Enantioselective synthesis of indolizidine and quinolizidine derivatives from chiral non-racemic bicyclic lactams

Article abstract of DOI:10.1016/j.tet.2004.04.055

Chiral non-racemic bicyclic lactams 2b,c, derived from (R)- and (S)-phenylglycinol, were used in the enantioselective synthesis of (-)-lupinine and 5-epitashiromine, respectively. The efficiency of the synthesis relied on the high diastereoselectivities of formation and reduction of compounds 2b,c.

Full text of DOI:10.1016/j.tet.2004.04.055

Tetrahedron 60 (2004) 5433–5438
Enantioselective synthesis of indolizidine and quinolizidine
derivatives from chiral non-racemic bicyclic lactams
*
Claude Agami, Luc Dechoux, Severine Hebbe and Cecilia Menard
´
´
´
` ´ ´
Laboratoire de Synthese Asymetrique (UMR 7611), Universite P. et M. Curie, 4 place Jussieu, 75005 Paris, France
Received 21 November 2003; revised 24 March 2004; accepted 22 April 2004
Abstract—Chiral non-racemic bicyclic lactams 2b,c, derived from (R)- and (S)-phenylglycinol, were used in the enantioselective synthesis
of (2)-lupinine and 5-epitashiromine, respectively. The efficiency of the synthesis relied on the high diastereoselectivities of formation and
reduction of compounds 2b,c.
q 2004 Elsevier Ltd. All rights reserved.
Regarding the enantioselective synthesis of polysubstituted
piperidines,1 chiral non-racemic bicyclic lactams2 derived
from homochiral b-amino alcohols are commonly con-
sidered as the most useful starting material. In these
syntheses, the bicyclic ring system is usually generated
by cyclocondensation of d-oxoacid derivatives with suitable
b-amino alcohols.
systems of the C5 substituent and on a high stereocontrol of
the reductive opening of the oxazolidine ring.
More recently, we described the diastereoselective synthesis
of the cis bicyclic lactams 2.6
Here, we wish to report full experimental details of this
work, as well as two applications directed towards the
enantioselective synthesis of (2)-lupinine and 5-epitashiro-
mine. These two compounds possess the quinolizidine and
indolizidine structural skeletons widely found in natural
alkaloids.7 Whereas a quite large number of enantio-
selective syntheses of chiral non-racemic lupinine have
been described,8 one publication only reported the synthesis
of enantiopure 5-epitashiromine.9
In previous papers, we described the enantioselective
synthesis of 2,3-disubstituted piperidines3 4 and 5
(R¼Me) from the chiral non-racemic bicyclic lactams4 2
and 3. These bicyclic compounds were obtained by aza-
annulation5 of b-enaminoesters 1 derived from (S)-phenyl-
glycinol with acryloyl chloride (Scheme 1).
To the best of our knowledge, the synthesis of bicyclic
lactams bearing an ester or a ketone moiety on C5 have not
been reported so far. The efficiency of these transform-
ations, that is the synthesis of enantiopure 2,3-disubstituted
piperidines, rely on a simple introduction in the bicyclic
1. Results and discussion
A possible precursor of (2)-lupinine 10b (n¼2) is the
Scheme 1.
Keywords: Bicyclic lactams; Lupinine; Epitashiromine; Quinolizidine; Indolizidine.
*
Corresponding author. Tel.: þ33-1-44-26-26-20; fax: þ33-1-44-27-26-20; e-mail address: dechoux@ccr.jussieu.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.055

5434
C. Agami et al. / Tetrahedron 60 (2004) 5433–5438
Figure 1.
bicyclic lactam 2b, which already bears the two stereogenic
centers present in 10b. The compound 2b could be obtained
from the TBS-protected (R)-phenylglycinol ent-6 and
b-ketoester 11b (n¼2). Using the same strategy, bicyclic
lactam 2c, arising from TBS-protected (S)-phenylglycinol 6
and b-ketoester 11c (n¼1), should be a valuable precursor
for the synthesis of 5-epitashiromine 10c (Fig. 1).
expected bicyclic lactams 2a,b,c were obtained in quanti-
tative yields and excellent diastereoselectivities (.95%).
Overall yields starting from (R)-or (S)-phenylglycinol were
higher than 80%.
Absolute configurations of cis lactams 2b,c and trans
lactams 3b,c were deduced from the structures of com-
pounds 2a (R¼Me) and 3a (R¼Me) which have been
1
In order to prepare enaminoesters 9a,b,c (Scheme 2) by an
aza-annulation process, condensation of TBS-protected
(R)-phenylglycinol 6 with b-ketoester (n¼2)10 11b and of
TBS-protected (S)-phenylglycinol ent-6 with b-ketoester
(n¼1) 11c and methylacetoacetate, in methanol, yielded
b-enaminoesters 7a,b,c. Silica gel chromatography afforded
purified enaminoesters 7b and 7c (respective yields: 39
and 42%). These low yields resulted from the instability
of b-enaminoesters on silica gel. Nevertheless, unpurified
enaminoesters 7a,b,c were obtained in nearly quantitative
yields and they were used as such in the next step.
previously established by NOE H NMR experiments and
X-ray analysis.4 It was in particular observed that the
chemical shift of the proton a to the ester moiety in
the major cis lactams diastereoisomers 2b,c were found
up field (2.6–2.7 ppm) from that of trans isomers 3b,c
(3.1–3.2 ppm).
Reduction of the oxazololactams 2b,c using 4 equiv. of
BH3·THF yielded the piperidines 12b and 12c, respectively,
with a high facial selectivity (d.e..95%) and in a
quantitative manner (Scheme 3). We have already shown
that the stereoselectivity was not governed by the stereo-
genic center bearing the ester moiety but by the more remote
phenyl-bearing stereocenter adjacent to the nitrogen.3
Meyers11 reduced similar bicyclic lactams with BH3·THF
and noted that the reduction occurred also with retention of
configuration. More recently, Amat12 presented a more
exhaustive study showing that the diastereoselectivity of the
reduction of 2-aryloxazolidino-d-lactams are dependent on
the nature of the reducing agent.
The aza-annulation reaction was performed by adding
1.2 equiv. of acryloyl chloride derivatives to b-enamino-
esters 7a,b,c in THF at 0 8C. Cyclization with acryloyl
chloride was successful and yielded fair amounts of the
expected TBS-protected 3,4-dihydro-2-pyridones 8a,b,c.
Deprotection of compounds 8a,b,c with HF-pyridine at
0 8C worked properly and excellent yields of compounds
9a,b,c were obtained if the crude materials were used
without purification by silica gel chromatography. It is
noteworthy that, the bicyclic lactams 2a,b,c were formed
directly with low diastereoselectivities (d.e.,20%) when
using basic deprotection conditions involving tetrabutyl-
ammonium-fluoride (TBAF).
The final steps of the two syntheses were similar to those of
the previously reported synthesis of (2)-Coniceine
(Meyers13e). Both our syntheses included cylization by
reductive amination.13 The aldehydes were deprotected by
heating the piperidines 12b,c in a 4:1 mixture of acetone and
water with 2 mol equiv. p-toluenesulfonic acid. Hydro-
genation of the resulting aminoaldehyde, in methanol
containing a 0.3 mol equiv. of Pd/C, removed the N-benzyl
group and allowed the reductive amination leading to
At this stage, the alcohols 9a,b,c were purified by silica gel
chromatography. Intramolecular Michael addition was
performed in basic media using 0.1 mol equiv. of LiHMDS
in THF, at 0 8C, during 40 min. Under these conditions, the
Scheme 2. (i) MeOH, reflux; (ii) acryloyl chloride, THF; (iii) HF.pyridine, THF; (iv) LiHMDS, THF.

C. Agami et al. / Tetrahedron 60 (2004) 5433–5438
5435
Scheme 3. (i) BH3·THF, THF; (ii) p-toluenesulfonic acid, acetone, H2O; (iii) Pd/C, H2, MeOH; (iv) LiAlH4, THF.
quinolizidine 13b and indolizidine 13c with 60 and 29%
yield, respectively, for the two steps. The reduction of
compounds 12b,c with LiAlH4 in THF for 24 h gave
(2)-lupinine 10b and 5-epitashiromine 10c in 60% yield.
The products were purified by silica gel chromatography.
Comparison of the 1H NMR and 13C NMR of (2)-10b8d and
10c9 confirmed the structures of the compounds. The value
of the optical rotation of (2)-10c [a]D¼221.5 [lit14 [a]D for
(2)-lupinine 221] confirmed the absolute stereo-
chemistry and the optical purity of (2)-lupinine. For
5-epitashiromine, a very low absolute value was found
(around 0). An equivalent low value was obtained for
the same stereoisomer 10b [a]D¼21.3 [lit9 [a]D for
5-epitashiromine þ1.1].
of LiHMDS (0.173 mL, 1 M in THF). After 2 h at 0 8C
(40 min for substrates 9b,c), the reaction was quenched with
an saturated aqueous solution of NH4Cl and extracted with
CH2Cl2 (3£20 mL). The combined organic layers were
dried over MgSO4 and concentrated under reduced pressure.
The crude product was used without further purification in
the next step (white crystal, 0.50 g, 100%).
3.2.1. (3S)-(8S)-(8aR)-8a-Methyl-5-oxo-3-phenyl-hexa-
hydro-oxazolo[3,2-a]pyridine-8-carboxylic acid methyl
ester (2a).3 White crystal, 100%. 1H NMR (CDCl3):
d¼1.47 (s, 3H), 2.12–2.24 (m, 2H), 2.49 (m, 1H), 2.65
(m, 1H), 2.76 (dd, J¼8.5, 9 Hz, 1H), 3.78 (s, 3H), 3.99 (dd,
J¼7.8, 9.2 Hz, 1H), 4.55 (dd, J¼8.2, 9 Hz, 1H), 5.33 (t,
J¼8 Hz, 1H), 7.19–7.36 (m, 5H). 13C NMR (CDCl3): d¼
20.3, 20.5, 29.8, 50.1, 52.4, 58.7, 70.2, 93.9, 125.5, 127.4,
128.7, 139.2, 168.4, 171.4. Mp: 115 8C. [a]2D0¼þ137 (c
0.68, CHCl3). Anal. Calcd for C16H19NO4: C: 66.42, H:
6.62, N: 4.84. Found: C: 66.37, H: 6.78, N: 4.77. IR (CHCl3)
2. Conclusion
Chiral non-racemic cis bicyclic lactams 2, starting from (R)-
and (S)-phenylglycinol, allow an easy access to indolizidine
and quinolizidine heterocycles. As a result, (2)-lupinine
10b and 5-epitashiromine 10c were synthezised in 19 and
7% overall yield, respectively. The efficiency of these
syntheses relied on the direct introduction in the lactam
ring of the carbonyl function and on the high stereoselec-
tivities of formation and reduction of bicyclic lactams 2.
We are currently working on enantioselective syntheses of
matrine15 and its stereoisomers.
1734, 1655, 1395 cm21
.
3.2.2. (3R)-(8R)-(8aS)-8a-(3-[1,3]Dioxolan-2-yl-propyl)-
5-oxo-3-phenyl-hexahydro-oxazolo[3,2-a]pyridine-8-
carboxylic acid methyl ester (2b).3 White crystal, 100%.
1H NMR (CDCl3): d¼1.12–2.74 (m, 11H), 3.66–3.72 (m,
2H), 3.72 (s, 3H), 3.75–3.79 (m, 2H), 4.05 (dd, J¼6.7, 9 Hz,
1H), 4.44 (dd, J¼8.2, 9 Hz, 1H), 4.64 (t, J¼4.2 Hz, 1H),
5.33 (t, J¼7 Hz, 1H), 7.17–7.28 (m, 5H). 13C NMR
(CDCl3): d¼17.9, 19.7, 29.5, 33.5, 33.8, 49.1, 52.4, 58.5,
64.8, 69.4, 95.8, 103.9, 125.8, 127.3, 128.5, 139.2, 169.4,
171.5. Mp: 138 8C. [a]D20¼2100 (c 0.78, CHCl3). Anal.
Calcd for C21H27NO6: C: 64.77, H: 6.99, N: 3.60. Found: C:
63.51, H: 7.12, N: 3.47.
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded on a Bruker ARX
250 spectrometer at 250 and 62.9 MHz, respectively;
chemical shifts are reported in ppm from TMS. All reaction
with organometallic were conducted under argon. Column
chromatography was performed on silica gel, 230–400.
TLC were run on Merck Kieselgel 60F254 plates. THF was
distilled from sodium/benzophenone ketyl.
3.2.3. (3S)-(8S)-(8aR)-8a-(2-[1,3]Dioxolan-2-yl-ethyl)-5-
oxo-3-phenyl-hexahydro-oxazolo[3,2-a]pyridine-8-carb-
oxylic acid methyl ester (2c). White solid, 100%. 1H NMR
(CDCl3): d¼1.35–2.73 (m, 9H), 3.59–3.84 (m, 4H), 3.69
(s, 3H), 4.03 (dd, J¼6.75, 9.25 Hz, 1H), 4.43 (dd, J¼8.25,
9 Hz, 1H), 4.63 (t, J¼4 Hz, 1H), 5.32 (t, J¼7.5 Hz, 1H),
7.13–7.29 (m, 5H). 13C NMR (CDCl3): d¼19.3, 27.2, 27.3,
29.2, 48.8, 52.2, 58.3, 64.6, 64.7, 69.0, 95.4, 103.3, 125.8,
127.1, 128.3, 138.3, 169.2, 171.2. Mp: 95 8C. [a]2D0¼þ88 (c
1.23, CHCl3). Anal. Calcd for C20H25NO6: C, 63.99, H:
6.71, N: 3.73. Found: C: 64.27, H: 7.06, N: 3.63.
3.2. General procedure for the synthesis of bicyclic
lactams 2
Synthesis of (3S)-(8S)-(8aR)-8a-Methyl-5-oxo-3-phenyl-
hexahydro-oxazolo[3,2-a]pyridine-8-carboxylic
3.2.4. (3S)-(8R)-(8aR)-8a-Methyl-5-oxo-3-phenyl-hexa-
hydro-oxazolo[3,2-a]pyridine-8-carboxylic acid methyl
ester (3a).3 White crystal, obtained by epimerisation of 2a
acid
methyl ester 2a. To a solution of compound 9a (0.50 g,
1.73 mmol) in THF (17.5 mL) at 0 8C was added a solution

5436
C. Agami et al. / Tetrahedron 60 (2004) 5433–5438
1
with 0.5 mol equiv. NaHMDS in THF. H NMR (CDCl3):
d¼1.48 (s, 3H), 2.04–2.12 (m, 2H), 2.39–2.68 (m, 2H),
3.10 (t, J¼4 Hz, 1H) 3.65 (s, 3H), 3.87 (dd, J¼7.8, 9 Hz,
1H), 4.33 (dd, J¼8.2, 8.7 Hz, 1H), 5.24 (t, J¼7.7 Hz, 1H),
7.11–7.30 (m, 5H). 13C NMR (CDCl3): d¼19.9, 25.9, 27.5,
47.0, 51.9, 59.4, 70.1, 93.8, 125.7, 127.3, 128.6, 139.6,
169.2, 171.5. Mp: 57 8C. [a]2D0¼þ106 (c 0.87, CHCl3).
Anal. Calcd for C16H19NO4: C: 66.42; H: 6.62; N: 4.84.
Found: C: 66.25; H: 6.78; N: 4.66. IR (CHCl3) 1736, 1655,
3.87 (m, 6H), 4.41 (s, 1H), 4.45–4.53 (m, 1H), 4.66 (t,
J¼4 Hz, 1H), 7.11–7.24 (m, 5H), 9.06 (brd, J¼9 Hz, 1H).
13C NMR (CDCl3): d¼25.8, 18.2, 22.2, 24.7, 32.3, 33.1,
49.9, 58.6, 64.8, 68.0, 82.4, 104.0, 126.6, 127.4, 128.5,
140.6, 164.9, 170.9. [a]2D0¼þ179 (c 0.85, CHCl3). Anal.
Calcd for C24 H39NO5Si: C: 64.11, H: 8.74, N: 3.11. Found:
C, 63.77, H: 8.98, N: 3.19.
3.3.3. {3[1S]}-(2Z)-3-[2-(tert-Butyl-dimethyl-silanyloxy)-
1-phenyl-ethylamino]-5-[1,3]dioxolan-2-yl-pent-2-carb-
oxylic acid methyl ester (7c). Oil, 100%. 1H NMR
(CDCl3): d¼20.17 (s, 3H), 20.13 (s, 3H), 0.73 (s, 9H),
1.66–1.72 (m, 2H), 2.09–2.17 (m, 2H), 3.55 (s, 3H), 3.59–
3.81 (m, 6H), 4.44 (s, 1H), 4.52–4.60 (m, 1H), 4.74 (t,
J¼4.25 Hz, 1H), 7.10–7.25 (m, 5H), 9.08 (brd, J¼7.5 Hz,
1H). 13C NMR (CDCl3): d¼25.7, 18.1, 25.7, 26.5, 32.1,
49.9, 58.5, 64.9, 68.0, 82.3, 103.1, 126.6, 127.4, 128.4,
140.4, 164.6, 170.8. [a]2D0¼2176 (c 1.08, CHCl3). Anal.
Calcd for C23 H37NO5Si: C: 63.41, H: 8.56, N: 3.22. Found:
C: 63.45, H: 8.41, N: 3.09.
1399 cm21
.
3.2.5. (3R)-(8S)-(8aS)-8a-(3-[1,3]Dioxolan-2-yl-propyl)-
5-oxo-3-phenyl-hexahydro-oxazolo[3,2-a]pyridine-8-
carboxylic acid methyl ester (3b). Oil, obtained by
epimerisation of 2b with 0.5 mol equiv. NaHMDS in
THF. 1H NMR (CDCl3): d¼1.35–2.05 (m, 8H), 2.40–
2.70 (m, 2H), 3.26 (t, J¼4 Hz, 1H), 3.64 (s, 3H), 3.70–3.88
(m, 5H), 4.31 (t, J¼8.75 Hz, 1H), 4.74 (t, J¼4 Hz, 1H), 5.21
(t, J¼8 Hz, 1H), 7.15–7.28 (m, 5H). 13C NMR (CDCl3):
d¼18.1, 19.5, 27.5, 33.2, 36.5, 42.5, 51.9, 59.4, 64.8, 70.0,
95.7, 103.9, 125.6, 127.2, 128.5, 139.6, 169.4, 171.7.
3.4. General procedure for the synthesis of 3,4-dihydro-
2-pyridones 8
3.2.6. (3S)-(8R)-(8aR)-8a-(2-[1,3]Dioxolan-2-yl-ethyl)-5-
oxo-3-phenyl-hexahydro-oxazolo[3,2-a]pyridine-8-carb-
oxylic acid methyl ester (3c). Oil, obtained by epimerisa-
Synthesis of {[1(1S)]}-1-[2-(tert-Butyl-dimethyl-silanyl-
oxy)-1-phenyl-ethyl]-2-methyl-6-oxo-1,4,5,6-tetrahydro-
pyridine-3-carboxylic acid methyl ester 8a. To a solution of
b-enaminoester 7a (4 g, 11.5 mmol) in THF (57 mL) was
added at 0 8C acryloyl chloride (1.03 mL; 12.6 mmol). After
15 min at 0 8C, the mixture was quenched with an aqueous
solution of NaHCO3 (15 mL) and extracted with CH2Cl2
(3£25 mL). The organic phase was concentrated at reduced
pressure. The residue was chromatographed on silica gel
(AcOEt/Cyclohexane: 15/85) to furnish 4.6 g of compound
8a. Yellow oil, 100%.
1
tion of 2c with 0.5 mol equiv. NaHMDS in THF. H NMR
(CDCl3): d¼1.50–2.25 (m, 6H), 2.37–2.66 (m, 2H), 3.21
(t, J¼4 Hz, 1H), 3.64 (s, 3H), 3.65–3.90 (m, 5H), 4.32 (t,
J¼8.5 Hz, 1H), 4.80 (dd, J¼3.0, 4.75 Hz, 1H), 5.20 (t, J¼
8.2 Hz, 1H), 7.14–7.28 (m, 5H). 13C NMR (CDCl3): d¼
19.3, 27.3, 28.0, 30.1, 42.5, 51.8, 59.4, 64.8, 64.9, 69.8,
95.5, 103.2, 125.6, 127.1, 128.4, 139.3, 169.4, 171.5.
3.3. General procedure for the synthesis of b-enamino-
esters 7
Synthesis of {3(1S)}-(2Z)-3-[2-(tert-Butyl-dimethyl-silanyl-
oxy)-1-phenyl-ethylamino]-but-2-carboxylic acid methyl ester
7a. To a TBS-protected (S)-phenylglycinol 6 (3 g, 11.9 mmol)
in methanol (59 mL), methylacetoacetate (1.42 mL,
13.1 mmol) was added. After refluxing for 24 h (10 days
for the synthesis of b-enaminoester 7b and 7c), the solvent
was evaporated under reduced pressure to yield enamino-
esters 7a (oil, 4.17 g, 100%) Compounds 7b and 7c were
chromatographed on silica gel (AcOEt/cyclohexane: 5/95).
3.4.1. {[1(1S)]}-1-[2-(tert-Butyl-dimethyl-silanyloxy)-1-
phenyl-ethyl]-2-methyl-6-oxo-1,4,5,6-tetrahydro-pyri-
dine-3-carboxylic acid methyl ester (8a). Yellow oil,
100%. 1H NMR (CDCl3): d¼20.05 (s, 3H), 20.02 (s, 3H),
0.78 (s, 9H), 2.32 (s, 3H), 2.34–2.60 (m, 4H), 3.64 (s, 3H),
4.21–4.27 (m, 1H), 4.35–4.42 (m, 1H), 5.17 (t, J¼7 Hz,
1H), 7.09–7.25 (m, 5H). 13C NMR (CDCl3): d¼25.6, 17.6,
18.0, 21.0, 25.7, 32.4, 51.4, 60.4, 63.3, 110.1, 126.3, 127.0,
128.3, 138.8, 150.3, 167.8, 171.3. [a]2D0¼þ30.4 (c 0.91,
CHCl3). Calcd for C22H33NO4Si: C: 65.47, H: 8.24, N: 3.47.
Found: C: 65.20, H: 7.97, N: 3.72.
3.3.1. {3(1S)}-(2Z)-3-[2-(tert-Butyl-dimethyl-silanyloxy)-
1-phenyl-ethylamino]-carboxylic acid methyl ester (7a).
Oil, 100%. 1H NMR (CDCl3): d¼20.14 (s, 3H), 20.09 (s,
3H), 0.76 (s, 9H), 1.74 (s, 3H), 3.59 (s, 3H), 3.67 (dd, J¼6.5,
10 Hz, 1H), 3.78 (dd, J¼4.8, 10 Hz, 1H), 4.42 (s, 1H),
4.48–4.56 (m, 1H), 7.11–7.30 (m, 5H), 9.09 (brd, J¼
7.5 Hz, 1H). 13C NMR (CDCl3): d¼25.8, 18.2, 19.8, 25.7,
49.9, 59.1, 67.9, 83.0, 126.6, 127.4, 128.5, 140.4, 161.8,
170.6.[a]2D0¼2261 (c 1.46, CHCl3). Anal. Calcd for C19
H31NO3Si: C: 65.29, H: 8.94, N: 4.01. Found: C: 65.15, H:
8.85, N: 4.15.
3.4.2. {1[1R]}-1-[2-(tert-Butyl-dimethyl-silanyloxy)-1-
phenyl-ethyl]-2-(2-[1,3]dioxolan-2-yl-ethyl)-6-oxo-1,4,
5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester
(8b). Oil, 100%. 1H NMR (CDCl3): d¼20.04 (s, 3H),
20.02 (s, 3H), 0.78 (s, 9H), 1.41–2.90 (m, 10H), 3.63 (s,
3H), 3.66–3.81 (m, 4H), 4.23–4.36 (m, 2H), 4.63 (t, J¼
4.25 Hz, 1H), 5.17 (t, J¼6.75 Hz, 1H), 7.12–7.22 (m, 5H).
13C NMR (CDCl3): d¼25.6, 18.0, 21.0, 23.9, 25.7, 29.6,
33.3, 34.2, 51.4, 60.0, 63.5, 64.6, 103.9, 110.2, 126.2, 126.9,
128.3, 139.0, 154.7, 167.3, 171.8. [a]2D0¼25.6 (c 0.65,
CHCl3).
3.3.2. {3[1R]}-(2Z)-3-[2-(tert-Butyl-dimethyl-silanyloxy)-
1-phenyl-ethylamino]-6-[1,3]dioxolan-2-yl-hex-2-carb-
oxylic acid methyl ester (7b). Oil, 100%. 1H NMR
(CDCl3): d¼20.19 (s, 3H), 20.15 (s, 3H), 0.72 (s, 9H),
1.40–1.57 (m, 4H), 1.99–2.15 (m, 2H), 3.55 (s, 3H), 3.59–
3.4.3. {1[1S]}-1-[2-(tert-Butyl-dimethyl-silanyloxy)-1-
phenyl-ethyl]-2-(2-[1,3]dioxolan-2-yl-ethyl)-6-oxo-1,4,
5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester

C. Agami et al. / Tetrahedron 60 (2004) 5433–5438
5437
(8c). Oil, 100%. 1H NMR (CDCl3): d¼20.03 (s, 3H),
20.05 (s, 3H), 0.80 (s, 9H), 1.75–3.04 (m, 8H), 3.65 (s,
3H), 3.68–3.82 (m, 4H), 4.24–4.31 (dd, J¼6, 10 Hz, 1H),
4.34–4.41 (dd, J¼7.75, 10 Hz, 1H), 4.71 (t, J¼4.5 Hz, 1H),
5.21 (t, J¼7 Hz, 1H), 7.11–7.27 (m, 5H). 13C NMR
(CDCl3): d¼25.5, 18.0, 21.0, 24.3, 25.7, 32.5, 32.8, 51.4,
60.0, 63.4, 64.8, 103.5, 110.1, 126.3, 126.9, 128.3, 138.9,
154.2, 167.2, 171.7. [a]2D0¼þ3.5 (c 1.22, CHCl3). Anal.
Calcd for C26H39NO6Si: C: 63.77, H: 8.03, N: 2.86. Found:
C, 63.61, H: 8.22, N: 2.92.
nol 10b. To a solution of quinolizidine 13b (0.032 g,
0.162 mmol) in THF (1.7 mL), at 0 8C, was added LiAlH4
(0.013 g, 0.32 mmol). After 15 h at reflux, the reaction was
quenched successively with H2O (0.3 mL), a solution of
NaOH (0.2 mL of 15% aqueous solution) and H2O (0.9 mL)
and extracted with CH2Cl2 (3£10 mL). The organic phase
was concentrated at reduced pressure. The residue was
chromatographed on silica gel (MeOH/CH2Cl2: 20/80) to
furnish 16.5 mg of compound 10b (oil, 60%).
3.6.1. [(1R)-(2R)]-(Octahydro-quinolizin-1-yl)-methanol
(10b). Oil, 60%. 1H NMR (CDCl3): d¼1.15–1.81 (m, 11H),
1.97–2.12 (m, 3H), 2.75–2.80 (m, 2H), 3.63 (d, J¼10.5 Hz,
1H), 4.09 (dd, J¼2.5, 11 Hz, 1H). 13C NMR (CDCl3): d¼
22.9, 24.6, 25.6, 29.7, 31.4, 38.1, 57.0, 65.1, 66.0. [a]2D0¼
221.5 (c 0.36, EtOH).
3.5. General procedure for the synthesis of 3,4-dihydro-
2-pyridones 9
Synthesis of [1(1S)]-1-(2-Hydroxy-1-phenyl-ethyl)-2-
methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic
acid methyl ester 9a. To a solution of b-enaminoester 8a
(1.14 g; 2.82 mmol) in THF (29 mL) was added, at 0 8C,
0.80 mL of HF.pyridine (70% solution of HF). After 30 min
at 0 8C, the mixture was allowed to reach room temperature.
After 20 h the reaction was quenched with an aqueous
solution of NaHCO3 (10 mL) and extracted with CH2Cl2
(3£15 mL). The organic phase was concentrated at reduced
pressure. The residue was chromatographed on silica gel
(AcOEt/Cyclohexane: 30/70) to furnish 0.719 g of com-
pound 9a. Oil, 88%.
3.6.2. [(8S)-(8aS)]-(Octahydro-indolizin-8-yl)-methanol
1
10c. Oil, 60%. H NMR (CDCl3): d¼1.30–1.85 (m, 9H),
1.92–2.10 (m, 3H), 2.30 (brs, OH), 2.90–3.05 (m, 2H), 3.65
(d, J¼10 Hz, 1H), 4.06 (dd, J¼5, 10 Hz, 1H). 13C NMR
(CDCl3): d¼20.7, 23.2, 25.6, 29.7, 35.3, 53.2, 54.4, 65.6,
66.7.
3.7. General procedure for the synthesis of piperidines
12
3.5.1. [1(1S)]-1-(2-Hydroxy-1-phenyl-ethyl)-2-methyl-6-
oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid
Synthesis of [1(1S)]-(2S)-(3S)-1-(2-Hydroxy-1-phenyl-
ethyl)-2-methyl-piperidine-3-carboxylic acid methyl ester
12a.3 To a solution of bicyclic lactam 2a (230 mg,
0.79 mmol) in THF (8 mL) was added at room temperature
a solution of BH3·Me2S in THF (1.58 mL, 3.17 mmol). The
mixture was stirred for 24 h at room temperature and
quenched with 10 mL H2O. The aqueous phases was
extracted with CH2Cl2. The organic phase was evaporated
under reduced pressure and the residue was chromato-
graphed on silica gel (AcOEt/Cyclohexane: 30/70) to
furnish 134 mg of piperidine 12a (oil, 61%).
1
methyl ester (9a). Oil, 88%. H NMR (CDCl3): d¼2.23
(s, 3H), 2.40–2.58 (m, 4H), 3.65 (s, 3H), 4.17–4.35 (m,
2H), 5.24 (t, J¼6 Hz, 1H), 7.14–7.28 (m, 5H). 13C NMR
(CDCl3): d¼17.3, 20.9, 32.3, 51.5, 60.8, 63.7, 111.5; 126.3,
127.2, 128.5, 137.8, 149.5, 167.6, 172.9. [a]2D0¼þ15.7 (c
1.87; CHCl3).
3.5.2. [1(1R)]-2-(3-[1,3]Dioxolan-2-yl-propyl)-1-(2-
hydroxy-1-phenyl-ethyl)-6-oxo-1,4,5,6-tetrahydro-pyri-
1
dine-3-carboxylic acid methyl ester (9b). Oil, 53%. H
NMR (CDCl3): d¼1.40–1.50 (m, 4H), 2.38–2.41 (m, 2H),
2.48–2.61 (m, 3H), 2.77–2.83 (m, 1H), 3.64 (s, 3H), 3.68–
3.82 (m, 4H), 4.26 (d, J¼6 Hz, 2H), 4.66 (t, J¼4.2 Hz, 1H),
5.20 (t, J¼6 Hz, 1H), 7.11–7.27 (m, 5H). 13C NMR
(CDCl3): d¼20.8, 23.6, 29.2, 32.4, 32.9, 51.3, 60.2, 63.5,
64.5, 103.7, 111.6, 126.2, 127.0, 128.3, 138.2; 153.8, 167.0,
173.0. [a]D20¼þ19 (c 0.96, CHCl3). Calcd for C21H27NO6:
C: 64.77, H: 6.99, N: 3.60. Found: C: 64.46, H: 7.30, N:
3.44.
3.7.1. [1(1S)]-(2S)-(3S)-1-(2-Hydroxy-1-phenyl-ethyl)-2-
methyl-piperidine-3-carboxylic acid methyl ester 12a.3
1
Oil, 61%. H NMR (CDCl3): d¼0.90 (d, J¼6.5 Hz, 3H),
1.30–1.69 (m, 4H), 2.25–2.40 (m, 1H), 2.56–2.64 (m, 2H),
3.04–3.08 (m, 1H), 3.48 (s, 3H), 3.62–3.82 (m, 3H), 7.12–
7.25 (m, 5H). 13C NMR (CDCl3): d¼11.9, 23.5, 23.8, 43.7,
46.3, 51.4, 52.7, 61.8, 64.1, 127.6, 128.2, 128.5, 138.7,
174.0. HRMS Calcd for C16H24NO3: 278.1756. Found:
278.1761. IR (CHCl3): 3440, 1731 cm21
.
3.5.3. [1(1S)]-2-(2-[1,3]Dioxolan-2-yl-ethyl)-1-(2-
hydroxy-1-phenyl-ethyl)-6-oxo-1,4,5,6-tetrahydro-pyri-
dine-3-carboxylic acid methyl ester (9c). Oil, 43%. H
3.7.2. [1(1R)]-(2R)-(3R)-2-(3-[1,3]Dioxolan-2-yl-propyl)-
1-(2-hydroxy-1-phenyl-ethyl)-piperidine-3-carboxylic
1
1
acid methyl ester (12b).3 Oil, 100%. H NMR (CDCl3):
NMR (CDCl3): d¼1.76–1.84 (m, 2H), 2.41–2.48 (m, 2H),
2.51–2.59 (m, 2H), 2.62–2.74 (m, 1H), 2.82–2.94 (m, 1H),
3.01 (brs, OH), 3.66 (s, 1H), 3.68–3.85 (m, 4H), 4.28–4.35
(m, 2H), 4.76 (t, J¼4.2 Hz, 1H), 5.29 (t, J¼5.7 Hz, 1H),
7.11–7.29 (m, 5H). 13C NMR (CDCl3): d¼21.1, 23.9, 32.6,
51.7, 60.6, 64.2, 64.9, 103.4, 112.1, 126.4, 127.3, 128.6,
137.9, 153.3, 167.4, 173.5. [a]2D0¼212 (c 2.32, CHCl3).
d¼1.22–1.95 (m, 10H), 2.35 (m, 1H), 2.60–2.76 (m, 2H),
3.15 (m, 1H), 3.59 (s, 3H), 3.71–3.90 (m, 6H), 3.99 (t, J¼
5.75 Hz, 1H), 4.77 (t, J¼4.5 Hz, 1H), 7.24–7.30 (m, 5H).
13C NMR (CDCl3): d¼21.3, 21.4, 22.8, 27.3, 33.8, 41.7,
41.9, 51.5, 57.9, 62.7, 64.5, 64.8, 104.4, 127.6, 128.3, 128.5,
140.1, 174.5. [a]2D0¼258.5 (c 0.48, CHCl3). HRMS Calcd
for C21H32NO5: 378.2280. Found: 378.2287. IR (CHCl3)
3448, 1728 cm21
.
3.6. General procedure for the synthesis of alkaloids 10
3.7.3. [1(1S)]-(2S)-(3S)-2-(2-[1,3]Dioxolan-2-yl-ethyl)-1-
(2-hydroxy-1-phenyl-ethyl)-piperidine-3-carboxylic
Synthesis [(1R)-(2R)]-(Octahydro-quinolizin-1-yl)-metha-

5438
C. Agami et al. / Tetrahedron 60 (2004) 5433–5438
acid methyl ester (12c). Oil, 91%. 1H NMR (CDCl3):
d¼1.18–1.99 (m, 8H), 2.35–2.85 (m, 3H), 3.22–3.29 (m,
1H), 3.58 (s, 3H), 3.73–3.90 (m, 6H), 3.98 (t, J¼5.5 Hz,
1H), 4.77 (t, J¼4.5 Hz, 1H), 7.23–7.27 (m, 5H). 13C NMR
(CDCl3): d¼21.0, 21.2, 22.1, 30.6, 41.1, 41.3, 51.4, 56.8,
63.1, 64.7, 64.8, 104.4, 127.5, 128.2, 128.4, 140.5, 174,4.
[a]2D0¼þ44 (c 1.17, CHCl3).
Lett. 2002, 43, 3661. (e) Amat, M.; Perez, M.; Llor, N.; Bosch,
J.; Lago, E.; Molins, E. Org. Lett. 2001, 3, 611.
2. For reviews see: (a) Groaning, M. D.; Meyers, A. I.
Tetrahedron 2000, 56, 9843. (b) Meyers, A. I.; Brengel,
G. P. J. Chem. Soc., Chem. Commun. 1997, 1.
´
3. Agami, C.; Dechoux, L.; Menard, C.; Hebbe, S. J. Org. Chem.
2002, 67, 7573.
4. Agami, C.; Dechoux, L.; Hebbe, S. Tetrahedron Lett. 2002,
43, 2521.
3.8. General procedure for the synthesis of quinolizidine
and indolizidine 13
5. (a) Hickmott, P. W.; Sheppard, G. J. Chem. Soc., C 1971,
1358. (b) Hickmott, P. W.; Sheppard, G. J. Chem. Soc., C
1971, 2112.
Synthesis of (1R)-(2R)-Octahydro-quinolizine-1-carboxylic
acid methyl ester 13b. To a solution of piperidine 12b
(0.155 g, 0.41 mmol) in acetone (3.2 mL) and water
(0.8 mL) was added p-toluenesulfonic acid (0.156 g,
0.82 mmol). After 6 h, the solvents were evaporated under
reduced pressure. At the crude product in methanol (4 mL)
and under an atmosphere of hydrogen was added Pd/C 10%
(130 mg, 0.123 mmol). The reaction mixture was stirred
24 h at room temperature and then filtered over celite. The
reaction was then quenched with an aqueous solution of
NaHCO3 (10 mL) and extracted with CH2Cl2 (3£10 mL).
The organic phase was dried over MgSO4 and concentrated
at reduced pressure. The crude product was chromato-
graphed on silica gel (MeOH/CH2Cl2: 10/90) to furnish
49 mg of quinolizidine 13b (oil, 60%).
6. Agami, C.; Dechoux, L.; Hebbe, S. Tetrahedron Lett. 2003,
44, 5311.
7. The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.;
Academic: San Diego, 2000; Vol. 54.
8. (a) Mangeney, P.; Hamon, L.; Raussou, S.; Urbain, N.;
Alexakis, A. Tetrahedron 1998, 54, 10349. (b) Tate, E. W.;
Zard, S. Z. Tetrahedron Lett. 2002, 43, 4683. (c) Ledoux, S.;
Marchalant, E.; Celerier, J. P.; Lhommet, G. Tetrahedron Lett.
2001, 42, 5397. (d) Morley, C.; Knight, D. W.; Share, A. C.
J. Chem. Soc., Perkin Trans. 1 1994, 2903, and references
cited herein.
9. Ha, D. C.; Park, S. H.; Choi, K. S.; Yun, C. S. Bull. Korean
Chem. Soc. 1998, 19, 728.
10. Compound 11b and 11c were prepared by alkylation of the
di-anion of methylacetoacetate with 2-(2-bromoethyl)-1,3-
dioxolane and 2-bromomethyl-1,3-dioxolane, respectively.16
11. (a) Meyers, A. I.; Andres, C. J.; Resek, J. E.; Woodall, C. C.;
McLaughlin, M. A.; Lee, P. H.; Price, D. A. Tetrahedron 1999,
55, 8931. (b) Meyers, A. I.; Price, D. A. Chirality 1998, 10, 88.
(c) Meyers, A. I.; Price, D. A.; Andre, C. J. Synlett 1997, 533.
12. Amat, M.; Canto, M.; Llor, N.; Bosch, J. Chem. Commun.
2002, 526.
3.8.1. (1R)-(2R)-Octahydro-quinolizine-1-carboxylic
acid methyl ester (13b). Oil, 60%. 1H NMR (CDCl3):
d¼1.14–2.04 (m, 13H), 2.48–2.50 (m, 1H), 2.78–2.84 (m,
2H), 3.56 (s, 3H). 13C NMR (CDCl3): d¼22.0, 24.3, 24.8,
26.9, 28.9, 44.4, 51.1, 54.9, 57.0, 62.6, 173.8. [a]2D0¼218 (c
0.42, CHCl3).
13. (a) Royer, J.; Husson, H. P. Tetrahedron Lett. 1985, 26, 1515.
(b) Yamaguchi, R.; Hata, E.; Matsuki, T.; Kawanisi, M. J. Org.
Chem. 1987, 52, 2094. (c) Comins, D. L.; Zeller, E.
Tetrahedron Lett. 1991, 42, 5889. (d) Gnecco, D.; Marazano,
C.; Das, B. C. J. Chem. Soc., Chem. Commun. 1991, 625.
(e) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60,
7084. (f) Wong, Y. S.; Gnecco, D.; Marazano, C.; Chiaroni,
A.; Riche, C.; Billion, A.; Das, B. C. Tetrahedron 1998, 54,
9357.
3.8.2. (8S)-(8aS)-Octahydro-indolizine-8-carboxylic acid
methyl ester (13c). Oil, 29%. 1H NMR (CDCl3): d¼1.34–
2.19 (m, 11H), 2.75–2.77 (m, 1H), 2.95–3.01 (m, 2H), 3.60
(s, 3H). 13C NMR (CDCl3): d¼20.0, 22.1, 23.7, 24.7, 41.1,
50.9, 51.6, 54.3, 63.0, 172.7.
References and notes
14. Podkowinska, H.; Skolik, J. Org. Magn. Res. 1984, 22, 379.
15. For total syntheses of racemic matrine see: (a) Chen, J.;
Brown, L. J.; Gonnela, N. C. J. Chem. Soc., Chem. Commun.
1986, 905. (b) Boiteau, L.; Boivin, J.; Liard, A.; Quiclet-Sire,
B.; Zard, S. Z. Angew. Chem., Int. Ed. 1998, 37, 1128.
16. (a) Kato, M.; Kamat, V. P.; Yoshikoshi, A. Synthesis 1988,
699. (b) Paulvannan, K.; Schwarz, J. B.; Stille, J. R.
Tetrahedron Lett. 1993, 34, 215.
1. For recent applications see: (a) Amat, A.; Canto, M.; Llor, N.;
Ponzo, V.; Perez, M.; Bosch, J. Angew. Chem., Int. Ed. 2002,
41, 335. (b) Amat, M.; Perez, M.; Llor, N.; Bosch, J. Org. Lett.
2002, 4, 2787. (c) Amat, M.; Canto, M.; Llor, N.; Escolano, C.;
Molins, E.; Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67,
5343. (d) Allin, S. M.; Vaidya, D. G.; James, S. L.; Allard,
J. E.; Smith, T. A. D.; McKee, V.; Martin, W. P. Tetrahedron