cis-3a-(o-nitrophenyl)octahydroindol-4-one. Building blocks for the synthesis of indole alkaloids

Article abstract of DOI:10.1016/S0040-4039(00)93461-0

A four-step synthesis of 3a-aryloctahydroindol-4-ones (1) in which the key step is the ozonolysis of 2-allyl-2-(o-nitrophenyl)-1,3-cyclohexanedione (5) followed by reductive aminocyclization was been accomplished. An asymmetric synthesis of the bicyclic s

Full text of DOI:10.1016/S0040-4039(00)93461-0

Tetzahedron Letters, Vol.32, No.38, pp 5183-5186, 1991
Printed inGreat Britain
0040-4039/91 $3.00+ .00
Pergamon Press plc
cis-3a-(o-Nitrophenyl)octahydroindol.4.ones.
Building Blocks for the Synthesis of Indole Alkaloids
Daniel Sola and Josep Bonjoch*
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028-Barcelona, Spain
Key Words: 3a-Aryloctahydroindol-4-ones; reductive aminocyclization; indole alkaloids; asymmetric synthesis
Abstract- A four-step synthesis of 3a-aryloctahydroindol-4-ones (1) in which the key step is the
ozonolysis of 2-allyl-2-(o-nitrophenyl)-l,3-cyclohexanedione (5) followed by reductive aminocyclization has
been accomplished. An asymmetric synthesis of the bicyclic system 1 from chiral amines is achieved by
means of this procedure.
The preparation of cis-3a-aryloctahydroindol-4-ones has been developed so far only in the context of the
synthesis of Amaryllidaceae alkaloids, where the aryl group is 3,4-methylenedioxyphenyl. In the first synthesis
by Whitlock and Smith1 the last key step consists in the closure of the pyrrolidine ring by formation of the C3-C3a
bond from a 2-phenyl-3-aziridinyl-2-cyclohexenone. In the last years, Overman has exploited the tandem cationic
aza-Cope rearrangement/Mannich cyclization2 for the preparation of this type of compounds using 2-amino-1-(1-
arylvinyl)cyclopentanols as intermediates (last bond formed C3a-C7a).
O
6
N-C7a
Ar
cj~
I
S c h e m e
1
R
In this paper we describe a concise synthesis of 3a-(o-nitrophenyl)octahydroindol-4-ones (1), a class of
compounds that can be considered valuable synthetic precursors of the indole alkaloids possessing the hexahydro-
a.....five-membered ring:
21-norpandolan-type alkaloids
..... six-membered ring:
Aspidosperma alkaloids
b.....six-membered ring:
Strychnos alkaloids
-NO2
5183

5184
pyrrolo[2,3-d]carbazole unit such as Strychnos,3 Aspidosperma,4 and 21-norpandolan type5 alkaloids.
Our approach implies the elaboration of the pyrrolidine ring by introduction of the amine moiety into an
appropriate carbocyclic derivative by means of a double reductive amination. The first one, in an intermolecular
way, upon the aldehyde group of the tricarbonyl derivative resulting from the ozonolysis of 2-allyl-2-(o-
nitrophenyl)-l,3-cyclohexanedione (5) and the second one, in an intramolecular manner, upon one of the two
enantiotopic ketone carbonyl groups.6
The required dione 5, having the crucial quaternary C-3a center, was prepared from 1,3-cyclohexanedione
(Scheme 2) through a three-step sequence involving arylation with o-fluoronitrobenzene, O-allylation of the enolic
arylated derivative 3 and, finally, Claisen rearrangement of the resulting O-allyl vinyl ether 4.7
o
i
ii
3
4
oo2
O- ~ N O2
O-~NO2
~
+
V
_
R
R
5
1
2
R
yield (%) 5 >1 + 2
1 / 2 ratio
. . . . . . . . . . . . . . . .
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a
b
c
d
e
CH2CO2Et
CH3
CH2C6H5
CH2CH2SeC6H5
(R)-CH(CH3)C6H5
51
62
56
41
35
1:1
1.5:1
2.1:1
2.5:1
4:1
Reagents and conditions: (i) o-fluoronitrobenzene, K2CO3, DMSO, 3h, 75°C (30%); (ii) BrCH2CH=CH2,
K2CO3, acetone, rfx, 3h (81%); (iii) toluene, 180-190°C, overnight (85%); (iv) 03, CH2CI2, -78°C, 5 min; (v)
RNH2.HCI, NaBH3CN, MeOH, 4 h, rt.
S c h e m e
2
The conversion of 5 to the target 3a-(o-nitrophenyl)octahydroindolone systems 1 was effected through a
one-pot procedure that involves six successive chemical transformations: ozonolysis of the allyl group, ozonide
cleavage with sodium cyanoborohydride, aldimine formation, aldimine reduction, cyclization, ar)d further
reduction of the resulting N-C7a iminium salt.8 Even though the process failed with ammonium chloride, the N-
unsubstituted octahydroindole If (1, R = H) could be obtained in excellent yield (80%) by treatment (1,2-
dichloroethane, 3 h, 80°C) of lb with 1-chloroethyl chloroforrnate10 and further refluxing in methanol.

5185
In all cases both epimers were easily separated by flash chromatography;7, t1 in each series the trans isomer
(2) eluted first, whereas the cis isomer (1) appeared as the more polar epimer. The cis stereochemistry of
compounds 1 as well as their preferred conformation was apparent from the NMR data. Thus, the 7a-methine
proton appears as a doublet of doublets (J = 6.6 and 3.7 Hz), which is consistent only with an equatorial
disposition of 7a-H with respect to the cyclohexane ring. The 13C-NMR chemical shifts of C-6 and C-7a for both
epimers corroborate this assignment. Other characteristic differences between the two epimers, probably due to a
different conformation along the C3a-Ar bond, are: (i) the carbonyl IR absorption, which appears at 1715 cm-I in
the trans epimers but at 1698 cm-1 in the cis isomers; (ii) the 1H-NMR chemical shift of the most deshielded
aromatic proton, which appears as a doublet at 8 8.90 (+ 0.1 ppm) in the trans-derivatives 2, but at ~ 7.80 (+0.1
ppm) in the cis series 1.
Ar
O
Ar
O
N ~ R
1
H
2
Ar --- o-nitrophenyl
1 3 C - N M R Data of 3 a - ( o - N i t r o p h e n y i ) o c t a h y d r o i n d o l - 4 - o n e s
1
and 2a
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l a
l b
51.8
l c
l d
le
If
2a
2b
2c
2d
53.7
30.0
63.1
207.4
38.7
23.1
25.6
76.2
50.l
2e
45.1
30.0
63.0
207.7
38.7
23.7
25.8
74.5
58.9
14.6
2-C
48.7
33.6
61.7
208.6
37.1
19.8
23.0
68.3
51.6
170.8
48.5
33.5
62.1
50.3
33.3
61.9
47.4
33.4
62.0
44.2
34.9
64.4
50.9
30.3
62.7
53.3
30.1
63.3
50.9
30.0
63.2
3-C
33.2
62.4
3a-C
4-C
208.5
37.8
20.5
22.4
70.2
38.1
209.0
37.2
19.8
22.1
68.6
54.8
208.8 209.4
209.5
36.2
20.1
27.9
67.3
207.2 207.4
207.3
38.8
23.3
25.7
76.9
59.0
5-C
37.1
19.7
22.2
68.7
48.4
27.0
36.8
19.5
20.7
66.1
59.0
22.2
38.5
23.1
38.6
22.7
25.7
78.4
40.8
6-C
7-C
25.6
7a-C
Other
75.4
54.3
171.2
60.6; 14.0
27.2
60.2; 13.8
a Recorded in CDC13; 8 values in ppm from TMS.
When the chiral (R)-~-methylbenzylamine was used, the process displayed a good level of diastereo-
selection. The ratio of the diastereomeric products obtained (78:15:5:2) in this reaction was determined by
analytical HPLC as well as by column chromatography. The configuration of the new stereogenic centers in the
major epimer was assigned as 3aR, 7aS from its NMR data and by comparison with a related compound. 12 The
utilization of the products and the application of the processes reported in this letter to the synthesis of indole
alkaloids is in progress.

5186
Acknowledgment. Support for this research was provided by DGICYT (Spain) through Grant PB88-0316.
D. S. thanks the Pedro i Pons Foundation (Barcelona) for a fellowship.
R E F E R E N C E S AND N O T E S
1. Whitlock, H. W.; Smith, G. L. J. Am. Chem. Soc. 1967, 89, 3600-3606.
2. Overman, L. E.; Mendelson, L. T.; Jacobsen, E. J. J. Am. Chem. Soc. 1983, 105, 6629-6637.
3. For a review, see: Bosch, J.; Bonjoch, J. in "Studies in Natural Products Chemistry", vol. 1, Atta-ur-
Rahman, ed.; Elsevier: Amsterdam, 1988; pp. 31-88.
4. For a review, see: Overman, L. E.; Sworin, M. in "Alkaloids: Chemical and Biological Perspectives",
vol.3, Pelletier, S. W., ed.; Wiley, New York, 1984; pp 275-307.
5. Kan, C.; Husson, H.-P.; Jacquemin, H.; Kan, S.-K.; Lounasmaa, L. Tetrahedron Lett. 1980, 21, 55-58.
6. For a one-pot ozonolysis-reductive amination intermolecular sequence, see: Martin, S. F.; Puckette, T.
A.; Colapret, J. A. J. Org. Chem. 1979, 44, 3391-3396.
7. All compounds reported were homogeneous by TLC analysis and showed 1H-NMR, I3C-NMR, and IR
spectra consistent with the assigned structures. All yields are from material purified by flash column
chromatography. The molecular composition of all compounds was determined by combustion analysis.
8. In some runs the nine-membered lactone 67 was formed as a by-product
(<5% yield). Reduction of the initially formed aldehyde followed by attack of
the resulting alkoxy group to one of the ketone carbonyl groups with
subsequent ring enlargement9 accounts for its formation. When the reaction
was conduced without the amine, lactone 6 was isolated in 31% yield (not
optimized). IR (NaC1) 1740, 1708, 1526, and 1351 cm-1; 13C-NMR (50
MHz, CDC13) 22.1 (4-C), 33.4 (8-C), 35.8 (3-C), 42.2 (5-C), 50.3 (7-C),
61.6 (9-C), 124.0 (3'-C), 127.9 (4'-C), 130.3 (6'-C), 133.3 (5'-C), 133.4
(I'-C), 149.5 (2'-C), 172.3 (2-C), 211.5 (6-C).
( ~ - - - - ~
N
I
,,,v,,,,'-,,,~,O
I
I
6
O
9. (a) Stach, H.; Hesse, M. Tetrahedron 1988, 44, 1573-1590. (b) Ohnuma, T.; Tabe, M.; Shiiya, K.;
Ban, Y. Tetrahedron Lett. 1983, 24, 4249-4252 and preceeding papers.
10. Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T. J. Org. Chem. 1984, 49, 2081-2082.
11. Treatment of 2b under acidic conditions (0.1 N HC1, rfx, 24 h or AcOH, 90°C, overnight) in order to
equilibrate both epimers via a retro-Mannich/cyclization sequence gave no trace of the cis derivative lb.
Similarly, 2b was not detected when lb was refluxed in the presence ofp-TsOH (THF, overnight).
12. le(3aR, 7aS): [tX]D= + 22.8 (C, 2.0, CH3OH). The aliphatic 1H-NMR signals due to the tx-methylbenzyl
chain appear at 8 1.17 (d) and 3.66 (q), whereas in the related derivative (3aS, 7aR)-1-[(R)-ot-methyl-
benzyl]-3a-[3,4-(methylenedioxy)phenyl]-l,2,3,3a,5,6,7,7a-octahydroindol-4-one
(L. E. Overman and S.
Sugai, Helv.Chim. Acta 1985, 68, 745-749) the resonances occur at ~ 1.34 (d) and 6 4.14 (q).
(Received in UK 8 July 1991)