Intramolecular isom?unchnone cycloaddition approach to the antitumor agent camptothecin

Article abstract of DOI:10.1016/j.tet.2011.02.017

A novel, convergent approach to the antitumor agent camptothecin has been developed with a rhodium (II)-catalyzed intramolecular [3+2] cycloaddition as the key step.

Full text of DOI:10.1016/j.tet.2011.02.017

Tetrahedron 67 (2011) 2579e2584
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
€
Intramolecular isomunchnone cycloaddition approach to the antitumor agent
camptothecin
y
y
,
z
*
*
Franc¸ ois Grillet , Cyrille Sabot , Regan Anderson , Matej Babjak, Andrew E. Greene, Alice Kanazawa
ꢀ
ꢀ
ꢀ
Departement de Chimie Moleculaire, UMR-5250, ICMG FR-2607, Universite Joseph Fourier-CNRS, BP 53, 38041, Grenoble Cedex 09, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 January 2011
Received in revised form 4 February 2011
Accepted 7 February 2011
Available online 13 February 2011
A novel, convergent approach to the antitumor agent camptothecin has been developed with a rhodium
(II)-catalyzed intramolecular [3þ2] cycloaddition as the key step.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Camptothecin
€
Isomunchnone
Intramolecular [3þ2] cycloaddition
1. Introduction
derivatives have gained FDA approval: Irinotecan (2, Camptosar)3 to
treat colorectal cancers and topotecan (3, Hycamtin)4 for ovarian
Camptothecin (1, Fig. 1) is a naturally occurring DNA top-
oisomerase I poison, which was first isolated from Camptotheca
acuminata by Monroe Wall and co-workers in 1966.1 Owing to its
remarkable antiproliferative activity, this pentacyclic alkaloid has
attracted enormous attention from different members of the syn-
thetic community, particularly since the discovery by Liu and co-
workers that the cytotoxicity of camptothecin is due to a novel
mechanism of action that involves the ubiquitous nuclear enzyme
topoisomerase I.2 To date, two water-soluble camptothecin
and small-cell lung cancers (Fig. 1).
It can be expected that additional camptothecinoids will emerge
as anticancer drugs as many other analogs of 1, such as lurtotecan
(4), exatecan (5), karenitecin (6), and diflomotecan (7), are cur-
rently in clinical evaluation (Fig. 2).5
NMe
N
NH2
O
O
Me
F
O
O
R2 R3
N
N
R1
N
N
O
N
O
O
N
HO
HO
O
O
O
Lurtotecan
Exatecan
HO
O
4
5
1, R1 = R2 = R3 = H (Camptothecin)
2, R1 = OH, R2 = CH2NMe2, R3 = H (Topotecan)
3, R1 = OOCPipPip, R2 = H, R3 = Et (Irinotecan)
TMS
F
O
O
N
N
N
Fig. 1. Camptothecin and analogs.
F
N
O
O
HO
HO
O
O
* Corresponding authors. E-mail addresses: r.anderson@irl.cri.nz (R. Anderson),
Karenitecin
Diflomotecan
Alice.Kanazawa@ujf-grenoble.fr (A. Kanazawa).
y
These authors contributed equally to this work.
Present address: Carbohydrate Team, Industrial Research Limited, PO Box
6
7
z
31-310, Lower Hutt, New Zealand.
Fig. 2. Structures of lurtotecan, exatecan, karenitecin, and diflomotecan.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.017

2580
F. Grillet et al. / Tetrahedron 67 (2011) 2579e2584
A number of elegant total syntheses of camptothecin have been
TMS
PhS
O
TMS
(COCl)2, py, CH2Cl2;
EtMgBr, THF;
TBAF, THF
reported6 since the first success achieved by Stork and Schultz in
1971.7 Because of the pharmacological importance of camptothe-
cinoids and their challenging structural features, we too have been
interested in developing new synthetic strategies for this important
class of compounds.8,9 Herein, a convergent approach to campto-
NEt2
PhS
Et2NH
72%
O
14
13
€
thecin, employing a novel intramolecular [3þ2] isomunchnone
OH
OH
NEt2
MCPBA, CH2Cl2
NEt2
cycloaddition, is described.
PhS
PhSO2
As outlined retrosynthetically in Scheme 1, the
g-lactone de-
O
O
73% from 14
rivative 8 was envisaged as the direct precursor of camptothecin;
a one-pot conversion of this derivativeintocamptothecin had earlier
been described by Bristol-Myers Squibb researchers.10 The penta-
15
16
O
O
cycle 8 would be formed by a Friedlander reaction,11 employing the
€
N
Cl
O
O
CONEt2
ketone derived by benzylic-type oxidation of pyridone 9. This pyr-
idone would in turn be produced from sulfone 10 by reduction. The
requiredsulfone 10 was viewed as arising through an intramolecular
17
O
THF
N
O
SO2Ph
X
[3þ2] cycloaddition of the isomunchnone intermediate 11,12 which
O
€
66%
would be generated from the densely functionalized diazoimide 12.
It should be pointed out that the need of an EWG for this cyclization
to proceed was recognized during preliminary experimentation.13
The phenylsulfonyl group was chosen in the belief that it could be
readily introduced and subsequently removed selectively.
18, X = H, H
12, X = N2
p-ABSA, Et3N
MeCN
87%
Scheme 2. Synthesis of diazoimide 12.
Gratifyingly, the crucial intramolecular cycloaddition of 12 pro-
ceeded smoothly in the presence of rhodium acetate in refluxing
benzene to produce a 5:1 mixture of cycloadducts (Scheme 3). The
major isomer 19 was easily isolated in 64% yield by recrystallization
from ethyl acetate.17 Although both diastereoisomers should meld in
a subsequent intermediate, only the major isomer was advanced.
O
O
N
N
O
N
N
O
O
HO
( )-1
8
CONEt2
O
O
O
O
O
O
O
O
Rh2(OAc)4
H
H
O
O
Benzene, reflux;
SmI2
N
N
O
O
N
N
12
O
O
recrystallization
64%
THF
82%
CONEt2
CONEt2
HO
PhSO2
H
PhSO2
19
CONEt2
CONEt2
PhSO2
10
20
9
O
O
O
O
H
AcCl, Et3N
DMAP, CH2Cl2
89%
DDQ
N
N
O
O
O
N
Benzene, reflux
95%
O
O
O
N2
CONEt2
SO2Ph
CONEt2
O
CONEt2
H
PhSO2
R
O
N
O
10, R = SO2Ph
9, R = H
21
Ra-Ni
PhSO2
CONEt2
O
EtOH, reflux
81%
11
12
Scheme 3. Synthesis of pyridone 9.
Scheme 1. Retrosynthesis of camptothecin.
Conversion of piperidone 19 into pyridone 9 began with
samarium (II) iodide-promoted bridge cleavage to afford 20 in high
yield.18 Dehydration of this intermediate could then be accom-
plished under acetylation conditions to provide in 89% yield the
unsaturated sulfone 21. Dehydrogenation of this compound in the
presence of DDQ, followed by sulfone reduction with Raney-nickel
in refluxing ethanol, gave pyridone 9 in 81% yield (56% from 19).19
Benzylic-type oxidation of 9 to the corresponding ketone
was first attempted through hydroxylation [SeO2 or
NaHMDSeO2eP(OEt)3], followed by DesseMartin periodinane
oxidation, as used with related compounds in our previous
work.8 Unfortunately, this approach proved unsuccessful. The
2. Results and discussion
The preparation of the key substrate 12 began with the synthesis
of hydroxy sulfone 16, which was easily accessible starting from
vinylsilane 1314 (Scheme 2). The olefin was first acylated with oxalyl
chloride in the presence of pyridine, following the protocol de-
veloped by Hojo and co-workers.15 The resulting acid chloride,
without isolation, was then treated with diethylamine to provide
the desired a-ketoamide 14 as a 10:1 E/Z mixture in 72% yield. The
addition of ethylmagnesium bromide to 14, followed by desilyla-
tion, produced alcohol 15, which was oxidized with m-chlor-
operbenzoic acid to afford the desired E-hydroxy sulfone 16 in 73%
overall yield after purification (three steps).
Hydroxy sulfone 16 was next transformed into ester 18 through
acylation with acid chloride 17, derived from the corresponding
carboxylic acid (prepared from commercially available trime-
thylsilylpyrrolidinone and Meldrum’s acid16). Diazo transfer using
4-acetamidobenzenesulfonyl azide (p-ABSA) then smoothly con-
verted 18 into the cyclization substrate 12. The overall yield for the
six-step sequence was 30% (82%/step).
€
desired Friedlander substrate 23 could be effectively secured,
however, by using tert-butoxybis(dimethylamino)methane (Bre-
dereck’s reagent)20
(
22, 89%), followed by photooxygenation in
the presence of tetraphenylporphine (TPP) at low temperature
(Scheme 4).20b,21,22 This SiO2-sensitive ketone was used directly in
€
the Friedlander condensation to afford the target quinoline 8 in 41%
non-optimized yield (two steps). The spectral data for this com-
pound were in excellent accord with those recorded in the
literature.10

F. Grillet et al. / Tetrahedron 67 (2011) 2579e2584
2581
[q, 2H, J¼7.2 Hz, CON(CH2CH3)CH2CH3], 6.23 (s, 1H,C¼CHCO),
7.40e7.50 (m, 5H, CArH); 13C NMR (75 MHz):
O
O
O
O
d
ꢁ0.9 [Si(CH3)3], 12.6
t-BuOCH(NMe2)2
N
N
O
O
[CON(CH2CH3)CH2CH3], 14.4 [CON(CH2CH3)CH2CH3], 39.1 [CON
(CH2CH3)CH2CH3], 41.9 [CON(CH2CH3)CH2CH3], 123.7 (C¼CH),
129.9 (CAr), 130.0 (CArH), 134.9 (CArH), 167.6 (CONEt2), 173.2
(C¼CH), 185.1 (COCONEt2); HRMS (ESI) calcd for C17H25NO2SSiNa:
358.1267; found: 358.1260.
THF, reflux
89%
CONEt2
CONEt2
X
22, X = CHNMe2
9
O2, hv
TPP, CH2Cl2
23, X = O
NTol
NH2
4.1.2. (ꢂ)-(E)-2-Ethyl-2-hydroxy-N,N-diethyl-4-(phenylthio)but-3-
enamide (15). A 1.0 M solution of ethylmagnesium bromide in THF
(24.2mL, 24.2mmol)was addedto a solutionof ketoamide 14 (5.06 g,
15.1 mmol) inTHF (175 mL) at ꢁ65 ꢀC. The mixture was stirred below
ꢁ30 ꢀC for 2.5 h, after which it was quenched with a saturated
aqueous solution of ammonium chloride. The crude product was
isolated with ether and then treated with a solution of TBAF$3H2O
(3.67 g, 14.0 mmol) in THF (25 mL). The reaction mixture was stirred
under argon for 1.5 h, whereupon the solvent was removed by rotary
evaporation under reduced pressure. The resulting residue was par-
tially purified by silica gel column chromatography (ether) to provide
alcohol 15 (3.75 g) as a yellow oil. An analytical sample was obtained
from comparable material by a second silica gel column chroma-
O
ref 10
N
N
( )-1
O
TsOH, PhMe, reflux
O
41% from 22
CONEt2
8
Scheme 4. Synthesis of
g
-lactone 8.
3. Conclusion
In summary, we have developed an original approach to racemic
camptothecin, based on an intramolecular 1,3-dipolar cycloaddi-
tion involving a highly functionalized isomunchnone intermediate,
tography (pentane/ether, 90/10). IR (cmꢁ1
)
y
: 3360, 2974, 2933, 2876,
€
1622, 1461, 1439, 1378, 1344,1264; 1H NMR (400 MHz):
d
0.84 (t, 3H,
that is relatively concise and flexible. Asymmetric ethylation of a-
ketoamide 14 should be feasible,23 which would provide access to
natural camptothecin and several new derivatives. This possibility
and other aspects of the approach are currently under study in our
laboratory.
J¼7.6 Hz, CH3CH2), 1.09 [t, 6H, J¼6.8 Hz, CON(CH2CH3)2], 1.80 (q, 2H,
J¼7.6 Hz, CH3CH2), 3.16e3.53 [m, 4H, CON(CH2CH3)2], 5.26 (br, 1H,
OH), 5.87 (d, 1H, J¼15.2 Hz, PhSCH¼CH), 6.54 (d, 1H, J¼15.2 Hz,
PhSCH¼CH), 7.15e7.35 (m, 5H, CArH); 13C NMR (100 MHz):
d 7.7
(CH3CH2), 12.4 [CON(CH2CH3)CH2CH3], 13.7 [CON(CH2CH3)CH2CH3],
31.1 (CH3CH2), 41.6 [CON(CH2CH3)CH2CH3], 42.2 [CON(CH2CH3)
CH2CH3], 76.0 (COH), 126.5 (PhCH]CH), 127.1 (CArH), 129.1 (CArH),
130.2 (CArH), 132.3 (PhSCH]CH), 134.2 (CAr), 172.4 (CONEt2); HRMS
(ESI) calcd for C16H23NO2SNa: 316.1342; found: 316.1331.
4. Experimental section
4.1. General
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. Reactions were
monitored by TLC using silica gel 60F254 0.2 mm-thickness plates
with visualization by UV (254 nm) and through staining with
a phosphomolybdic acid or KMnO4 solution in EtOH. For pre-
parative scale chromatography, silica gel 60 (0.04e0.063 mm) was
4.1.3. (ꢂ)-(E)-2-Ethyl-2-hydroxy-N,N-diethyl-4-(phenylsulfonyl)but-
3-enamide (16). m-CPBA (7.24 g, 70%, 29.4 mmol) was added to
a solution of the above alcohol 15 in dichloromethane (120 mL) at
0 ꢀC. The mixture was stirred at 0 ꢀC for 2 h and then aqueous NaOH
was added. The crude product was isolated with dichloromethane
(150 mL) in the usual manner and purified by silica gel column
chromatography (pentane/ethyl acetate, 50/50) to provide hydroxy
€
used. Melting point determinations were carried out on a Buchi B-
545 apparatus. IR spectra were recorded with a Nicolet iS10FT-IR
spectrometer using a diamond ATR Golden Gate sampler. NMR
spectra were recorded at 300 MHz or 400 MHz on Bruker spec-
sulfone 16 (3.58 g, 73% from 14) as a colorless oil. IR (cmꢁ1
)
y
: 3440,
0.87 (t,
2977, 2920, 2851,1625,1442,1312,1141; 1H NMR (400 MHz):
d
3H, J¼7.6 Hz, CH3CH2), 1.06e1.26 [br, 6H, CON(CH2CH3)2], 1.78e2.00
(m, 2H, CH3CH2), 3.19e3.65 [br, 4H, CON(CH2CH3)2], 5.31 (s, 1H, OH),
6.73 (d, 1H, J¼4.4 Hz, PhSO2CH¼CH), 7.12 (d, 1H, J¼14.4 Hz,
PhSO2CH¼CH), 7.51e7.55 (m, 2H, CArH), 7.60e7.64 (m, 1H, CArH),
trometers. The chemical shifts are given in parts per million (d) and
referenced to the residual solvent peak. Unless otherwise stated,
CDCl3 was used as the solvent. High resolution mass spectra
(HRMS) were recorded on a Thermoquest Orbitrap spectrometer at
7.84e7.87 (m, 2H, CArH); 13C NMR (100 MHz):
d 7.6 (CH3CH2), 12.5
ꢀ
the LCOSB, Universite Pierre et Marie Curie, Paris.
[CON(CH2CH3)CH2CH3], 13.8 [CON(CH2CH3)CH2CH3], 29.6 (CH3CH2),
41.7 [CON(CH2CH3)2], 75.8 (COH), 127.7 (CArH), 129.3 (CArH), 132.4
(PhSO2CH¼CH), 133.6 (CArH), 139.9 (CArH), 145.3 (PhSO2CH¼CH),
170.3 (CONEt2); HRMS (ESI) calcd for C16H23NO4SNa: 348.1240;
found: 348.1227.
4.1.1. N,N-Diethyl-2-oxo-4-(phenylthio)-4-(trimethylsilyl)but-3-en-
amide (14). Pyridine (1.68 mL, 20.8 mmol) was added to a solution
of oxalyl chloride (2.72 mL, 30.7 mmol) in dichloromethane
(80 mL) at 0 ꢀC. The resulting yellow solution was stirred for 1 h,
after which 1-(trimethylsilyl-1-phenylthio)ethylene14 (4.34 g,
20.8 mmol) was added dropwise. The mixture was stirred at 20 ꢀC
for 3 days, whereupon diethylamine (10.8 mL, 103.5 mmol) was
added dropwise at ꢁ60 ꢀC. The mixture was stirred overnight and
then quenched with water and extracted with ether. The com-
bined organic phases were washed with 1 N HCl, dried over an-
hydrous Na2SO4, filtered, and evaporated under reduced pressure.
The resulting crude product was purified by silica gel column
chromatography (pentane/ether, from 10/90 to 40/60) to give
ketoamide 14 ( 5.06 g, 72%, 10:1 E/Z mixture) as an orange solid: IR
4.1.4. (ꢂ)-(E)-3-(Diethylcarbamoyl)-1-(phenylsulfonyl)pent-1-en-3-
yl 3-oxo-3-(2-oxopyrrolidin-1-yl)propanoate (18). A 2.5 M solution
of n-butyllithium in hexanes (10.5 mL, 26.3 mmol) was added to
a solution of 3-oxo-3-(2-oxopyrrolidin-1-yl)propanoic acid16 (4.58 g,
26.8 mmol) in dry THF (160 mL) at ꢁ78 ꢀC and the resulting solution
wasstirredfor15min. Oxalyl chloride(2.3mL,26.8 mmol)wasadded
andthe resulting yellow solutionwas stirred at ꢁ78 ꢀC for 15 min and
then at 0 ꢀC for 24 h. After being stirred for 1 h at 20 ꢀC, the reaction
mixture was treated with a solution of hydroxy sulfone 16 (1.29 g,
4.0 mmol) in dry THF (10 mL) and stirred for 24 h. Water (30 mL) and
then a saturated aqueous solution of sodium bicarbonate (90 mL)
were added and the product was extracted with dichloromethane.
The combined organic phases were washed with water, dried over
(cmꢁ1
(400 MHz) major isomer:
CON(CH2CH3)2], 3.20 [q, 2H, J¼7.2 Hz, CON(CH2CH3)CH2CH3], 3.30
)
y
: 2971, 1635, 1502, 1477, 1439, 1249, 1084, 843; 1H NMR
d
0.36 [s, 9H, Si(CH3)3], 1.07e1.11 [m, 6H,

2582
F. Grillet et al. / Tetrahedron 67 (2011) 2579e2584
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude product was purified by sílica gel column chroma-
tography (dichloromethane/ethyl acetate, 85/15) ꢁt1o give ester 18
(NpyCCHSO2Ph), 128.7 (CArH), 129.1 (CArH), 134.2 (CArH), 138.2 (CAr),
162.5 (CO), 167.0 (CO), 168.1 (CO); HRMS (ESI) calcd for
C23H28N2O7SNa: 499.1509; found: 499.1508.
(1.26 g, 66%) as a white solid: mp 37e38 ꢀC; IR (cm
)
y: 2977, 2936,
0.78 (t, 3H,
1748, 1695, 1645, 1401, 1148; 1H NMR (300 MHz):
d
4.1.7. (1SR,3aSR,8aRS,9SR,9aSR)-1-Ethyl-8a-hydroxy-N,N-diethyl-
3,4-dioxo-9-(phenylsulfonyl) decahydrofuro[3,4-f]indolizine-1-car-
boxamide (20). Piperidone 19 (210 mg, 0.44 mmol) was treated
with a 0.1 M solution of SmI2 in THF (30 mL, 3 mmol) at ꢁ78 ꢀC. The
reaction mixture was stirred below ꢁ40 ꢀC for 1.5 h, after which
saturated aqueous solutions of Na2S2O3 and NaHCO3 were added.
The mixture was extracted with dichloromethane, which was
washed with brine, dried over anhydrous Na2SO4, filtered, and
evaporated under reduced pressure. The resulting crude solid was
recrystallized from ethyl acetate to provide alcohol 20 (174 mg,
J¼7.2 Hz, CH3CH2), 1.02 [t, 6H, J¼6.9 Hz, CON(CH2CH3)2], 1.93e2.15
(m, 3H, CH3CH2, NpyCH2CHH), 2.33e2.64 (m, 3H, NpyCH2CHH, Npy
-
COCH2), 3.10e3.51 [br, 4H, CON(CH2CH3)2], 3.80 (t, 2H, J¼7.2 Hz,
NpyCH2), 3.97(s, 2H, COCH2CO), 6.58(d,1H,J¼15.3Hz,PhSO2CH¼CH),
7.10 (d, 1H, J¼15.3 Hz, PhSO2CH¼CH), 7.48e7.72 (m, 3H, CArH),
7.80e7.97 (m, 2H, CArH);13C NMR (75 MHz):
d6.8(CH3CH2),11.7[CON
(CH2CH3)CH2CH3], 13.3 [CON(CH2CH3)CH2CH3] 16.6 (CH3CH2), 28.6
(NpyCH2CH2), 32.7 (NpyCH2CH2CH2), 40.4 [CON(CH2CH3)2], 43.3
(COCH2CO), 44.9 (NpyCH2), 84.8 (CO2C), 127.3 (CArH), 129.1 (CArH),
130.6 (PhSO2CH¼CH), 133.4 (CArH), 139.6 (CArH), 142.9
(PhSO2CH¼CH), 164.1 (CO), 164.9 (CO), 165.4 (CO), 175.3 (CO); HRMS
(ESI) calcd for C23H30N2O7SNa: 501.1666; found: 501.1661.
82%) as a white solid: mp 159e161 ꢀC; IR (cmꢁ1
2966, 2889, 1784, 1634, 1460, 1307, 1251, 1151, 1006, 965; 1H NMR
(400 MHz, DMSO-d6):
) y: 3169, 2989,
d
0.59 (t, 3H, J¼7.2 Hz, CH3CH2), 0.99e1.11
[m, 6H, CON(CH2CH3)2], 1.87e2.14 (m, 5H), 3.02e3.22 (m, 4H),
3.34e3.48 (m, 3H), 3.62e3.64 (br, 1H), 4.18 (s, 1H), 4.57e4.72 (br,
1H), 6.81 (s, 1H, OH), 7.67 (t, 2H, J¼7.6 Hz, CArH), 7.77 (t, 1H,
J¼7.6 Hz, CArH), 7.91 (d, 2H, J¼7.6 Hz, CArH); 13C NMR (100 MHz,
4.1.5. (ꢂ)-(E)-3-(Diethylcarbamoyl)-1-(phenylsulfonyl)pent-1-en-3-
yl 2-diazo-3-oxo-3-(2-oxopyrrolidin-1-yl)propanoate (12). To a so-
lutionof ester 18 (0.970 g, 2 mmol)inacetonitrile(1.3mL)wereadded
triethylamine (550
mL, 3.9 mmol) and 4-acetamidobenzenesulfonyl
DMSO-d6): d 7.5 (CH3CH2), 12.2 [CON(CH2CH3)CH2CH3], 13.8 [CON
azide (450 mg,1.9 mmol). The reaction mixture was stirred overnight
at 20 ꢀC and then concentrated under reduced pressure. Dichloro-
methane (4 mL) was added and the solids were filtered and rinsed
with the same solvent. The filtrate was concentrated to afford the
crude product, which was purified by silica gel column chromatog-
raphy (pentane/ethyl acetate, from 60/40 to 40/60) to give diazo
(CH2CH3)CH2CH3], 20.2 (NpyCH2CH2), 25.6 (CH3CH2), 37.4 (CH2),
40.9 (CH), 41.8 [CON(CH2CH3)2], 44.5 (NpyCH2), 46.8 (CH), 64.6
(PhSO2CH), 88.1 (NpyCCHSO2Ph), 89.6 (CO2C), 128.7 (CArH), 129.5
(CArH), 134.3 (CArH), 137.8 (CArH), 161.2 (CO), 167.5 (CO), 171.3
(CO); HRMS (ESI) calcd for C23H30N2O7SNa: 501.1666; found:
501.1661.
compound 12 (820 mg, 87%) as a white solid: mp 46e47 ꢀC; IR (cmꢁ1
)
y
: 3047, 2974, 2936, 2145, 1733, 1700, 1650, 1327, 1144; 1H NMR
4.1.8. (1SR, 3aSR, 9aRS)-1-Ethyl-N,N-diethyl-3,4-dioxo-9-(phenyl-
sulfonyl)-1,3,3a,4,6,7,8,9a-octahydrofuro[3,4-f]indolizine-1-carbox-
amide (21). DMAP (59 mg, 0.48 mmol) and triethylamine (0.52 mL,
3.7mmol)wereaddedtoasolutionofalcohol20(49 mg, 0.102mmol)
in dichloromethane (5 mL) under argon. The resulting solution was
cooled to ꢁ78 ꢀC and acetyl chloride (0.032 mL, 0.45 mmol) was
added in dichloromethane (1 mL). The reaction mixture was allowed
to warm to 20 ꢀC and stirred for 30 h, whereupon it was treated with
aqueous NH4Cl. The mixture was extracted with chloroform, which
was washed with brine, dried over anhydrous Na2SO4, filtered, and
evaporated under reduced pressure. The crude product was purified
by silica gel column chromatography (pentane/ethyl acetate, 40/60)
to give sulfone 21 (42 mg, 89%) as a yellow solid: dec 229e230 ꢀC; IR
(300 MHz):
d
0.71 (t, 3H, J¼7.5 Hz, CH3CH2), 0.85e1.09 [br, 6H, CON
(CH2CH3)2], 1.92e2.10 (m, 3H, CH3CH2, NpyCH2CHH), 2.38e2.57 (m,
3H, NpyCH2CHH, NpyCOCH2), 3.08e3.42 [br, 4H, CON(CH2CH3)2], 3.75
(t, 2H, J¼6.9 Hz, NCH2), 6.65 (d,1H, J¼15.3 Hz, PhSO2CH¼CH), 7.01 (d,
1H, J¼15.3 Hz, PhSO2CH¼CH), 7.44e7.65 (m, 3H, CArH), 7.78e7.90 (m,
2H, CArH); 13C NMR (75 MHz):
d 6.9 (CH3CH2), 11.9 [CON(CH2CH3)
CH2CH3], 13.3 [CON(CH2CH3)CH2CH3], 17.5 (CH3CH2), 28.6
(NpyCH2CH2), 32.5 (NpyCH2CH2CH2), 40.6 [CON(CH2CH3)2], 46.2
(NpyCH2), 70.1 (C]N2), 85.3 (CO2C), 127.5 (CArH), 129.2 (CArH), 131.3
PhSO2CH¼CH, 133.6 (CArH), 139.7 (CAr), 142.6 (PhSO2CH¼CH), 158.7
(CO), 159.3 (CO), 165.5 (CO), 173.9 (CO); HRMS (ESI) calcd for
C23H28N4O7SNa: 527.1571; found: 527.1565.
(cmꢁ1
1077; 1H NMR (400 MHz):
)
y
: 3060, 2919, 2845, 1790, 1687, 1628, 1381, 1310, 1210, 1127,
4.1.6. (1SR,3aSR,8aRS,9SR,9aRS)-1-Ethyl-3a,8a-epoxy-N,N-diethyl-
3,4-dioxo-9-(phenylsulfonyl) decahydrofuro[3,4-f]indolizine-1-car-
boxamide (19). A mixture of diazo compound 12 (400 mg, 0.8 mmol)
and Rh2(OAc)4 (7 mg, 0.016 mmol) was dried under high vacuum for
1 h. Dry benzene (13 mL) was then added and the mixture was
refluxedfor 1.5h. After being cooled, thereaction mixturewasfiltered
through Celite and the solids were rinsed with dichloromethane. The
filtrate was concentrated under reduced pressure and the resulting
solid was recrystallized from ethyl acetate to provide pureꢁp1iperidone
d
0.92 (t, 3H, J¼7.1 Hz, CH3CH2), 1.10e1.35
[m, 7H, CH3CHH, CON(CH2CH3)2], 1.93e2.05 (m, 2H, NpyCH2CH2),
2.35e2.47 (m, 1H, CH3CHH), 2.70e2.82 (m, 1H, NpyCH2CH2CHH),
2.99e3.11 (m, 1H, NpyCH2CH2CHH), 3.15e3.47 [m, 4H, CON
(CH2CH3)2], 3.55e3.70 (m, 1H, NpyCHH), 3.77 (d, 1H, J¼11.0 Hz,
PhSO2CCH), 3.80e3.90 (m, 1H, NpyCHH), 4.44 (d, 1H, J¼11.0 Hz,
COCHCO), 7.54e7.66 (m, 3H, CArH), 8.15e8.21 (m, 2H, CArH); 13C NMR
(100 MHz):
d 8.0 (CH3CH2), 12.3 [CON(CH2CH3)CH2CH3], 14.3 [CON
(CH2CH3)CH2CH3], 21.0 (NpyCH2CH2), 27.8 (CH3CH2), 31.2
(NpyCH2CH2CH2), 42.8 (PhSO2CCH), 42.9 [CON(CH2CH3)CH2CH3],
43.0 [CON(CH2CH3)CH2CH3], 45.5 (COCHCO), 47.3 (NpyCH2), 91.3
(CO2C), 108.6 (PhSO2C), 128.4 (CArH), 129.1 (CArH), 133.3 (CArH), 141.5
(CAr),153.7(PhSO2CCN),159.7(CO),165.7(CO),167.8(CO);HRMS(ESI)
calcd for C23H28N2O6SNa: 483.1560; found: 483.1556.
19 (240 mg, 64%) as a white solid: mp 212e214 ꢀC; IR (cm
)
y
: 2901,
1803,1739,1632,1445,1378,1309,1150; 1H NMR (400 MHz):
d 0.81 (t,
3H, J¼7.6 Hz, CH3CH2), 1.15 [t, 3H, J¼7.2 Hz, CON(CH2CH3)CH2CH3],
1.19 [t, 3H, J¼7.2 Hz, CON(CH2CH3)CH2CH3], 1.81e2.03 (m, 2H,
CH3CH2), 2.14e2.33 (m, 3H, NpyCH2CH2, NpyCH2CH2CHH), 2.97e3.05
(m, 1H, NpyCH2CH2CHH), 3.17e3.27 [m, 2H, CON(CHHCH3)CHHCH3],
3.39e3.53 [m, 2H, NpyCHH, CON(CHHCH3)CH2CH3], 3.70e3.84 [m,
2H, CON(CH2CH3)CHHCH3], 3.91 (d, 1H, J¼4.4 Hz, PhSO2CHCH), 4.14
(d, 1H, J¼4.4 Hz, PhSO2CH), 7.56 (t, 2H, J¼8.0 Hz, CArH), 7.67 (t, 1H,
4.1.9. (ꢂ)-1-Ethyl-N,N-diethyl-3,4-dioxo-9-(phenylsulfonyl)-1,3,4,6,7,8-
hexahydrofuro[3,4-f]indolizine-1-carboxamide (10). A mixture of sul-
fone 21 (39 mg, 0.085 mmol) and DDQ (34 mg, 0.15 mmol) in dry
benzene (4.5 mL) was heated at reflux for 7 h and then concentrated
under reduced pressure. The residue was diluted with dichloro-
methane, which was washed with a saturated aqueous solution of
NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure. The resulting crude product was
J¼8.0 Hz, CArH), 8.09 (d, 2H, J¼8.0 Hz, CArH); 13C NMR (100 MHz):
d 7.9
(CH3CH2), 12.3 [CON(CH2CH3)CH2CH3], 14.4 [CON(CH2CH3)CH2CH3],
25.8 (NpyCH2CH2), 28.1 (NCH2CH2CH2), 29.3 (CH3CH2), 42.2 [CON
(CH2CH3)CH2CH3], 42.4 [CON(CH2CH3)CH2CH3], 44.2 (NpyCH2), 53.8
(PhSO2CHCH), 68.8 (PhSO2CH), 85.3 (COCCO), 89.7 (CO2C), 107.4

F. Grillet et al. / Tetrahedron 67 (2011) 2579e2584
2583
purified by silica gel column chromatography (EtOAc) to give sulfone
10 (37 mg, 95%) as a white solid: mp 110e112 ꢀC; IR (cmꢁ1
: 3060,
2966, 2930, 1770, 1684, 1637, 1566, 1501, 1442, 1307, 1207, 1151, 1083;
1H NMR (400 MHz):
6H, CON(CH2CH3)2], 2.09e2.29 (m, 2H, NCH2CH2), 2.43e2.55 (m, 1H,
CH3CHH), 2.67e2.79 (m, 1H, NCH2CH2CHH), 3.13e3.26 (m, 1H,
CH3CHH), 3.28e3.40 [m, 4H, CON(CH2CH3)2], 3.40e3.53 (m, 1H,
NCH2CH2CHH), 3.99e4.08 (m, 1H, NCHH), 4.22e4.31 (m, 1H, NCHH),
7.52e7.66 (m, 3H, CArH), 8.19e8.25 (m, 2H, CArH); 13C NMR
oxygen was irradiated with a 500-W lamp for 35 min. Evaporation of
)
y
the solvent under reduced pressure gave crude ketone 23, which was
used in the next step without purification: 1H NMR (300 MHz):
d 0.87
d
0.79 (t, 3H, J¼7.5 Hz, CH3CH2), 1.02e1.37 [m,
(t, 3H, J¼7.5 Hz, CH3CH2),1.13 [t, 3H, J¼6.9 Hz, CON(CH2CH3)CH2CH3],
1.24 [t, 3H J¼6.8 Hz, CON(CH2CH3)CH2CH3], 2.04e2.22 (m, 1H),
2.30e2.45(m,1H), 3.01(t, 2H, J¼6.9Hz),3.11e3.54(m, 3H), 4.37(t, 2H,
J¼6.9 Hz), 7.40 (s, 1H, CpyH).
A solution of the crude ketone 23, (E)-N-(2-aminobenzylidene)-4-
methylaniline (65 mg, 0.31 mmol), and p-toluenesulfonic acid mon-
ohydrate (2.1 mg, 0.01 mmol) in toluene (6 mL) was refluxed for 1 h
(DeaneStark equipped condenser). The mixture was diluted with
chloroform and washed with a saturated aqueous solution of NaHCO3
and brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by pre-
parative TLC (ethyl acetate) to provide quinolꢁin1e 8 (7 mg, 41%, two
)y:3066, 2971, 2936,
(100 MHz):
d 8.3 (CH3CH2), 12.3 [CON(CH2CH3)CH2CH3], 14.1 [CON
(CH2CH3)CH2CH3], 20.7 (NpyCH2CH2), 28.6 (CH3CH2), 33.9
(NpyCH2CH2CH2), 42.1 [CON(CH2CH3)2], 49.5 (NpyCH2), 92.5 (CO2C),
112.1 (Cpy), 114.5 (Cpy), 128.0 (CArH), 129.1 (CArH), 133.7 (CArH), 141.4
(CAr), 155.1 (CpyNCO), 161.9 (PhSO2CpyCpy), 165.6 (CO), 166.1 (CO);
HRMS (ESI) calcd for C23H26N2O6SNa: 481.1404; found: 481.1399.
steps)asayellowsolid:mp206e208ꢀC; IR (cm
4.1.10. (ꢂ)-1-Ethyl-N,N-diethyl-3,4-dioxo-1,3,4,6,7,8-hexahydrofuro
[3,4-f]indolizine-1-carboxamide (9). To a solution of sulfone 10
(30 mg, 0.065 mmol) in ethanol (0.5 mL) was added Raney Nickel
(w1 g). The mixture was then heated at reflux for 6 h, after which it
was cooled to 20 ꢀC and filtered through a pad of Celite. The filtrate
was concentrated under reduced pressure and the resulting crude
product was purified by silica gel column chromatography (CH2Cl2/
2877, 1761, 1675, 1628, 1592, 1540, 1431, 1372, 1216, 1160, 1051; 1H NMR
(400 MHz):
d
0.93 (t, 3H, J¼7.4 Hz, CH3CH2), 1.16 [t, 3H, J¼7.0 Hz, CON
(CH2CH3)CH2CH3], 1.27 [t, 3H, J¼7.0 Hz, CON(CH2CH3)CH2CH3],
2.18e2.31 (m, 1H, CH3CHH), 2.42e2.53 (m, 1H, CH3CHH), 3.15e3.38
(m, 2H), 3.46e3.55 (m, 1H), 3.91e4.00 (m, 1H), 5.33 (d, 1H, J¼23 Hz,
NpyCHH), 5.38 (d, 1H, J¼23 Hz, NpyCHH), 7.70 (t, 1H, J¼7.2 Hz, CArH),
7.85(t,1H,J¼7.2 Hz, CArH),7.88(s,1H, CArH), 7.96 (d,1H, J¼8.0Hz, CArH),
methanol, 95/5) to give pyridone 9 (17 mg, 81%). IR (cmꢁ1
2980, 2939, 2882,1771,1666,1632,1590,1562,1435,1264,1084,1052;
1H NMR (400 MHz):
)
y: 3056,
8.24 (d,1H, J¼8.4Hz,CArH), 8.43 (s,1H, CArH); 13C NMR (100 MHz):
d8.7
(CH3CH2), 12.5 [N(CH2CH3)CH2CH3], 14.8 [N(CH2CH3)CH2CH3], 31.7
(CH3CH2), 42.7 [N(CH2CH3)CH2CH3], 42.8 [N(CH2CH3)CH2CH3], 50.3
(NCH2CAr), 88.8 (CO2C), 97.9 (CpyH),112.3 (CAr),128.1 (CArH),128.5(CAr),
128.6 (CArH), 129.6 (CAr), 130.1 (CArH), 130.8 (CArH), 131.2 (CArH), 149.1
(CAr), 151.6 (CAr), 152.2 (CAr), 156.0 (CAr), 166.3 (CO), 166.6 (CO), 168.8
(CO); HRMS (ESI) calcd for C24H23N3O4Na: 440.1581; found: 440.1578.
d
0.86 (t, 3H, J¼7.2 Hz, CH3CH2),1.12 [t, 3H, J¼6.9
Hz, CON(CH2CH3)CH2CH3], 1.22 [t, 3H, J¼6.8 Hz, CON(CH2CH3)
CH2CH3],1.93e2.11 (m,1H, CH3CHH), 2.19e2.40 (m, 3H, CH3CHH and
NpyCH2CH2), 3.07e3.33 [m, 4H, CON(CH2CH3)CHHCH3, CON
(CHHCH3)CH2CH3 and NpyCH2CH2CH2], 3.41e3.55 [m, 1H, CON
(CH2CH3)CHHCH3], 3.82e3.98 [m, 1H, CON(CHHCH3)CH2CH3],
4.10e4.30 (m, 2H, NpyCH2), 6.69 (s, 1H, CpyH); 13C NMR (100 MHz):
Acknowledgements
d
7.5 (CH3CH2), 12.4 [CON(CH2CH3)CH2CH3], 14.7 [CON(CH2CH3)
CH2CH3], 21.3 (NpyCH2CH2), 31.9 (CH3CH2), 32.8 (NCH2CH2CH2), 42.7
[CON(CH2CH3)2] 48.8 (NpyCH2), 88.1 (CO2C), 98.5 (CpyH), 110.1
(COCpyCO), 156.4 (CpyNCO), 158.6 (CpyHCpyCpy), 166.3 (CO), 166.9
(CO), 168.3 (CO); HRMS (ESI) calcd for C17H22N2O4Na: 341.1472;
found: 341.1461.
We thank Dr. J. Einhorn for his interest in our work. Financial
ꢀ
support from Universite Joseph Fourier, the CNRS (UMR 5616,
FR2607), and the French Ministry of Research (stipend to F.G.) is
gratefully acknowledged.
Supplementary data
4.1.11. (ꢂ)-(E)-8-[(Dimethylamino)methylene]-1-ethyl-N,N-diethyl-
3,4-dioxo-1,3,4,6,7,8-hexahydrofuro[3,4-f]indolizine-1-carboxamide
(22). Bredereck’s reagent (0.025 mL, 0.121 mmol) was added to
a solution of pyridone 9 (16 mg, 0.050 mmol) in THF (0.8 mL). The
reaction mixture was refluxed for 45 min and then concentrated
under reduced pressure. The crude solid was triturated with ether to
give enamine 22 (17 mg, 89%) as an ochre solid: mp 157e159 ꢀC; IR
Copies of 1H and 13C NMR spectra of all new compounds. Sup-
plementary data related to this article can be found online at
doi:10.1016/j.tet.2011.02.017. These data include MOL files and
InChIKeys of themost important compounds describedin this article.
(cmꢁ1
1H NMR (400 MHz):
)
y
: 3107, 2975, 2936, 1746, 1619, 1534, 1378, 1280, 1113, 1048;
0.87 (t, 3H, J¼7.3 Hz, CH3CH2),1.12 [t, 3H, J¼7.0
References and notes
d
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