Stereoselective synthesis of 3-aryloctahydroindoles and application in a formal synthesis of (-)-pancracine

Article abstract of DOI:10.1021/ol902761a

[Chemical equation presented] A stereoselective synthesis of 3-aryloctahydroindoles from enantiomerically enriched y-nitroketones has been developed. Reduction of imines derived form the nitroketones provides the trans-fused octhaydroindole motif selectively. The cis-octahydroindole skeleton is accessible by an invertive cyclization strategy involving a diastereomerically pure nitromesylate intermediate. This approach was employed in the synthesis of an advanced intermediate to (-)-pancracine. The γ-nitroketone starting materials are readily available via an organocatalytic Michael reaction.

Full text of DOI:10.1021/ol902761a

ORGANIC
LETTERS
2010
Vol. 12, No. 3
556-559
Stereoselective Synthesis of
3-Aryloctahydroindoles and Application
in a Formal Synthesis of (-)-Pancracine
Sunil V. Pansare,* Rajinikanth Lingampally, and Raie Lene Kirby
Department of Chemistry, Memorial UniVersity, St. John’s,
Newfoundland, Canada A1B 3X7
spansare@mun.ca
Received November 30, 2009
ABSTRACT
A stereoselective synthesis of 3-aryloctahydroindoles from enantiomerically enriched γ-nitroketones has been developed. Reduction of imines
derived form the nitroketones provides the trans-fused octhaydroindole motif selectively. The cis-octahydroindole skeleton is accessible by
an invertive cyclization strategy involving a diastereomerically pure nitromesylate intermediate. This approach was employed in the synthesis
of an advanced intermediate to (-)-pancracine. The γ-nitroketone starting materials are readily available via an organocatalytic Michael reaction.
The octahydroindole ring system has attracted considerable
attention due to its importance in natural product chemistry
and medicine. For example, the octahydroindole motif is
found in several bioactive natural products such as the
Amaryllidaceae1 and sceletium1,2 alkaloids and also the
aeruginosins.3 Recently, applications of octahydroindole
scaffolds in the diversity-oriented synthesis of Amarylli-
daceae alkaloid type structures,4 glycomimetics,5 and gly-
cosidase inhibitors6 have been reported. The stereochemistry
of the ring junction in the octahydroindole influences its
biological profile. Thus, cis-octahydroindoles have been
utilized in peptide ꢀ-turn mimics7 and also have noradrena-
line uptake inhibitor activity,8 whereas the trans-octahy-
droindole motif has been employed in ACE inhibitors.9 The
synthesis of octahydroindoles therefore continues to be
actively investigated,10 and selective access to either the cis-
or the trans-octahydroindole motif is of particular interest.
Herein, we describe preliminary results on a simple, stereo-
selective approach to cis- or trans-3-aryloctahydroindoles
from readily available γ-nitroketone precursors.
(1) (a) Zhong, J. Nat. Prod. Rep. 2009, 26, 363, and references cited
therein. (b) Unver, N. Phytochem. ReV. 2007, 6, 125. (c) Rinner, U.;
Hudlicky, T. Synlett 2005, 3, 365.
(2) (a) Jeffs, P. W. Alkaloids 1981, 19, 1. (b) Hayashi, M.; Unno, T.;
(7) Kyle, D. J.; Green, L. M.; Blake, P. R.; Smithwick, D.; Summers,
M. F. Peptide Res. 1992, 5, 206.
Takahashi, M.; Ogasawara, K. Tetrahedron Lett. 2002, 43, 1462
.
(3) (a) Bonjoch, J.; Catena, J.; Isabal, E.; Lopez-Canet, M.; Valls, N.
Tetrahedron: Asymmetry 1996, 7, 1899. (b) Hoshina, Y.; Doi, T.; Takahashi,
T. Tetrahedron 2007, 63, 12740. (c) Hanessian, S.; Ersmark, K.; Wang,
X.; Del Valle, J. R.; Blomberg, N.; Xue, Y.; Fjellstrom, O. Biorg. Med.
Chem. Lett. 2007, 17, 3480. (d) Hanessian, S.; Wang, X.; Ersmark, K.; Del
Valle, J. R.; Klegraf, E. Org. Lett. 2009, 11, 4232.
(8) Boes, M.; Burkard, W. P.; Moreau, J. L.; Schoenholzer, P. HelV.
Chim. Acta 1990, 73, 932.
(9) Brion, F.; Marie, C.; Mackiewicz, P.; Roul, J. M.; Buendia, J.
Tetrahedron Lett. 1992, 33, 4889.
(10) Recent reports: (a) Cordero-Vargas, A.; Urbaneja, X.; Bonjoch, J.
Synlett 2007, 2379. (b) Saito, M.; Matsuo, J.; Ishibashi, H. Tetrahedron
2007, 63, 4865. (c) Reimann, E.; Ettmayr, C.; Polborn, K. Monatsh. Chem.
2004, 135, 557. (d) Hanessian, S.; Tremblay, M.; Petersen, J. F. W. J. Am.
Chem. Soc. 2004, 126, 6064. (e) Prevost, N.; Shipman, M. Tetrahedron
2002, 58, 7165.
(4) Keaney, G. F.; Johannes, C. W. Tetrahedron Lett. 2007, 48, 5411.
(5) Gravier-Pelletier, C.; Le Merrer, Y. Curr. Org. Synth. 2007, 4, 1.
(6) Gravier-Pelletier, C.; Maton, W.; Bertho, G.; Le Merrer, Y. Tetra-
hedron 2003, 59, 8721.
10.1021/ol902761a  2010 American Chemical Society
Published on Web 01/07/2010

Our interest in octahydroindoles stems from our studies
on the enantioselective organocatalytic synthesis of γ-ni-
troketones from cyclic ketones and 2-nitrovinyl arenes via
an enamine-based, organocatalytic Michael addition reac-
tion.11 A large number of studies12 have demonstrated the
utility of this reaction, and the development of new catalysts
for this reaction continues at a remarkable pace. Clearly, the
full potential of the organocatalytic ketone-nitroalkene
Michael reaction will be realized when the enantiomerically
enriched γ-nitroketone products find applications in other
synthetic endeavors.13
With this objective in mind, γ-nitroketones 112h-3 were
prepared by employing our secondary-secondary diamine
salt catalyzed Michael addition protocol.11 The nitroketones
were obtained in good yield and high diastereomeric and
enantiomeric excess. Partial reduction of the nitro group17c
in 1, 2, and 3 with Zn/aq NH4Cl provided the cyclic nitrones
4-6, respectively, in good yields (Scheme 1).
Scheme 1. Synthesis of 3-Arylhexahydroindole 1-Oxides
Generally, γ-nitrocarbonyl compounds can be converted
to the corresponding nitrones14 or pyrrolines15 selectively,
and these can serve as precursors to pyrrolidines.16 Hence,
at the outset, a stereoselective synthesis of octahydroindoles
from cyclohexanone-derived γ-nitroketones, by reduction of
the derived nitrones or imines,17 appeared attractive. Ste-
reocontrol in the reduction step may be anticipated to be a
function of the stereocenters R and/or ꢀ′ to the ketone. These
stereocenters, in turn, are readily set by the organocatalytic
Michael addition reaction. While a few reports describe the
reduction of tetrahydrobenzo[e]indole and tetrahydropyr-
rolo[f]quinoline ring systems (embedded imine functionality)
to the corresponding cis-fused hexahydro products,15 reduc-
tion of a hexahydro[2H]indole to a mixture of cis and trans
octahydroindoles is also reported.18 The challenges associated
with the conversion of tetralin-based γ-nitroketones into cis-
or trans-hexahydrobenz[e]indoles have been detailed in a
recent study.19 Evidently, methodology that provides ste-
reocontrolled access to octahydroindoles would be useful.
The nitrone 4 was chosen as a candidate for reduction
studies toward the octahydroindole system. Treatment of 4
with NaBH4 in methanol provided a 2/1 mixture of the cis-
and trans-hydroxylamines 7 and 8, respectively.20 A brief
survey of reducing conditions was conducted (Table 1) with
(11) (a) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624.
(b) Pansare, S. V.; Kirby, R. L. Tetrahedron 2009, 65, 4557.
(12) Reviews: (a) Kotsuki, H.; Ikishima, H.; Okuyama, A. Heterocycles
2008, 75, 757. (b) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007,
30, 3123. (c) Enders, D.; Seki, A. Eur. J. Org. Chem. 2002, 1877. (d) Review
on enamine catalysis: Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. ReV. 2007, 107, 5471. Selected recent reports: (e) Ni, B.; Zhang,
Q.; Dhungana, K.; Headley, A. D. Org. Lett. 2009, 11, 1041. (f) Mandal,
T.; Zhao, C.-G. Angew. Chem., Int. Ed. 2008, 47, 7714. (g) Almasi, D.;
Alonso, D. A.; Gomez-Benoga, E.; Nagel, Y.; Najera, C. Eur. J. Org. Chem.
2007, 2328. (h) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W.
Chem.sEur. J. 2006, 12, 4321.
Table 1. Reduction of Nitrone 4
(13) Recent reports: (a) Elsner, P.; Jiang, H.; Nielsen, J. B.; Pasi, F.;
Jorgensen, K. A. Chem.Commun. 2008, 5827. (b) Ruiz, N.; Reyes, E.;
Vicario, J. L.; Badia, D.; Carrillo, L.; Uria, U. Chem.sEur. J. 2008, 14,
9357. (c) Andrey, O.; Vidonne, A.; Alexakis, A. Tetrahedron Lett. 2003,
44, 7901. (d) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King,
S. A.; Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.;
Wittenberger, S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097.
(14) Hideg, K.; Lex, L. J. Chem. Soc., Perkin Trans. 1 1986, 1431.
(15) (a) Dickerson, T. J.; Lovell, T.; Meijler, M. M.; Noodleman, L.;
Janda, K. D. J. Org. Chem. 2004, 69, 6603. (b) Glassco, W.; Suchocki, J.;
Goerge, C.; Martin, B. R.; May, E. L. J. Med. Chem. 1993, 36, 3381. (c)
Chavdarian, C. G.; Seeman, J. I.; Wooten, J. B. J. Org. Chem. 1983, 48,
492.
entry
reducing agent/conditions
7/8
yield 7 + 8 (%)
1
2
3
4
5
6
7
8
NaBH4/MeOH, rt
NaBH(OAc)3, rt
NaBH3CN/AcOH, -10 °C
NaBH3CN/pivalic acid, 0 °C
L-Selectride
LiAlH4
H2, Pd/C, 1 atm
Pd/C, HCO2NH4
1.5/1
1/1
2/1
2.5/1
1/1
1/1
50
76
44
67
89
90
(16) Recent report: (a) Ruiz, N.; Reyes, E.; Vicario, J. L.; Badia, D.;
Carrillo, L.; Uria, U. Chem.sEur. J. 2008, 14, 9357. General review on
the synthesis of pyrrolidines: (b) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri,
A.; Petrini, M. Chem. ReV. 2005, 105, 933.
a
50
a trans-Octahydroindole 10 was obtained.
(17) (a) Rahaim, R. J., Jr.; Maleczka, R. E., Jr. Org. Lett. 2005, 7, 5087.
(b) Sanchez, I. H.; Larraza, M. I.; Rojas, I.; Kuri Brena, F.; Flores, H. J.;
Jankowski, K. Heterocycles 1985, 23, 3033. (c) Klutchko, S.; Sonntag, A. C.;
von Strandtmann, M.; Shavel, J. J. Org. Chem. 1973, 38, 3049.
(18) The catalytic hydrogenation of 3a-phenylhexahydro-2H-indole
provides a mixture of cis- and trans-octahydroindole products; see: Whitlock,
H. W., Jr.; Smith, G. L. J. Am. Chem. Soc. 1967, 89, 3600.
the objective of improving the cis/trans ratio. However,
selective reduction of 4 to 7 or 8 was not observed in any of
(20) Hydroxylamines 7 and 8 are only moderately stable at ambient
temperature and gradually decompose to the nitrone 4 in solution.
(19) Degnan, A. P.; Meyers, A. I. J. Org. Chem. 2000, 65, 3503.
Org. Lett., Vol. 12, No. 3, 2010
557

these experiments, and the best result was obtained with
sodium cyanoborohydride/pivalic acid (7/8 ) 2.5/1). Surpris-
ingly, the catalytic hydrogenation of 4 (H2, Pd/C, 1 or 3 atm;
H2, PtO2, 1 atm) in ethanol generated a mixture of products
which did not contain any of the anticipated hydroxy-
lamines.21 Transfer hydrogenation of 4 provided the trans-
octahydroindole product. This stereochemical result is com-
parable to previous observations by Sanchez on the catalytic
hydrogenation (RaNi, i-PrOH, 50 psi, 55 °C) of an analogue
of 1, lacking the dioxolane functionality, which provided only
the corresponding trans-octahydroindole (presumably by
reduction of the nitrone formed in situ).17b Hydrogenation
of 1 under less forcing conditions (RaNi, 45 psi, EtOH,
ambient temperature) provided the pyrroline analogue (imine)
of nitrone 4.
tetrathiomolybdate.24 This method was also applicable to the
nitrones 5 and 6 to provide the imines 12 and 13, respec-
tively, in reasonable yields (Table 2). Curiously, reduction
Table 2. Conversion of Nitrones 4-6 to trans-Octahydroindoles
compd
Ar
R
yield (%)
trans/cis
11
12
13
10
14
15
a
3,4-(OCH2O)Ph
4-OMePh
2-naphthyl
3,4-(OCH2O)Ph
4-OMePh
2-naphthyl
1
O(CH2)2O
H
H
O(CH2)2O
H
H
70
62
64
75
75
72
Hydroxylamines 7 and 8 were separated and reduced with
indium metal22 to the cis-octahydroindole 9 and its trans
isomer 10, respectively (Scheme 2). The stereochemical
10/1
>19/1a
6/1
Single diastereomer by H NMR
Scheme 2
.
Reduction of Hydroxylamines 7 and 8
of the imines with NaBH4 provided the trans-octahydroin-
doles25 as the major products (Table 2) with some of the cis
product being observed (1H NMR) only in the reduction of
11 and 13 (trans/cis ratio of 10/1 and 6/1, respectively). The
reasons for the marked difference in stereoselectivity of
reduction of the nitrone 4 and the imine 11 as well as the
imines 12 and 13 are not apparent. Also, the dependence of
trans/cis ratios on the nature of the relatively similar 3-aryl
substituents in 11-13 is intriguing.
Although the imine reduction method provides access to
the trans 3-aryloctahydroindoles as major products, the cis
isomers are not available in good yield from either the
nitrones or the imines. Therefore, an alternative approach
was examined for which 9 was chosen as the representative
target. We reasoned that a strategy involving the direct
assembly of the pyrrolidine ring by stereoselective C-N
bond formation from an appropriate precursor derived from
the nitroketone 1 would be more fruitful. Toward this end,
the γ-nitroketone 1 was subjected to a stereoselective
reduction with L-Selectride to provide the nitro alcohol 16
(axial alcohol) as a single diastereomer (Scheme 4). A
Mitsunobu reaction of alcohol 16 (Ph3P, di-2-methoxyethy-
lazodicarboxylate (DMEAD),26 4-nitrobenzoic acid) followed
by hydrolysis of the 4-nitrobenzoate provided the nitro
alcohol 17 (equatorial alcohol) as a single diastereomer.27
Mesylation of 17 provided the key substrate for the ring
1
assignments are based on H NMR data for the N-Cbz
derivative of 9 which is in agreement with that reported in
the literature.23 It is noteworthy that 9 is a known intermedi-
ate to the montanine-type Amaryllidaceae alkaloids, par-
ticularly (-)-pancracine.23 Given the lack of stereoselectivity
in the reduction of nitrone 4 and the known cis selectivity
in the reduction of a tetrahydrobenzo[e]indole system,15b,c
we turned our attention to the reduction of the imine analog
of 4 as an alternative approach to the corresponding cis-
octahydroindole. Although the required imine 11 can be
obtained (along with nitrone 4) by reduction of the nitroke-
tone 1 with Zn/acetic acid, a more efficient route involves
deoxygenation of the nitrone 4 with benzyltriethylammonium
(21) Torsell, K. G. B. Nitrile Oxides, Nitrones and Nitronates in Organic
Synthesis; VCH Publishers: Weinheim, 1988.
(22) Cicchi, S.; Bonanni, M.; Cardona, F.; Revuelta, J.; Goti, A. Org.
Lett. 2003, 5, 1773.
(23) Ikeda, M.; Hamada, M.; Yamashita, T.; Matsui, K.; Sato, T.;
Ishibashi, H. J. Chem. Soc., Perkin Trans. 1 1999, 1949. A one-step catalytic
hydrogenation (H2, Pd/C) of 4 to 9 is envisioned as an approach to the
montanine alkaloids in a patent; see: Wang, W.; Wang, J.; Li, H. WO
2006007586. However, the actual implementation of this proposal is not
described. Application of the organocatalytic Michael reaction to the
synthesis of montanine alkaloids has also been indicated in a conference
abstract; see: Wang, W.; Wang, J.; Li, H. Abstracts of Papers, 229th ACS
National Meeting 2005, ORGN-356. However, to the best of our knowledge,
a detailed report has not appeared in the journal literature. The earlier work
by Sanchez17b and our results with 4 suggest that the stereoselective
synthesis of cis-3-aryloctahydroindoles such as 9 by the catalytic hydrogena-
tion of nitroketones such as 1 or nitrones such as 4 is challenging.
(24) Ilankumaran, P.; Chandrasekaran, S. Tetrahedron Lett. 1995, 36,
4881.
(25) The stereochemical assignments are based on the similarities in
1
the H NMR spectra of 10, 14, and 15.
(26) The use of DMEAD, which is reduced to a water-soluble hydrazine
dicarboxylate, simplifies the purification of the Mitsunobu product. (a)
Sugimura, T.; Hagiya, K. Chem. Lett. 2007, 36, 566. (b) Haigya, K.;
Marumoto, N.; Misaki, T.; Sugimura, T. Tetrahedron 2009, 65, 6109.
DMEAD is commercially available.
(27) The ketone 1 was unreactive toward i-Bu2AlOi-Pr, a reducing agent
that is known to selectively generate equatorial alcohols from cyclic ketones;
see: (a) Cha, J. S.; Kwon, O. O. J. Org. Chem. 1997, 62, 3019. (b) Bahia,
P. S.; Jones, M. A.; Snaith, J. S. J. Org. Chem. 2004, 69, 9289.
558
Org. Lett., Vol. 12, No. 3, 2010

closure reaction. Gratifyingly, reduction of the nitro group
in the mesylate with Fe/NH4Cl directly provided the cis-
octahydroindole 9 as a single diastereomer in excellent yield
(97%, Scheme 3). This result is indicative of an SN2-type
Scheme 4. Conversion of 9 to (-)-Pancracine Intermediate 19
Scheme 3. Synthesis of cis-Octahydroindole 9
highlight the utility of the organocatalytic synthesis of
γ-nitroketones. Current efforts focus on other reactions of
bicyclic nitrones related to 4.
Acknowledgment. These investigations were supported
by the Natural Sciences and Engineering Research Council
of Canada and the Canada Foundation for Innovation.
reaction of the intermediate amino mesylate which proceeds
with complete inversion at the ring junction. It is reasonable
to assume that the overall conversion of 1 to 9 is representa-
tive of a general approach to cis-octahydroindoles from
cyclohexanone-derived γ-nitroketones. The efficiency of the
intramolecular nucleophilic displacement should render this
strategy relatively insensitive to substitution in the γ-ni-
troketone starting material. Having established a stereose-
lective synthesis of the cis-octahydroindole 9, we proceeded
to utilize 9 in a formal synthesis of (-)-pancracine.28
Treatment of 9 with aqueous formaldehyde followed by
removal of the acetal protecting group, by adaptation of the
literature method,23 provided the methanomorphanthridine
18. Oxidation of 18 with DDQ, as described by Hoshino,28g
provided 19 which is an advanced intermediate in the
Overman synthesis of (-)-pancracine.28c (Scheme 4). In
conclusion, a stereoselective synthesis of cis- as well as trans-
3-aryloctahydroindoles was developed from enantiomerically
enriched γ-nitroketones. The methodology was applied in a
short formal synthesis of (-)-pancracine. These studies
Supporting Information Available: Experimental meth-
ods, spectroscopic data, 1H and 13C data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902761A
(28) Synthesis of (-)-pancracine : (a) Jin, J.; Weinreb, S. M. J. Am.
Chem. Soc. 1997, 119, 2050. (b) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc.
1997, 119, 5773. (c) Overman, L. E.; Shim, J. J. Org. Chem. 1993, 58,
4662. Formal synthesis of (-)-pancracine: (d) Anada, M.; Tanaka, M.;
Shimada, N.; Nambu, H.; Yamawaki, M.; Hashimoto, S. Tetrahedron 2009,
65, 3069. Formal synthesis of (+)-pancracine: (e) Chang, M.-Y.; Chen,
H.-P.; Lin, C.-Y.; Pai, C.-Li. Heterocycles 2005, 65, 1999. Synthesis of
racemic pancracine: (f) Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.;
Kemmler, M. J. Chem. Soc., Perkin Trans. 1 2001, 1345. (g) Ishizaki, M.;
Kurihara, K.-I.; Tanazawa, E.; Hoshino, O. J. Chem. Soc. Perkin Trans. 1
1993, 101. (h) Ishizaki, M.; Hoshino, O.; Iitaka, Y. J. Org. Chem. 1992,
57, 7285. (i) Ishizaki, M.; Hoshino, O.; Iitaka, Y. Tetrahedron Lett. 1991,
32, 7079. (j) Overman, L. E.; Shim, J. J. Org. Chem. 1991, 56, 5005. Formal
synthesis of racemic pancracine: (k) Pandey, G.; Banerjee, P.; Kumar, R.;
Puranik, V. G. Org. Lett. 2005, 7, 3713. (l) Ikeda, M.; Hamada, M.;
Yamashita, T.; Ikegami, F.; Sato, T.; Ishibashi, H. Synlett 1998, 1246. Also
see ref 23.
Org. Lett., Vol. 12, No. 3, 2010
559