-proline as the catalyst.
Subsequently, we deprotected N-PMP amine 7, employing
H5IO6 under acidic conditions.7 Although cleavage to the free
amine by itself proceeded smoothly, isolation of the ꢀ-ami-
noketone appeared problematic due to side reactions (e.g., self-
condensation) while concentrating the organic layer after
workup. This problem was circumvented by in situ formation
of the HCl-salt 8 prior to concentration of the reaction mixture.
Inspired by our own research on iminium ion type cycliza-
tions,4a,8 we envisioned that conversion of compound 8 into
the corresponding imine 4 should lead to a precursor that would
be prone to a Mannich cyclization. This idea was underlined
by recent work by Davis and co-workers,9 who carried out
similar types of Mannich cyclizations involving furan nucleo-
philes. The precursor imine 4 was prepared by condensation of
8 with cinnamaldehyde in the presence of triethylamine as a
base to liberate the amino group. The condensation was carried
out in 1,2-dichloroethane via successive concentration of the
reaction mixture under reduced pressure to azeotropically
remove water. Because this experiment was conducted in a
rotary evaporator, fresh triethylamine and 1,2-dichloroethane
were repeatedly added to the residue after each concentration
sequence until nearly complete consumption of cinnamaldehyde
was observed by HPLC analysis. The Mannich cyclization was
then effected by stirring a solution of the crude imine 4 in 1,2-
dichloroethane in the presence of an excess of (+)-camphor-
sulfonic acid (CSA) to yield 10 as a single diastereoisomer. It
appeared to be crucial to dry the CSA prior to use and conduct
the reaction under exclusion of moisture, since the imine was
extremely prone to acidic hydrolysis. To prevent side reactions
during workup and purification, the amine of the resulting 2,6-
disubstituted piperidinone 10 was directly acylated with viny-
SCHEME 4. LS-Selectride Reduction of Piperidinone ent-10
lacetic acid via standard DCC-coupling, leading to the stable
piperidinone 12. The total yield of 12 after silica gel purification
was 44% over the three steps (Scheme 3).
Similar steps were also carried out by using the L-proline
route resulting in ent-12 in a comparable yield and complete
diastereoselectivity. HPLC analysis and 1H NMR studies
(NOESY) on the purified product ent-10 proved that it was
formed as a cis-disubstituted diastereoisomer. This outcome can
be rationalized by invoking the chairlike cationic intermediate
11 (Scheme 3), in which both the aryl and the stryrenyl
substituent will preferentially occupy the least hindered equato-
rial positions.
Additionally, we tried to alkylate the crude piperidinone ent-
10 with 3-bromo-1-butene. Although mass spectrometry of the
reaction mixture showed formation of a product with the
expected mass, we were unable to isolate the desired product,
possibly due to decomposition of the formed product during
workup. Anticipating the required conversion of the ketone into
the alcohol at a later stage in the synthesis, we reduced product
ent-10 with LS-Selectride and observed the formation of
products 14a and 14b in a 14:1 ratio, favoring the product with
the desired stereochemistry (14a, Scheme 4). However, alky-
lation of 14a/b with 3-bromo-1-butene failed and acylation under
the aforementioned conditions only led to poor conversion into
the desired amide. The mixture of stereoisomers in combination
with the unsuccessful attempts to transform 14a/b into a suitable
ring-closing metathesis precursor led us to return to the earlier
described route (Scheme 3).
(7) (a) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.;
Alsters, P. L.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron Lett. 2006, 47,
8109–8113. For an enzymatic deprotection method, see: (b) Verkade, J. M. M.;
van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Schoemaker, H. E.; Schu¨rmann,
M.; van Delft, F. L.; Rutjes, F. P. J. T. AdV. Synth. Catal. 2007, 349, 1332–
1336.
(8) For recent examples, see: (a) Kinderman, S. S.; Wekking, M. M. T.; van
Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org.
Chem. 2005, 70, 5519–5527. (b) Veerman, J. J. N.; Bon, R. S.; Hue, B. T. B.;
Girones, D.; Rutjes, F. P. J. T.; van Maarseveen, J. H.; Hiemstra, H. J. Org.
Chem. 2003, 68, 4486–4494.
(9) Davis, F. A.; Santhanaraman, M. J. Org. Chem. 2006, 71, 4222–4226.
3208 J. Org. Chem. Vol. 74, No. 8, 2009

SCHEME 5. Completion of (+)-Lasubine II Synthesis
× 125 mL) and the resulting aqueous phase was diluted with 125
mL of CH2Cl2. While stirring the mixture vigorously, the pH of
the aqueous layer was brought to 9 via addition of 5 M aqueous
KOH. The layers were separated and the aqueous layer was washed
with CH2Cl2 (3 × 125 mL). The combined organic layers were
dried (Na2SO4) and HCl/EtOAc (20 mL) was added. The resulting
mixture was concentrated until the product precipitated. The product
was isolated by filtration and dried in vacuo to afford the HCl salt
8 (3.6 g, 49%) as a pale yellow solid. Rf 0.38 (MeOH/DCM, 1:1).
Mp 158-161 °C. [R]20 -12 (c 0.94, MeOH). IR ν (cm-1) 1022,
D
1143, 1256, 1515, 1709, 2919, 3399 cm-1. 1H NMR (CD3OD, 300
MHz) δ 7.06-7.04 (m, 1H), 7.00-6.98 (m, 2H), 4.62 (dd, J )
7.3, 6.3 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.20 (d, J ) 7.5 Hz,
1H), 3.20 (d, J ) 6.1 Hz, 1H), 2.20 (s, 3H). 13C NMR (CDCl3, 75
MHz) δ 207.4, 151.3, 151.0, 130.3, 121.1, 113.1, 112.1, 56.6, 56.5,
52.1, 47.6, 30.0. HRMS (ESI) m/z calcd for C12H17NO3 (M + Na)+
246.11061, found 246.10966.
In the D-proline-based route, we observed that subsequent
treatment of piperidinone 12 with the Grubbs second generation
catalyst (6 mol %) followed by straightforward hydrogenation
of the resulting unsaturated lactam 16 led to the bicyclic structure
13 in good overall yield (Scheme 3).
As the next step, we investigated the stereoselective reduction
of the ketone functionality of 13. Both small and more sterically
demanding borohydride reducing agents were evaluated, but all
attempts led to the formation of undesired stereochemistry at
the C4 carbon. This was proven by subsequent LiAlH4 reduction
of the lactam, which provided (+)-2-epi-lasubine II (15) as the
(2R,6S)-1-But-3-enoyl-2-(3,4-dimethoxyphenyl)-6-styrylpiper-
idin-4-one (12). To a solution of 8 (3.50 g, 13.5 mmol) in dry
1,2-dichloroethane (200 mL) was added triethylamine (1.45 mL,
10.3 mmol) and trans-cinnamaldehyde (1.30 mL, 10.3 mmol). The
mixture was concentrated in vacuo. To the residue was added dry
1,2-dichloroethane (150 mL) and triethylamine (1.5 mL, 11 mmol).
The mixture was concentrated again in vacuo. Dry 1,2-dichloro-
ethane (150 mL), triethylamine (1.5 mL, 11 mmol), and trans-
cinnamaldehyde (0.38 mL, 3.0 mmol) were added to the residue.
The resulting mixture was concentrated in vacuo. To the residue
was added dry 1,2-dichloroethane (125 mL) and triethylamine (1.5
mL, 11 mmol). The resulting mixture was concentrated in vacuo
to afford the crude imine 4. The crude imine was dissolved in dry
1,2-dichloroethane (360 mL) and the resulting mixture was added
dropwise to a stirring solution of dry (+)-10-camphorsulfonic acid
(20.2 g, 87 mmol) in dry 1,2-dichloroethane (230 mL) at 60 °C.
The mixture was stirred for 5 h at 60 °C under an inert atmosphere.
The mixture was washed with an aqueous half-saturated sodium
bicarbonate solution (3 × 350 mL), dried (Na2SO4), and concen-
trated in vacuo affording the crude piperidinone 10. Vinylacetic
acid (3.8 mL, 45 mmol) and DCC (3.20 g, 15.5 mmol) were
dissolved in dry DCM (100 mL) and stirred for 1 h at room
temperature. The precipitate was removed by filtration and the
solution was diluted with DCM (500 mL). The crude piperidinone
10 and DMAP (2.38 g, 19.5 mmol) were added to this solution.
The mixture was stirred for 16 h under an argon atmosphere at
room temperature. The mixture was washed with aqueous hydro-
chloric acid (0.2 M, 500 mL), aqueous sodium bicarbonate (1 M,
500 mL), and brine (500 mL). The mixture was then dried (Na2SO4)
and concentrated. The residue was purified by column chromatog-
raphy (EtOAc/heptane, 1:2 f 1:1) to afford 12 (2.43 g, 44% over
1
exclusive diastereoisomer in all cases, based on H NMR data
comparison with literature (Scheme 5). Thus, both carbonyls
were reduced in a one-pot procedure by LiAlH4 as the reducing
agent. The resulting (+)-2-epi-lasubine II (15) was transformed
into (+)-lasubine II ((+)-1b) via a protocol from Zhu et al.
(Scheme 5).3c In addition, product ent-12 was converted via an
identical pathway into natural (-)-lasubine II ((-)-1b). NMR
spectra, optical rotations, and HPLC chromatograms of both
lasubine II enantiomers were in agreement with literature data.3
In conclusion, we developed a new stereoselective route to
both enantiomers of lasubine II. Key steps include an enanti-
oselective D- or L-proline-catalyzed Mannich reaction employing
commercially available starting compounds and a diastereose-
lective Mannich cyclization. Extension of this methodology to
other members of the same class of molecules is currently under
investigation in our laboratory.
Experimental Section
(R)-4-(3,4-Dimethoxyphenyl)-4-(4-methoxyphenylamino)bu-
tan-2-one (7). Under an ambient atmosphere, to a mixture of DMSO
(45 mL) and acetone (180 mL) was added 3,4-dimethoxybenzal-
dehyde (10.5 g, 63.2 mmol), p-anisidine (7.75 g, 62.9 mmol), and
D-proline (1.52 g, 13.2 mmol). The resulting mixture was stirred
for 24 h at rt. The reaction was quenched by the addition of
potassium phosphate buffer (0.5 M, pH 7, 100 mL). The resulting
mixture was stirred for another 10 min until a precipitate was
formed. The precipitate was isolated by filtration and dried in vacuo
to afford 7 (10.3 g, 50%) as a white solid. Rf 0.26 (EtOAc/heptane,
1:1). Mp 152-154 °C. [R]20D -2.7 (c 0.93, CHCl3). IR (ATR) 819,
1022, 1139, 1229, 1251, 1506, 1705, 3382 cm-1. 1H NMR (CDCl3,
300 MHz) δ 6.92-6.87 (m, 2H), 6.83-6.79 (m, 1H), 6.73-6.67
(m, 2H), 6.55-6.49 (m, 2H), 4.69 (t, J ) 6.5 Hz, 1H), 4.11 (br s,
1H), 3.85 (s, 6H), 3.70 (s, 3H), 2.89 (d, J ) 6.5 Hz, 2H), 2.11 (s,
3H). 13C NMR (CDCl3, 75 MHz) δ 207.4, 152.4, 149.2, 148.1,
141.0, 135.4, 118.2, 115.4, 114.7, 111.3, 109.5, 55.9, 55.7, 55.2,
51.4, 30.8. HRMS (ESI) m/z calcd for C19H23NO4 (M + H)+
330.17053, found 330.17086. HPLC ee >99%, chiralpak AD-H (250
× 4.6 mm), flow 1.0 mL/min, n-hexane/2-propanol 80/20, retention
times 14.9 min for 7 and 18.4 min for ent-7.
three steps) as a yellow oil. Rf 0.18 (EtOAc/heptane, 1:1). [R]20
D
+32 (c 0.095, CHCl3). IR (ATR) 1025, 1146, 1254, 1401, 1516,
1
1642, 1719 cm-1. H NMR (CDCl3, 200 MHz, T ) 323 K) δ
7.37-7.04 (m, 5H), 6.90-6.70 (m, 3H), 6.51-6.33 (m, 1H),
6.11-5.78 (m, 3H), 5.70-5.30 (m, 1H), 5.26-5.05 (m, 2H), 3.78
(s, 3H), 3.70 (s, 3H), 3.35-3.20 (m, 2H), 3.12 (dd, J ) 16.4, 5.2
Hz, 1H), 2,80 (dd, J ) 16.5 Hz, 6.8 Hz, 1H), 2.74 (d, J ) 5.4 Hz,
2H). 13C NMR (CDCl3, 75 MHz) δ 206.6, 171.3, 149.3, 148.4,
135.8, 133.8, 131.6, 131.3, 129.1, 128.4, 128.0, 126.2, 118.7. 118.2,
111.1, 110.0, 55.8, 55.7, 55.0-42.0 (br, 4C), 39.5. HRMS (ESI)
m/z calcd for C25H27NO4 (M + Na)+ 428.18378, found 428.18379.
HPLC chiralpak AD-H (250 × 4.6 mm), flow 1.0 mL/min
(n-hexane/2-propanol 80/20), retention times 12.4 min for 12 and
1
11.5 min for ent-12; dr >19:1 (determined by H NMR).
(4R,9aS)-4-(3,4-Dimethoxyphenyl)-3,4-dihydro-1H-quinoli-
zine-2,6(7H,9aH)-dione (16). To a solution of 12 (2.36 g, 5.82
mmol) in degassed DCM (125 mL) was added Grubbs second
generation catalyst (280 mg, 5.7 mol %). The mixture was stirred
for 2 h at 40 °C under an inert atmosphere. The mixture was
concentrated in vacuo and the residue was purified by column
chromatography (MeOH/EtOAc, 0f1%) to afford 16 (1.30 g, 74%)
(R)-4-Amino-4-(3,4-dimethoxyphenyl)butan-2-one Hydro-
chloride (8). Under ambient atmosphere, to a solution of 7 (9.3 g,
28 mmol) in MeCN/H2O (250 mL, 1:1) was added 1 M aqueous
H2SO4 (28 mL, 28 mmol) and H5IO6 (6.6 g, 29 mmol). The mixture
was stirred for 4 h at rt. The mixture was washed with CH2Cl2 (3
J. Org. Chem. Vol. 74, No. 8, 2009 3209

as an off-white solid. Rf 0.21 (EtOAc/MeOH, 49:1). Mp 148-151
°C. [R]20D -67 (c 0.20, CHCl3). IR (ATR) 1024, 1135, 1255, 1318,
1406, 1515, 1646, 1722, 2359 cm-1. 1H NMR (CDCl3, 300 MHz)
δ 6.75 (d, J ) 8.2 Hz, 1H), 6.68-6.60 (m, 2H), 6.03 (ddt, J ) 9.9,
4.6, 2.7 Hz, 1H), 5.80 (dd, J ) 6.2, 2.0 Hz, 1H), 5.73 (dt, J ) 9.9,
1.9 Hz, 1H), 4.85-4.70 (m, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.19
(dt, J ) 21.0, 4.1 Hz, 1H), 3.18 (dd, J ) 16.5 Hz, 6.3 Hz, 1H),
3.06 (ddt, J ) 21.5, 6.3, 2.8 Hz, 1H), 2.92 (dd, J ) 16.4, 2.3 Hz,
1H), 2.63 (d, J ) 9.0 Hz, 1H), 2.63 (d, J ) 7.9 Hz, 1H). 13C NMR
(CDCl3, 75 MHz) δ 206.0, 168.4, 149.2, 148.2, 133.6, 125.7, 124.3,
117.0, 111.2, 109.1, 55.8, 55.7, 52.9, 51.9, 45.3, 45.0, 33.4. HRMS
(ESI) m/z calcd for C17H19NO4 (M + Na)+ 324.12118, found
324.12128. HPLC chiralpak AD-H (250 × 4.6 mm), flow 1.0 mL/
min (n-hexane/2-propanol 80/20), retention times 24.5
min for 16 and 34.9 min for ent-16.
pak AD-H (250 × 4.6 mm), flow 1.0 mL/min (n-hexane/2-propanol
80/20), retention times 23.9 min for 13 and 27.8 min for ent-13.
(+)-2-epi-Lasubine II (15). To a solution of 13 (787 mg, 2.59
mmol) in dry THF (50 mL) was added LiAlH4 (496 mg, 13.1
mmol). The mixture was brought to 60 °C and stirred for 3 h under
an inert atmosphere. The reaction was quenched by adding H2O
(644 mg, 1.3 mg/mg LiAlH4), aqueous NaOH (15% in H2O, 644
mg, 1.3 mg/mg LiAlH4), and H2O (1.61 g, 3.25 mg/mg LiAlH4).
The resulting mixture was stirred vigorously for 10 min and the
precipitate was removed by filtration. The filtrate was concentrated
in vacuo. The residue was purified by column chromatography
(MeOH/EtOAc, 0f7.5%) to afford 15 (698 mg, 92%) as a yellow
oil. Rf 0.20 (DCM/MeOH, 9:1). [R]20 +57 (c 0.46, MeOH). IR
D
(ATR) 738, 1030, 1136, 1225, 1259, 1453, 1504, 2354, 2934, 3353
cm-1. 1H NMR (CDCl3, 300 MHz) δ 7.10-6.60 (m, 3H), 3.88 (s,
3H), 3.86 (s, 3H), 3.81-3.65 (m, 1H), 2.91 (dd, J ) 11.6, 2.6 Hz,
1H), 2.72-2.63 (m, 1H), 2.05-1.88 (m, 3H), 1.75-1.14 (m, 9H).
13C NMR (CDCl3, 75 MHz) δ 147.9, 136.6, 120.0-119.0 (br, 2C),
111.6-109.0 (br, 2C), 68.4, 68.2, 60.9, 55.9, 55.8, 52.9, 45.1, 42.8,
33.6, 26.0, 24.6. HRMS (ESI) m/z calcd for C17H25NO3 (M + H)+
292.19127, found 292.18992. HPLC chiralpak AD-H (250 × 4.6
mm), flow 1.0 mL/min (n-hexane/2-propanol 80/20), retention times
6.8 min for 15 and 8.2 min for ent-15.
(4R,9aR)-4-(3,4-Dimethoxyphenyl)tetrahydro-1H-quinolizine-
2,6(7H,8H)-dione (13). To a solution of 16 (1.19 g, 3.95 mmol)
in MeOH (60 mL) was added 10% Pd/C (459 mg, 11 mol %). A
hydrogen atmosphere was applied (balloon) and the mixture was
stirred for 16 h at rt. The catalyst was removed by filtration over
Celite and the solution was concentrated in vacuo. The residue was
purified by column chromatography (MeOH/EtOAc, 0f2%) to
afford 13 (885 mg, 74%) as a white solid. Rf 0.54 (DCM/MeOH,
9:1). Mp 181-183 °C. [R]20 -122 (c 0.26, CHCl3). IR (ATR)
Acknowledgment. This work forms part of the Ultimate
Chiral Technology project supported in part with funds
provided by SNN (Cooperation Northern Nederlands) and
EFRO (European Fund for Regional Development).
D
1
1024, 1143, 1255, 1410, 1441, 1511, 1639, 1722, 2941 cm-1. H
NMR (CDCl3, 300 MHz) δ 6.76 (d, J ) 8.3 Hz, 1H), 6.69 (d, J )
2.1 Hz, 1H), 6.65 (ddd, J ) 8.2, 2.2, 0.9 Hz, 1H), 5.84 (dd, J )
5.9, 2.3 Hz, 1H), 4.15-3.98 (m, 1H), 3.83 (s, 3H), 3.81 (s, 3H),
3.10 (dd, J ) 16.7, 6.0 Hz, 1H), 2.94 (dd, J ) 16.7, 2.4 Hz, 1H),
2.67-2.53 (m, 2H), 2.46 (d, J ) 6.8 Hz, 1H), 2.46 (d, J ) 9.2 Hz,
1H), 2.10-1.60 (m, 4H). 13C NMR (CDCl3, 75 MHz) δ 206.3,
170.2, 149.1, 148.1, 133.8, 117.0, 111.2, 109.2, 55.8, 55.7, 52.9,
52.2, 45.2, 44.8, 32.1, 30.8, 20.4. HRMS (ESI) m/z calcd for
C17H21NO4 (M + H)+ 304.15488, found 304.15461. HPLC chiral-
Supporting Information Available: NMR spectra, HPLC
chromatograms, and characterization data of routes to both
enantiomers and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO900141F
3210 J. Org. Chem. Vol. 74, No. 8, 2009