Enantioselective synthesis of (S)-1,6,7,8,9,9a-hexahydroquinolizin-4-one. Formal synthesis of the lycopodium alkaloids senepodine G and cermizine C

Article abstract of DOI:10.1016/j.tetasy.2008.04.022

The synthesis of the title compound, a key intermediate in the synthesis of some lycopodium and lupin alkaloids, is reported. From a stereochemical standpoint the key steps are the stereoselective cyclocondensation of ketodiester 1 with (R)-phenylglycinol and the stereocontrolled reduction, with retention of configuration, of the oxazolidine ring in the resulting oxazolopiperidone lactam 2.

Full text of DOI:10.1016/j.tetasy.2008.04.022

Tetrahedron: Asymmetry 19 (2008) 1233–1236
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Tetrahedron: Asymmetry
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Enantioselective synthesis of (S)-1,6,7,8,9,9a-hexahydroquinolizin-4-one.
Formal synthesis of the lycopodium alkaloids senepodine G and cermizine C
*
Mercedes Amat , Rosa Griera, Robert Fabregat, Joan Bosch
Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona, 08028-Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the title compound, a key intermediate in the synthesis of some lycopodium and lupin
alkaloids, is reported. From a stereochemical standpoint the key steps are the stereoselective cyclocon-
densation of ketodiester 1 with (R)-phenylglycinol and the stereocontrolled reduction, with retention
of configuration, of the oxazolidine ring in the resulting oxazolopiperidone lactam 2.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 31 March 2008
Accepted 22 April 2008
Available online 26 May 2008
1. Introduction
H
N
H
N
Me
2
Me
2
Senepodine G and cermizine C are two quinolizidine alkaloids,
which were isolated in 2004 from the club moss Lycopodium chin-
ense and Lycopodium cernuum, respectively (Fig. 1).1 Senepodine G
exhibits cytotoxicity against murine lymphoma L120 cells. Last
year a stereospecific total synthesis of these alkaloids was re-
ported, thus confirming the proposed structures.2
A key intermediate of the synthesis was unsaturated lactam 7,
which was prepared in enantiopure form from (S)-2-piperidineth-
anol. A stereoselective conjugate addition of Me2CuLi in the pres-
ence of BF3ꢀEt2O was used to introduce the C-2 methyl
substituent with the required configuration, whereas a MeMgBr
addition followed by HCl was used to install the C-4 methyl group.
The synthesis of cermizine C required a subsequent stereoselective
NaBH4 reduction step.
4
4
Me
cermizine C
Me
senepodine G
H
R
H
R= CHO leontiformine
R= H leontiformidine
N
N
H
Figure 1. Quinolizidine alkaloids synthesized from unsaturated lactam 7.
2. Results and discussion
In the racemic series, unsaturated lactam 7 has also been used
as a key intermediate in the total synthesis of the lupin alkaloids,
leontiformine and leontiformidine.3
In the context of our studies on the enantioselective synthesis
of piperidine-containing natural products from phenylglycinol-
derived oxazolopiperidone lactams,4 we herein report a conve-
nient synthesis of enantiopure unsaturated hexahydroquinolizin-
4-one 7.
The key step is the stereoselective cyclocondensation of the
achiral ketodiester 1, which already incorporates the nine carbon
atoms present in the target lactam 7, and (R)-phenylglycinol,
which acts as a chiral and latent form of ammonia. In this step, a
stereocenter at the nitrogen a-position is generated and the result-
ing enantiopure oxazolopiperidone lactam incorporates a butyrate
chain that allows the construction of the quinolizidone ring.
The synthetic sequence is outlined in Scheme 1.
Treatment of a toluene solution of ketodiester 15 with (R)-phen-
ylglycinol in the presence of a catalytic amount of AcOH in a Dean–
Stark apparatus gave a mixture (87% overall yield) of bicyclic
lactam 2 and its C-8a epimer (8a-epi-2), which were easily sepa-
rated by column chromatography. The major isomer 2 was isolated
in 73% yield.
Next, LiAlH4 reduction of 2 brought about both the reduction of
the lactam and ester carbonyl groups and the reductive opening of
the oxazolidine ring, which took place with complete retention of
configuration,6 to give piperidine diol 3 in 68% yield.7
Hydrogenation of 3 in the presence of (Boc)2O using Pd(OH)2 as
the catalyst afforded the protected piperidine alcohol derivative 4
in 83% yield, which was then oxidized (86% yield) with PDC in DMF
to give acid 5. A somewhat less satisfactory route to 5 was the
Dess–Martin oxidation of alcohol 4 (78%) followed by NaClO2 oxi-
dation of the resulting aldehyde (85%). Deprotection of 5 with
TMSCl followed by heating of the resulting amino acid in refluxing
xylene gave enantiopure quinolizidin-4-one 6 in 72% yield.8
* Corresponding author. Tel.: +34 93 402 45 40; fax: +34 93 402 45 39.
E-mail address: amat@ub.edu (M. Amat).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.022

1234
M. Amat et al. / Tetrahedron: Asymmetry 19 (2008) 1233–1236
(R)
C6H5
C6H5
OH
R
N
NH2
MeO2C
CO2Me
O
O
O
N
(CH2)3 CH2OH
LiAlH4
68%
toluene, AcOH
73%
8a
(CH2)3 CO2Me
1
2
3 R= (R)-CH(C6H5)CH2OH
4 R= Boc
H2, Pd(OH)2
(Boc)2O
83%
Boc
N
O
O
1. Me3SiCl
2. xylene, Δ
72%
1. tert-BuLi, PhSeCl
(CH2)3 COOH
N
N
2. O3
PDC
86%
9a
H
H
60%
5
6
7
Scheme 1. Enantioselective synthesis of unsaturated lactam 7.
Finally, bicyclic lactam 6 was converted to the target unsatu-
rated lactam 7 by treatment with tert-BuLi and PhSeCl, followed
by ozonolysis of the resulting mixture of seleno derivatives.9
The above preparation of the partially reduced quinolizin-4-one
7, a key intermediate in the synthesis of quinolizidine alkaloids,
illustrates further the potential of phenylglycinol-derived oxazolo-
piperidone lactams10 for the enantioselective synthesis of piperi-
dine-containing natural products.
lactam 2 (6.5 g, 73%) and 8a-epi-2 (1.2 g, 14%). Compound 2 (higher
Rf): IR (NaCl) 1735, 1650 cmꢁ1 1H NMR (CDCl3, 200 MHz) d 1.41–
;
1.99 (m, 8H), 2.24–2.70 (m, 4H), 3.60 (s, 3H, CH3), 3.86 (dd, J = 8.8,
8.0 Hz, 1H, H-3), 4.50 (t, J = 8.8 Hz, 1H, H-2), 5.36 (t, J = 8.0 Hz, 1H,
H-2), 7.15–7.38 (m, 5H, H-Ar); 13C NMR (CDCl3, 50,3 MHz) d 16.7
(CH2), 19.4 (CH2), 30.7 (CH2), 30.8 (CH2), 33.3 (CH2), 33.8 (CH2),
51.5 (CH3), 58.5 (CH), 69.4 (CH2), 95.6 (C), 125.4 (CH-o), 127.1
(CH-p), 128.5 (CH-m), 139.8 (C-i), 169.7 (CO), 173.4 (CO);
22
½aꢂD ¼ ꢁ94:2 (c 1.0, MeOH); Anal. Calcd for C18H23NO4: C, 68.12;
H, 7.30; N, 4.41. Found: C, 68.07; H, 7.28; N, 4.33. Compound 8a-
3. Experimental
epi-2 (lower Rf): IR (NaCl) 1733, 1650 cmꢁ1 1H NMR (CDCl3,
;
300 MHz) d 1.61–2.00 (m, 8H), 2.22–2.45 (m, 4H), 3.70 (s, 3H,
CH3), 3.92 (dd, J = 9.3, 1.8 Hz, 1H, H-3), 4.40 (dd, J = 9.3, 7.2 Hz,
1H, H-2), 4.94 (dd, J = 7.2, 1.8 Hz, 1H, H-2), 7.26–7.30 (m, 5H, H-
Ar); 13C NMR (CDCl3, 75,4 MHz) d 16.8 (CH2), 19.3 (CH2), 29.8
(CH2), 30.1 (CH2), 33.2 (CH2), 33.5 (CH2), 51.5 (CH3), 58.9 (CH),
71.2 (CH2), 94.8 (C), 126.1 (CH-o), 127.2 (CH-p), 128.4 (CH-m),
All non-aqueous reactions were performed under an inert
atmosphere. Drying of the organic extracts during the workup of
reactions was performed over anhydrous Na2SO4 or MgSO4. Evap-
oration of solvents was accomplished with a rotatory evaporator.
Thin-layer chromatography was carried out on SiO2 (Silica Gel 60
F254), and the spots were located by UV or 1% aqueous KMNO4.
22
141.5 (C-i), 167.2 (CO), 173.4 (CO); ½aꢂD ¼ ꢁ50:6 (c 1.2, MeOH);
Chromatography refers to flash column chromatography and was
carried out on SiO2 (Silica Gel 60, SDS, 35–70 l). Melting points
were determined in a capillary tube and are uncorrected. Unless
otherwise indicated, NMR spectra were recorded in CDCl3 at 200
or 300 MHz (1H) and 50.3 or 75.4 MHz (13C). The chemical shifts
are reported as d values, in parts per million (ppm) relative to
TMS (0 ppm) or relative to residual chloroform (7.26 ppm,
77.0 ppm) as an internal standard. IR spectra were recorded on a
Nicolet 205 FT-IR spectrophotometer with samples prepared as
thin films on NaCl salt plates, and only noteworthy absorptions
are listed. Optical rotations were measured on a Perkin–Elmer
241 polarimeter using a 1 dm cell with a total volume of 1 mL.
THF was distilled from sodium/benzophenone. Anhydrous solvents
for reactions were distilled at atmospheric pressure prior to use
and dried using standard procedures. Microanalyses were per-
formed by the Centre d’Investigació i Desenvolupament (CSIC),
Barcelona. High-resolution mass spectra (HRMS) were performed
by the Unidade de Espectrometria de Masas, Santiago de Compos-
tela and Unitat d’Espectrometria de Masses (SCT), Barcelona.
Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C,
67.90; H, 7.29; N, 4.31.
3.2. (S)-1-[(R)-1-Phenyl-2-hydroxyethyl]piperidine-2-butanol 3
At first LiAlH4 (239 mg, 6.3 mmol) was slowly added to a cooled
solution (0 °C) of lactam 2 (200 mg, 0.63 mmol) in anhydrous THF
(10 mL), and the mixture was stirred at rt for 1 h. The reaction mix-
ture was quenched with water, and the resulting mixture was
extracted with EtOAc. The organic extracts were dried and
concentrated, and the resulting residue was chromatographed
(EtOAc to 98:2 EtOAc–MeOH) to give alcohol 3 (119 mg, 68%) as
an oil: IR (NaCl) 3383 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 1.05–
;
1.84 (m, 13H), 2.37–2.45 (m, 1H), 2.85–2.91 (m, 1H), 3.59 (dd,
J = 10.5, 5.7 Hz, 1H), 3.68 (t, J = 6.3 Hz, 2H), 3.98 (t, J = 10.5 Hz,
1H), 4.29 (dd, J = 10.5, 5.7 Hz, 1H), 7.17–7.34 (m, 5H, H-Ar); 13C
NMR (CDCl3, 75.4 MHz) d 20.5 (CH2), 24.1 (CH2), 26.4 (CH2), 31.4
(CH2), 32.2 (CH2), 33.2 (CH2), 45.5 (CH2), 57.2 (CH), 59.5 (CH2),
60.5 (CH), 62.7 (CH2), 127.6 (CH-o), 128.1 (CH-p), 128.8 (CH-m),
22
135.9 (C-i); ½aꢂD ꢁ 84:7 (c 0.9, MeOH); HMRS calcd for C17H27NO2
3.1. Methyl (3R,8aR)-5-oxo-3-phenyl-2,3,5,6,7,8-
hexahydrooxazolo[3,2-a]piperidine-8a-butyrate 2
(M+H+): 278.2120, found: 278.2115.
3.3. (S)-1-(tert-Butoxycarbonyl)piperidine-2-butanol 4
(R)-Phenylglycinol (4.6 g, 33.4 mmol) was added to a solution of
ketodiester 1 (6.4 g, 27.8 mmol) and AcOH (2.4 mL, 41.7 mol) in
toluene (240 mL). The mixture was heated at reflux for 7 h with
azeotropic elimination of water produced by a Dean–Stark appara-
tus. The resulting mixture was cooled and concentrated to give an
oil. Flash chromatography (1:1 hexane–EtOAc to EtOAc) afforded
A solution of alcohol 3 (2.4 g, 8.7 mmol) and di-tert-butyl dicar-
bonate (3.8 g, 17.6 mmol) in EtOAc (300 mL) containing 40%
Pd(OH)2/C (960 mg) was stirred under hydrogen at rt for 24 h.
The catalyst was removed by filtration through a Celite pad, and

M. Amat et al. / Tetrahedron: Asymmetry 19 (2008) 1233–1236
1235
the filtrate was concentrated to give a residue, which was chro-
and washed with brine. The combined organic extracts were dried
matographed (8:2 to 1:1 hexane–EtOAc) to afford alcohol 4
and concentrated to give quinolizidin-4-one 6 (220 mg, 72%): IR
(1.9 g, 83%): IR (NaCl) 3442, 1692 cmꢁ1
;
1H NMR (CDCl3,
(NaCl) 1637 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 1.27–1.86 (m,
;
300 MHz) d 1.36–1.87 (m, 20H), 2.80–2.88 (m, 2H), 3.70 (t,
J = 6.6 Hz, 2H), 4.04 (d, J = 12.9 Hz, 1H), 4.30 (s, 1H); 13C NMR
(CDCl3, 75.4 MHz) d 18.8 (CH2), 22.3 (CH2), 25.5 (CH2), 28.2
(CH2), 28.3 (3CH3), 29.2 (CH2), 32.4 (CH2), 38.6 (CH2N), 50.1
9H), 1.90–2.05 (m, 1H), 2.32–2.44 (m, 3H), 3.10–3.30 (m, 1H),
4.75–4.82 (m, 1H); 13C NMR (CDCl3, 75.4 MHz) d 19.2 (CH2), 24.5
(CH2), 25.3 (CH2), 30.5 (CH2), 33.0 (CH2), 34.0 (CH2), 42.4 (CH2),
56.8 (CH), 169.3 (CNO); ½aꢂD ¼ ꢁ3:7 (c 1.0, CHCl3).
22
22
(CHN), 62.3 (CH2OH), 78.9 (C), 155.1 (CO); ½aꢂD ¼ ꢁ32:6 (c 1.0,
MeOH); Anal. Calcd for C14H27NO3: C, 65.33; H, 10.57; N, 5.44.
Found: C, 65.08; H, 10.59; N, 5.38.
3.6. (S)-1,6,7,8,9,9a-Hexahydroquinolizin-4-one 7
At first tert-BuLi (0.4 mL of
a 1.7 M solution in hexane,
3.4. (S)-1-(tert-Butoxycarbonyl)piperidine-2-butanoic acid 5
0.7 mmol) was slowly added at ꢁ78 °C to a solution of 6 (70 mg,
0.45 mmol) in THF (5 mL), and the mixture was stirred for
20 min. Then, a solution of PhSeCl (95 mg, 0.5 mmol) in THF
(2 mL) was slowly added, and the mixture was stirred at ꢁ78 °C
for 2 h. Saturated aqueous NH4Cl was added, and the resulting mix-
ture was extracted with EtOAc. The combined organic extracts
were dried and concentrated. The residue was chromatographed
(7:3 hexane–EtOAc) affording the two C-3 epimers of (9aS)-3-(phen-
ylselanyl)-1,2,3,6,7,8,9,9a-octahydroquinolizin-4-one. Higher Rf
3.4.1. Method A
PDC (23.2 g, 61.6 mmol) was added to a solution of alcohol 4
(2.6 g, 10.3 mmol) in anhydrous DMF (80 mL), and the mixture
was stirred at rt for 24 h. The reaction mixture was quenched with
water, and the resulting mixture was extracted with Et2O. The
organic extracts were dried and concentrated to give acid 5
(2.4 g, 86%) as an oil: IR (NaCl) 1689 cmꢁ1 1H NMR (CDCl3,
;
300 MHz) d 1.26–1.80 (m, 18H), 2.36–2.42 (m, 2H), 2.73 (t,
J = 12.5 Hz, 2H), 3.97 (d, J = 12.5 Hz, 1H), 4.22 (s, 1H); 13C NMR
(CDCl3, 75.4 MHz) d 19.0 (CH2), 21.4 (CH2), 25.6 (CH2), 28.5
(CH2), 28.5 (3CH3), 29.0 (CH2), 33.7 (CH2N), 38.7 (CH2CO), 49.9
(45 mg, 33%): IR (NaCl) 1624 cmꢁ1 1H NMR (CDCl3, 300 MHz) d
;
1.29–1.55 (m, 4H), 1.61–1.70 (m, 2H), 1.82–1.91 (m, 2H), 2.04–
2.24 (m, 2H), 2.41 (td, J = 13.0, 3.0 Hz, 1H), 3.23–3.32 (m, 1H),
4.04 (dd, J = 5.0, 3.0 Hz, 1H), 4.72–4.79 (m, 1H), 7.27–7.29 (m, 3H,
H-Ar), 7.65–7.68 (m, 2H, H-Ar); 13C NMR (CDCl3, 75.4 MHz) d
24.5 (CH2), 25.3 (CH2), 26.6 (CH2), 28.2 (CH2), 33.7 (CH2), 43.5
(CH2), 43.6 (CH), 56.9 (CH), 127.8 (CH-Ar), 128.9 (CH-Ar), 129.2
(C-i), 135.1 (CH-Ar), 167.8 (CNO). Lower Rf (51 mg, 37%): IR (NaCl)
22
(CHN), 79.3 (C), 155.2 (CO), 178.7 (COOH); ½aꢂD ¼ ꢁ40:8 (c 1.0,
MeOH); Anal. Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16.
Found: C, 61.54; H, 9.22; N, 4.92.
3.4.2. Method B
1636 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 1.08–1.21 (m, 1H), 1.25–
;
Dess–Martin reagent (850 mg, 2 mmol) was added to a solution
of alcohol 4 (360 mg, 1.4 mmol) in anhydrous CH2Cl2 (6 mL), and
the mixture was stirred at rt for 3 h. Then Et2O (12 mL), 1 M aque-
ous Na2S2O4 (2 mL), and saturated aqueous NaHCO3 (2 mL) were
added, and the resulting mixture was stirred for 45 min. The
aqueous layer was extracted with Et2O, and the combined organic
extracts were washed with brine, dried, and concentrated.
The resulting residue was chromatographed (7:3 hexane–EtOAc)
to give crude (S)-1-(tert-butoxycarbonyl)piperidine-2-butanal
1.50 (m, 2H), 1.65–2.15 (m, 7H), 2.39 (td, J = 13.0, 3.0 Hz, 1H),
3.15–3.25 (m, 1H), 3.99 (t, J = 4.0 Hz, 1H), 4.69–4.76 (m, 1H),
7.27–7.30 (m, 3H, H-Ar), 7.68–7.71 (m, 2H, H-Ar); 13C NMR (CDCl3,
75.4 MHz) d 24.1 (CH2), 25.1 (CH2), 26.8 (CH2), 27.2 (CH2), 34.1
(CH2), 42.6 (CH2), 43.5 (CH), 56.9 (CH), 127.9 (CH-Ar), 128.9 (CH-
Ar), 129.4 (C-i), 135.0 (CH-Ar), 168.3 (CNO).
A stream of ozone gas was bubbled through a cooled (ꢁ78 °C)
solution of the above-mentioned mixture of selenides (220 mg,
0.71 mmol) in anhydrous CH2Cl2 (25 mL) until it turned pale blue.
The solution was purged with O2, and the temperature was slowly
raised to 25 °C. After 30 min of stirring, the mixture was washed
with brine, and the organic solution was dried and concentrated.
The residue was chromatographed (7:3 hexane–EtOAc) to give 7
(92 mg, 85%) as an oil: IR (NaCl) 1668, 1614 cmꢁ1; 1H NMR (CDCl3,
300 MHz) d 1.38–1.55 (m, 3H), 1.72–1.85 (m, 3H), 2.14–2.25 (m,
1H), 2.46–2.58 (m, 2H), 3.39–3.48 (m, 1H), 4.62 (dd, J = 11.4,
1.8 Hz, 1H), 5.86–5.91 (m, 1H), 6.43–6.50 (m, 1H); 13C NMR (CDCl3,
75.4 MHz) d 23.8 (CH2), 24.7 (CH2), 30.9 (CH2), 33.3 (CH2), 42.9
(CH2), 54.6 (CH), 124.5 (CH), 137.9 (CH), 165.3 (CNO);
(280 mg, 85%) as an oil: IR (NaCl) 1687 cmꢁ1 1H NMR (CDCl3,
;
300 MHz) d 1.42–1.89 (m, 18H), 2.52–2.59 (m, 2H), 2.80 (t,
J = 12 Hz, 2H), 4.04 (d, J = 12 Hz, 1H), 4.30 (s, 1H), 9.83 (s, 1H);
13C NMR (CDCl3, 75,4 MHz) d 18.6 (CH2), 18.8 (CH2), 25.4 (CH2),
28.3 (CH2), 28.3 (3CH3), 28.8 (CH2), 38.5 (CH2N), 43.3 (CH2CO),
22
49.7 (CHN), 78.9 (C), 154.8 (CO), 202.0 (CHO); ½aꢂD ¼ ꢁ17:7 (c
1.0, MeOH).
A solution of the above aldehyde (1.3 g, 5 mmol) in CH3CN
(52 mL), tert-BuOH (155 mL), and 2-methyl-2-butene (3 mL) was
stirred rapidly as it was cooled (0 °C). A solution of NaClO2 (3.5 g,
39 mmol) and NaH2PO4 (552 mg, 4 mmol) in H2O (60 mL) was
added dropwise over a period of 10 min at 0 °C, and the mixture
was then partitioned between EtOAc (300 mL) and brine (90 mL).
The organic layer was washed with 1 M Na2S2O4 (2 ꢃ 100 mL),
dried, and concentrated. The resulting residue was chromato-
graphed (1:1 hexane–EtOAc) to give acid 5 (1.1 g, 85%).
22
22
½aꢂD ¼ þ45:1 (c 1.0, CHCl3). {lit.2 ½aꢂD ¼ þ47:0 (c 1.0, CHCl3)}.
Acknowledgments
Financial support from the Ministry of Science and Technology
(Spain)-FEDER (Project CTQ2006-02390/BQU) and the DURSI, Gen-
eralitat de Catalunya (Grant 2005SGR-0603) is gratefully
acknowledged.
3.5. (S)-1,2,3,6,7,8,9,9a-Octahydroquinolizin-4-one 6
TMSCl (505 lL, 4 mmol) was added to a solution of acid 5
(537 mg, 2 mmol) in CH3CN (12 mL) containing NaI (600 mg,
4 mmol). The mixture was stirred at rt for 1 h, filtered, and concen-
trated to give the crude amino acid (800 mg), which was used
without further purification in the next step.
A solution of the above-mentioned amino acid in xylene
(100 mL) was heated at reflux for 24 h with azeotropic elimination
of water produced by a Dean–Stark apparatus. The resulting mix-
ture was concentrated, and the residue was taken up in EtOAc
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1236
M. Amat et al. / Tetrahedron: Asymmetry 19 (2008) 1233–1236
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