A concise highly enantioselective cascade synthesis of indolizidine alkaloids with a quaternary stereocenter

Article abstract of DOI:10.1016/j.tetasy.2004.07.013

Enantiomerically pure indolizidinones bearing a quaternary stereocenter were obtained by Rh(II)-catalyzed decomposition of α-diazo ketodiesters through a carbenoid/spiro[5,5]ammonium ylide/Stevens [1,2]-shift with a ring-expansion cascade process. The isolation of stable chiral ammonium ylides, namely the key intermediates of the process, unambiguously confirmed the stereochemistry of the total process.

Full text of DOI:10.1016/j.tetasy.2004.07.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2609–2614
A concise highly enantioselective cascade synthesis of
indolizidine alkaloids with a quaternary stereocenter
b
Daniele Muroni,a Antonio Sabaa, and Nicola Culeddu
*
a
`
`
Dipartimento di Chimica, Facolta di Scienze, Universita di Sassari, Via Vienna 2, Sassari 07100, Italy
bCNRIstituto di Chimica Biomolecolare Sez. di Sassari, Via La Crucca, Baldinca- Li Punti, Sassari 07040, Italy
Received 3 April 2004; revised 6 July2004; accepted 12 July2004
Abstract—Enantiomericallypure indolizidinones bearing a quaternarystereocenter were obtained byRh(II)-catalyzed decomposi-
tion of a-diazo ketodiesters through a carbenoid/spiro[5,5]ammonium ylide/Stevens [1,2]-shift with a ring-expansion cascade pro-
cess. The isolation of stable chiral ammonium ylides, namely the key intermediates of the process, unambiguously confirmed the
stereochemistryof the total process.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
RO2C
RO2C
O
O
R'
N
R'
N
The tandem metallo-carbenoid/ylide/[1,2]-Stevens rear-
rangement sequence is of great potential as a method
for the synthesis of complex alkaloids.1 When looking
at the stereochemistryin the rearrangement of ammo-
nium2 or oxonium ylides,3 a high configuration reten-
tion level, during migration of a stereogenic center,
can be expected.4 Such a cascade sequence has been pro-
posed for a (ꢀ)-epilupinine synthesis, involving a not
isolable spirocyclic [5,6]-ammonium ylide generated
from a diazocarbonyl compound,5 and achieved with
remarkable diastereoselectivity, but modest enantio-
selectivity.6
1'a and b
R= (a) Me, (b) Bn; R'= CO2Et
1a and b
Figure 1.
sidase inhibitor to be selected for clinical testing as an
anticancer drug; its cost has hindered clinical trials).8
2. Results and discussion
L-Prolines 2a and 2b, bearing the nitrogen atom tethered
to an a-diazoketoester chain, were selected as the appro-
priate substrates for obtaining chiral alkaloids 1a and 1b
and 10a and 10b. The starting diazocompounds 3a and 3b
were prepared efficientlyin two steps byconjugate addi-
tion of 2a and 2b to ethyl 3-keto-pent-4-enoate9
followed bydiazo-transfer with tosylazide ( Scheme 1).
As part of an ongoing program on asymmetric synthesis
byintramolecular C–H activation via metal carbenes de-
rived from diazocarbonyls,7 we attempted to prepare
chiral indolizidinones 1a and 1b, which bear an asym-
metric quaternarycarbon, byusing the above sequential
protocol (Fig. 1).
These compounds are immediate precursors of swanso-
nine analogues, an important class of biologicallyactive
natural and unnatural chiral polyhydroxylated alka-
loids, whose development is required to achieve more
concise and competitive synthetic methods aimed at
lowering their high cost (swansonine is the first glyco-
O
O
CO2R
O
OEt
, Et3N
1)
O
N
CO2R
N
H
2) TsN3, Et3N
OEt
·HCl
N2
2a and b
3a and b
R= (a) Me, (b) Bn
*
Corresponding author. Tel.: +39-79-229538; fax: +39-79-229559;
e-mail: saba@uniss.it
Scheme 1.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.013

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D. Muroni et al. / Tetrahedron: Asymmetry 15 (2004) 2609–2614
chiral migrating group approach. Finally, the proline
moietychoice of 3a and 3b was suggested bya probably
more efficient [1,2]-shift of its carbon atom, due to the
presence of a conjugative stabilizing C@O ester group.11
3a and b
R = (a) Me, (b) Bn
Two transition metal catalysts and various reaction con-
ditions were studied (Table 1). When the diazo-decom-
position was carried out in refluxing toluene using
Rh2(OAc)4 as the catalyst, a 60/40 diastereomeric mix-
ture of 1a and 10a and 72/28 of 1b and 10b were obtained
in 84% and 85% yield, respectively. The Cu(acac)2 cata-
lyzed reaction afforded a 53/47 and 65/35 mixture with
90% yield. The diastereomers were resolved by flash
chromatography. The configuration assignment to the
newlyformed quaternarystereocenter was deduced
from 2D NOESY correlation studies. Thus, for the
major 1a and 1b stereoisomers, the NOESY trace of
the ethyl ester methylene protons showed a positive
NOE effect for the proton at C-8 (3.65 and 3.66ppm,
respectively). This effect was not observed when the
same experiments were performed for 10a and 10b. For
compounds 1a and 1b, 80% and 90% ee, respectively,
EtO2C
O
O
MLn
N
RO2C
RO2C
N
CO2Et
MLn
4a and b
4'a and b
O
EtO2C
RO2C
RO2C
O
N
were measured byusing the chiral reagent Eu(hfc)
,
N
3
and comparing the shift separations observed in the
1H NMR spectra to those obtained from the racemates
submitted to the same treatment.
CO2Et
5'a and b
5a and b
The enantiomeric excesses of the minor stereoisomers
10a and 10b were difficult to determine, since theycould
not be obtained totallyfree of 1a and 1b.
[1,2]shift
[1,2]shift
1'a and b
1a and b
Interestingly, when a CH2Cl2 solution of 3a was ref-
luxed, in the presence of Rh2(OAc)4 (Table 2) ylides
5a and 50a (60:40) were obtained in reasonable yield
and resolved byflash chromatography. Configuration
assignment to the ylides was deduced from 2D NOESY
correlation studies. Thus, for 5a and 5b, the NOESY
trace of the ethyl ester methylene protons shows a posi-
tive NOE effect for the methyl and benzyl protons at
3.65 and 5.11ppm, respectively. This effect was not ob-
served when the same experiments were performed for
Scheme 2.
1H NMR analysis of 3a and 3b, using the chiral reagent
Eu(hfc)3, indicated their enantiomeric purity, excluding
racemization during the N-alkylation conjugate step.
The notion of using such diazocompounds as the key
starting materials for a convenient approach toward
the targets 1 and 10 was attractive for the following rea-
sons. Due to the diazo group position on the chain of 3a
and 3b, [5,5]-spirocyclic ylides 5a and 5b were expected
to form, bynitrogen trapping of the metallocarbene pre-
cursors 4a and 4b, over competitive C–H-insertion pro-
cess, as depicted in Scheme 2. Moreover, the presence of
a substituent on the ylide carbon could result in an im-
proved enantioselectivityof the subsequent rearrange-
ment step, byincreasing the steric interaction to the
1
50a and 50b. H NMR analysis of 5a and 5b, using the
chiral reagent Eu(hfc)3, indicated their enantiomeric
purity, excluding racemization during the spirocycliza-
tion step.
Heating of ylide 5a in toluene at reflux (Table 3), with-
out catalyst, afforded alkaloid 1a cleanlyas a single dia-
stereoisomer (95% ee), in good yield. By decomposition
Table 1.
RO2C
RO2C
CO2Et
O
CO2Et
O
CO2R
O
O
N
Diazodecomposition
Toluene/reflux
+
OEt
N
N
N2
3a and b
1a and b
1'a and b
Substrate
Cat
Yield (%)
1a and 1b:10a and 10b
Ee of 1a and 1b (%)
3a
3a
3b
3b
Rh2(OAc)4
Cu(acac)2
Rh2(OAc)4
Cu(acac)2
84
90
85
90
60:40
53:47
72:28
65:35
80
68
84
90

D. Muroni et al. / Tetrahedron: Asymmetry 15 (2004) 2609–2614
2611
Table 2.
O
CO2R
EtO2C
O
O
N
Diazodecomposition
RO2C
O
RO2C
N
N
OEt
+
CH2Cl2 /reflux/Rh2(OAc)4
CO2Et
N
2
3a and b
5a and b
5'a and b
Substrate
Yield (%)
Diastereoselectivity( 5:50)
3a
3b
91
90
60:40
70:30
Table 3.
O
RO2C
CO2Et
O
EtO2C
RO2C
Rearrangement
Toluene/reflux
N
N
5a and b
Yield (%)
1a and b
Substrate
DiastereoselectivityEe of
1a,b (%)
5a
5b
83
85
100
100
95
95
performed under the same conditions, diazo benzylester
3b furnished ylides 5b and 50b as a 70:30 diastereomeric
mixture. Byheating ylide 5b in toluene at reflux without
a catalyst, alkaloid 1b, was obtained as a single diaste-
reomer in 95% ee.
narycarbon of the target indolizidinones bymigrating
of the template proline stereocenter through the asym-
metric nitrogen atom of the spirocyclic ammonium ylide
intermediate.
In summary, this report represents a very rapid highly
enantioselective synthetic approach to unnatural swans-
onine analogues.12 Our targets are characterized bythe
presence of a quaternaryasmy metric carbon atom,
whose construction is always of synthetic value.13
3. Conclusion
10
In spite of data previouslyreported,
the rhodium-
based catalysis for the generation of ammonium ylides
has been shown to be more effective. It is interesting
to note that in the refluxing toluene catalyzed protocol,
the overall yield, diastereoselectivity, and enantioselec-
Finally, it is noteworthy that this protocol overall may
meet the criteria of being atom-economic.14
tivitywere increased for the benzly diazoester
3b.
Rarely, during the decomposition of the diazocom-
pounds could the ammonium ylides be isolated, only
ever being obtained as achiral products.11 The isolation
of our stable ylides as pure diastereomers and enantio-
mers enabled us to probe the stereochemistryof the
complete cascade process unambiguously. Their thermal
reaction afforded the ring-expanded indolizidinones as
pure diastereomers in high enantiomeric excess. These
results maysuggest the ylide undergoes a [1,2]-Stevens
shift with retention; consequentlythis reaction step
could still be considered intramolecular, or involving
solvent caged radical pairs characterized bya veryfast
recombination.2e
4. Experimental
4.1. General
1H NMR (300MHz) and 13C NMR (75MHz) were re-
corded on a Varian VXR-300 spectrometer with TMS
as the internal standard. COSY, NOESY, HSQC, and
USQC-TOSCY spectra were recorded with a Bruker
Avance 600 equipped with inverse detection probe.
Infrared (IR) spectra were performed on a FT/IR-
480plus JASKO spectrophotometer. The optical rota-
tions were measured bya polarimeter P-1010 JASKO
in a 1dm tube. All reagents and solvents employed were
reagent grade materials purified bystandard methods
and redistilled before use.
The diastereomeric ratios observed for ylides 5a and 5b
and 50a and 50b, obtained in the CH2Cl2/Rh2(OAc)4
reaction of 3a and 3b, were in line with the above con-
clusions: these ratios are approximatelythe same as
those obtained for 1a and 1b and 10a and 10b in the re-
fluxing toluene/Rh2(OAc)4 system, respectively.
4.2. (2S)-1-(4-Diazo-4-ethoxycarbonyl-3-oxo-butyl)-pyr-
rolidine-2-carboxylic acid methyl ester 3a
To a stirred solution of L-proline methyl ester hydro-
chloride (1.0g, 0.006mol) and 3-oxo-pent-4-enoic acid
ethyl ester (0.85g, 0.006mol) in CH2Cl2 (15mL), a solu-
tion of Et3N (0.63mL, 0.0066mol) in CH2Cl2 (10mL)
In this cascade pathway, the stereochemical information
is transferred to the newlyformed stereogenic quater-

2612
D. Muroni et al. / Tetrahedron: Asymmetry 15 (2004) 2609–2614
was added dropwise and stirred for 30min. To the reac-
tion mixture, tosyl azide (1.20g, 0.0066mol) and a solu-
tion of Et3N (2.8mL, 0.02mol) in CH2Cl2 (10mL) were
added dropwise at 0°C . After the addition was com-
plete, the solution was warmed to room temperature
and stirred overnight. The solvent was evaporated and
the residue purified byflash chromatography(Et 2O/
4.4.2. (5R,6R)-1-Ethoxycarbonyl-6-methoxycarbonyl-1-
oxo-5-azonia[4,4]nonane-1-ylide 50a. 1H NMR: d 1.31
(t, 3H, J = 7.1), 1.90–2.50 (m, 1H), 2.24–2.43 (m, 2H);
2.52–2.75 (m, 2H), 2.90–3.13 (m, 1H), 3.55–3.74 (m,
2H), 3.75 (s, 3H), 3.89 (q, 1H, J = 9.3Hz), 4.02 (dd,
1H, J = 6.9 and 9.9Hz), 4.08–4.40 (m, 3H); 13C NMR
(CDCl3): d 14.9, 22.9, 27.9, 33.2, 52.9, 59.0, 65.8, 67.1,
77.5, 106.6, 162.8, 165.1, and 177.3.
petroleum ether/Et3N, 8:2:0.1) to give the diazo com-
25
D
pound 3a (1.25g, 70%) as a yellow oil: ½aŠ ¼ ꢀ56:1 (c
1.7, CHCl3); 1H NMR (CDCl3):
d 1.33 (t, 3H,
4.5. Ylides 5b and 50b
J = 7.05Hz), 1.75–2.01 (m, 3H), 2.01–2.20 (m, 1H),
2.42 (q, 1H, J = 7.8Hz), 2.70–2.85 (m, 1H), 3.00–2.15
(m, 3H), 2.15–3.25 (m, 2H), 3.73 (s, 3H), 4.29 (q, 2H,
J = 7.05Hz); 13C NMR (CDCl3): d 14.3, 23.1, 29.3,
38.9, 49.0, 51.8, 53.3, 61.3, 65.6, 76.2, 161.2, 174.5,
191.2; IR (neat) 2955, 2835, 2135, 1717, 1653,
1301cmꢀ1. Anal. Calcd for C13H19N3O5: C, 52.52; H,
6.44; N, 14.13. Found C, 52.43; H, 6.47; N, 14.09.
Following the above procedure, decomposition of di-
azoester 3b (0.373g, 0.001mol) gave a 70:30 mixture of
5b and 50b (0.310g, 90%). Purification on a column of
neutral alumina (CH2Cl2/MeOH, 95:5) gave 5b as a pale
oil and 50b not totallyfree of 5b.
4.5.1. (5S,6R)-1-Ethoxycarbonyl-6-benzyloxycarbonyl-1-
25
D
4.3. (2S)-1-(4-Diazo-4-ethoxycarbonyl-3-oxo-butyl)-pyr-
rolidine-2-carboxylic acid benzyl ester 3b
oxo-5-azonia[4,4]nonane-1-ylide 5b. ½aŠ ¼ ꢀ80:9 (c
0.22, CHCl3); 1H NMR: d 1.32 (t, 3H, J = 7.1Hz),
2.09–2.61 (m, 6H), 3.20–3.43 (m, 2H), 3.95–4.09 (m,
1H), 4.23 (q, 2H, J = 7.1Hz), 4.66 (q, 1H,
J = 10.8Hz), 5.18 (AB system, 2H), 5.69 (dd, 1H,
J = 8.4 and 11.4Hz), 7.29–7.41 (m, 5H); 13C NMR
(CDCl3): d 14.7, 19.2, 24.4, 32.9, 55.6, 58.9, 65.7, 68.1,
99.7, 128.3, 128.6, 134.2, 162.6, 166.4, 178.7; IR (neat):
2977, 1739, 1645, 1594, and 1417cmꢀ1. Anal. Calcd
for C19H23NO5: C, 66.07; H, 6.71; N, 4.06. Found: C,
66.15; H, 6.68; N, 4.02.
Following the above procedure, treatment of L-proline
benzyl ester hydrochloride (1.5g, 0.0062mol) with
3-oxo-pent-4-enoic acid ethyl ester (0.88g, 0.0062mol),
tosyl azide (1.34g, 0.0068mol), and Et3N, gave, after
flash chromatography(Et 2O/petroleum ether/Et3N,
6:4:0.1), diazo compound 3b (1.72g, 75%) as a yellow
25
D
1
oil: ½aŠ ¼ ꢀ43:3 (c 1.0, CHCl3); H NMR: d 1.32 (t,
3H, J = 7.05Hz), 1.72–2.02 (m, 3H), 2.02–2.20 (m,
1H), 2.46 (q, 1H, J = 8.7Hz), 2.73–2.90 (m, 1H), 3.00–
3.23 (m, 3H), 3.31 (dd, 1H, J = 5.6, 8.7Hz), 4.28 (q,
2H, J = 7.05Hz), 5.16 (s, 2H), 7.29–7.40 (m, 5H); 13C
NMR (CDCl3): d 14.2, 23.1, 29.2, 38.9, 48.8, 53.1,
61.3, 65.4, 66.2, 76.4, 128.0, 128.1, 128.4, 135.9, 161.1,
173.7, 191.1; IR (neat): 2978, 2823, 2135, 1716, 1654,
1456 and 1301cmꢀ1. Anal. Calcd for C19H23N3O5: C,
61.11; H, 6.21; N, 11.25. Found C, 61.20; H, 6.20; N,
11.26.
4.5.2. (5S,6R)-1-Ethoxycarbonyl-6-benzyloxycarbonyl-1-
oxo-5-azonia[4,4]nonane-1-ylide 50b. 1H NMR: d 1.28
(t, 3H, J = 7.1Hz); 1.92–2.11 (m, 1H), 2.26–2.42 (m,
2H), 2.50–2.80 (m, 2H), 3.00–3.18 (m, 1H), 3.60–3.82
(m, 2H), 3.91 (q, 1H, J = 9.3Hz), 3.98–4.31 (m, 4H),
5.14 (AB system, 2H), 7.28–7.43 (m, 5H); 13C NMR
(CDCl3): d 14.9, 23.1, 28.0, 32.9, 59.2, 66.0, 67.3, 68.1,
77.9, 107.3, 128.6, 128.7, 134.6, 162.8, 164.5, and
190.9.
4.4. Ylides 5a and 50a
To a refluxing solution of Rh2(OAc)4 (0.013g, 3mol%)
in 30mL of dryCH 2Cl2, a solution of 3a (0.297g,
0.001mol) in dryCH Cl2 (20mL) was added dropwise
2
4.6. General procedure for the diazo-decomposition in
toluene
over 30min. After stirring for another 30min at reflux,
the reaction mixture was cooled and concentrated to
give a 60:40 mixture of 5a and 50a. Purification byflash
chromatography(Et 2O/MeOH/Et3N, 5:5:0.1) gave
0.147g (55%) of 5a as a yellow amorphous solid and
0.096g (36%) of 50a not totallyfree of 5a.
To a refluxing solution of catalyst in 30mL of dry tolu-
ene was added dropwise a solution of diazo in 20mL of
drytoluene over 30min. After stirring for another
30min at reflux, the mixture was cooled, concentrated,
and purified byflash chromatography.
4.6.1. Indolizidinones 1a and 10a. (a) Following the gen-
eral procedure, decomposition of 3a (0.297g, 0.001mol)
with of Rh2(OAc)4 (0.013g, 3mol%), after flash chro-
matography(petroleum ether/ethly acetate, 8:2), gave
0.225g (84%) of the product as a 60:40 resolved mixture
of 1a and 10a. (b) Following the general procedure, the
decomposition of 3a (0.297g, 0.001mol) with Cu(acac)2
(0.013g, 5mol%) gave 0.270g (90%) of product as 53:47
resolved mixture of 1a and 10a. (c) Byheating of 0.147g
of ylide 5a in refluxing toluene for 30min, 0.123g (83%)
of 1a (95% ee) were obtained.
4.4.1. (5S,6R)-1-Ethoxycarbonyl-6-methoxycarbonyl-1-
25
oxo-5-azonia[4,4]nonane-1-ylide 5a. ½aŠ ¼ ꢀ69:6 (c
D
0.47, CHCl3); 1H NMR: d 1.36 (t, 3H, J = 7.1Hz),
2.13–2.35 (m, 2H), 2.35–2.57 (m, 2H), 2.62 (t, 2H,
J = 8.1Hz), 3.13–3.36 (m, 2H), 3.78 (s, 3H), 4.13–4.35
(m, 3H), 4.67 (q, 1H, J = 10.8Hz), 5.61 (dd, 1H,
J = 8.6 and 11.3Hz); 13C NMR (CDCl3): d 14.7, 19.5,
24.7, 32.9, 53.4, 55.8, 59.1, 66.0, 68.3, 99.8, 162.7,
167.2, and 178.8; IR (neat): 2961, 1739, 1592, 1441,
1263cmꢀ1. Anal. Calcd for C13H19NO5: C, 57.98; H,
7.11; N, 5.20. Found: C, 57.90; H, 7.15; N, 5.20.

D. Muroni et al. / Tetrahedron: Asymmetry 15 (2004) 2609–2614
2613
4.6.1.1. (8R,8R)-1-Oxo-hexahydro-indolizine-8,8a-
dicarboxylic acid 8a-ethyl ester 8-methyl ester 1a. Col-
3.12–3.22 (m, 1H), 4.13 (ddq, 2H, J = 7.2, 10.8, and
51Hz), 5.15 (s, 2H), 7.26–7.41 (m, 5H); 13C NMR
(CDCl3): d 14.0, 23.7, 24.2, 34.9, 44.8, 45.6, 46.7, 60.8,
66.6, 68.4, 128.2, 128.5, 129.6, 135.8, 166.9, 172.3,
206.3; IR (neat): 3033, 2938, 2849, 1766, 1731,
1455cmꢀ1. Anal. Calcd for C19H23NO5: C, 66.07; H,
6.71; N, 4.06. Found: C, 65.97; H, 6.72; N, 4.09.
25
D
orless oil; ½aŠ ¼ ꢀ92 (c 0.5, CHCl3), 95% ee; 1H
NMR: d 1.28 (t, 3H, J = 7.1Hz), 1.49–1.55 (m, 3H),
2.27 (dd, 1H, J = 2.7 and 13.5Hz), 2.42 (ddd, 1H,
J = 2.1, 7.1, and 18.3Hz), 2.78 (q, 1H, J = 8.9Hz),
2.85–2.95 (m, 1H), 3.35 (dt, 1H, J = 2.1 and 8.7Hz),
3.44 (q, 1H, J = 8.1Hz), 3.56–3.63 (m, 1H), 3.67 (s,
3H), 4.21 (q, 2H, J = 7.1Hz); 13C NMR (CDCl3): d
14.2, 21.5, 24.7, 36.0, 44.1, 46.4, 47.4, 51.9, 61.6, 73.1,
169.2, 172.4, and 208.8; IR (neat): 2950, 2855, 2748,
1765, 1736, 1443cmꢀ1. Anal. Calcd for C13H19NO5: C,
57.98; H, 7.11; N, 5.20. Found: C, 58.11; H, 7.06; N,
5.17.
Acknowledgements
This work was supported byM.I.U.R. and Regione
Autonoma della Sardegna. Thanks are due to Mr. Mauro
Mucedda for experimental assistance.
4.6.1.2. (8R,8aS)-1-Oxo-hexahydro-indolizine-8,8a-
dicarboxylic acid 8a-ethyl ester 8-methyl ester 10a. Col-
References and notes
25
D
orless oil; ½aŠ ¼ 80 (c 0.6, CHCl3), 90% ee; 1H NMR: d
1.30 (t, 3H, J = 7.1Hz), 1.52–1.71 (m, 1H), 1.71–1.83 (m,
1H), 1.92–2.04 (m, 1H), 2.22–2.60 (m, 4H), 2.78 (ddd,
1H, J = 1.8, 5.1, and 11.7Hz), 2.83–2.94 (m, 1H), 3.08
(dt, 1H, J = 3.3 and 12Hz), 3.17 (dt, 1H, J = 2.1 and
9.0Hz), 3.71 (s, 1H), 4.15–4.36 (m, 2H); 13C NMR
(CDCl3): d 14.3, 23.5, 24.1, 34.8, 44.5, 45.5, 46.6, 51.8,
60.8, 68.4, 167.0, 172.9, and 206.3; IR (neat): 2940,
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Soc. 1947, 93; (b) Brewster, H. H.; Kline, M. W. J. Am.
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J. Chem. Soc. 1963, 3397; (d) Schollkopf, U.; Ludwig, U.;
Ostermann, G.; Patsch, M. Tetrahedron Lett., 1969, 3415;
(e) Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc.,
Perkin Trans. 1 1983, 1009.
2847, 1776, 1731, 1438cmꢀ1
.
Anal. Calcd for
C13H19NO5: C, 57.98; H, 7.11; N, 5.20. Found: C,
57.89; H, 7.17; N, 5.15.
4.6.2. Indolizidinones 1b and 10b. (a) Following the gen-
eral procedure, the decomposition of 3a (0.373g,
0.001mol) with Rh2(OAc)4 (0.013g, 3mol%) in toluene
gave, after flash chromatography(petroleum ether/ethyl
acetate, 8:2), 0.225g (85%) of product as a resolved mix-
ture of 1b and 10b in the ratio of 72:28. (b) Following the
general procedure, the decomposition of 0.373g
(0.001mol) of 3b with 0.013g (5mol%) of Cu(acac)2
gave 0.310g (90%) of product as a resolved mixture of
1b and 10b in the ratio of 65:35. (c) The heating of
0.200g of ylide 5b in refluxing toluene for 30min gave
0.170g (85%) of 1a with 95% ee.
3. West, F. G.; Eberlein, T. H.; Tester, R. W. J. Chem. Soc.,
Perkin Trans. 1 1993, 2857; Roskamp, E. J.; Johnson, C.
R. J. Am. Chem. Soc. 1986, 108, 6062.
4. For a general review of the Stevens rearrangement, see:
`
Marko, I. E. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3,
pp 913–973; West, F. G.; Clark, J. S. In Nitrogen, Oxygen
and Sulfur Ylide Chemistry; Clark, J. S., Ed.; University
Press Oxford: Oxford, 2002; See also: Stevens, T. S.;
Creighton, E. M.; Gordon, A. B.; Macincol, M. T. J.
Chem. Soc. 1928, 3193.
5. For reviews of ammonium ylides generated by diazo
compounds, see: Doyle, M. P.; McKervey, M. A.; Ye, T.
Modern Catalytic Methods for Organic Synthesis with
Diazo-Compounds; John WileySons: New York, 1997;
West, F. G.; Naidu, B. N. J. Am. Chem. Soc. 1993, 116,
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7. Chelucci, G.; Saba, A. Angew. Chem., Int. Ed. Engl. 1995,
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4673; Chelucci, G.; Saba, A.; Valle, G. Tetrahedron:
Asymmetry 1995, 6, 807; Chelucci, G.; Saba, A. Tetrahe-
dron: Asymmetry 1997, 8, 699; Chelucci, G.; Culeddu, N.;
Saba, A.; Valenti, R. Tetrahedron Lett. 1999, 40, 8269;
Chelucci, G.; Saba, A.; Valenti, R.; Bacchi, A. Tetrahe-
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4.6.2.1. (8R,8aR)-1-Oxo-hexahydro-indolizine-8,8a-
dicarboxylic acid 8-benzyl ester 8a-ethyl ester 1b. Pale
25
D
yellow oil; ½aŠ ¼ ꢀ70:1 (c 1.5, CHCl3), 95% ee; 1H
NMR: d 1.27 (t, 3H, J = 7.1Hz), 1.42–1.74 (m, 3H),
2.24–2.44 (m, 2H), 2.68 (q, 1H, J = 8.7Hz), 2.81–2.99
(m, 2H), 3.27 (dt, 1H, J = 2.1 and 8.7Hz), 3.42 (q, 1H,
J = 7.8Hz), 3.60–3.68 (m, 1H), 4.20 (q, 2H,
J = 7.1Hz), 5.11 (AB system, 2H), 7.27–7.40 (m, 5H);
13C NMR (CDCl3): d 14.2, 21.6, 24.9, 36.0, 44.1, 46.4,
47.4, 61.6, 66.6, 73.2, 128.1, 128.2, 128.5, 135.7, 169.2,
171.7, 209.9; IR (neat): 3033, 2939, 2855, 1764, 1725,
and 1455cmꢀ1. Anal. Calcd for C19H23NO5: C, 66.07;
H, 6.71; N, 4.06. Found: C, 66.14; H, 6.75; N, 4.05.
4.6.2.2. (8R,8aS)-1-Oxo-hexahydro-indolizine-8,8a-
dicarboxylic acid 8-benzyl ester 8a-ethyl ester 10b. Yel-
25
D
1
low oil; ½aŠ ¼ 34:4 (c 0.88, CHCl3), 90% ee; H NMR:
1.22 (t, 3H, J = 7.1Hz), 1.50–1.71 (m, 3H), 1.71–1.84 (m,
1H), 1.94–2.09 (m, 1H), 2.25–2.46 (m, 2H), 2.46–2.62
(m, 2H), 2.78 (ddd, 1H, J = 1.8, 5.1, and 11.4Hz),
2.82–2.93 (m, 1H), 3.07 (dt, 1H, J = 3.3 and 11.7Hz),
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