Ethylene in organic synthesis: A new route to anticholenergic pyrrolidinoindolines, and other molecules with all carbon-quaternary centers via asymmetric hydrovinylation

Article abstract of DOI:10.1021/ol203052y

The asymmetric hydrovinylation (1 mol % Ni-cat., 1 atm, ethylene, >98% ee) products from 1-methylenetetralines are readily converted into 3, 3-disubstituted oxindoles and subsequently to pyrrolidinoindolines. These hydrovinylation products are also useful for the syntheses of enantiopure benzomorphans.

Full text of DOI:10.1021/ol203052y

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6596–6599
Ethylene in Organic Synthesis: A New
Route to Anticholenergic
Pyrrolidinoindolines, and Other Molecules
with All Carbon-Quaternary Centers via
Asymmetric Hydrovinylation
Hwan Jung Lim and T. V. RajanBabu*
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus,
Ohio 43210, United States
rajanbabu.1@osu.edu
Received November 12, 2011
ABSTRACT
The asymmetric hydrovinylation (1 mol % Ni-cat., 1 atm, ethylene, >98% ee) products from 1-methylenetetralines are readily converted into 3,
3-disubstituted oxindoles and subsequently to pyrrolidinoindolines. These hydrovinylation products are also useful for the syntheses of
enantiopure benzomorphans.
An all-carbon quaternary center at a benzylic posi-
tion is a structural motif that is common to many
pharmaceutically relevant classes of compounds. These
include acetylcholine esterase inhibitor (ꢀ)-physostigmine
and analogous pyrrolidinoindolines,1,2 analgesics3
(þ)-aphanorphine and (ꢀ)-eptazocine, and cytotoxic,
phenolic diterpenoids like (ꢀ)-standishinal4 (Figure 1).
The major challenge in the synthesis of these com-
pounds is the installation of the all-carbon quaternary
center, a topic that is of considerable topical interest.5 In
the context of the benzylic quaternary center in the
molecules listed above, many of the well-known enan-
tioselective CꢀC bond-forming reactions have been
employed with varying degrees of success. These include
the intramolecular Heck reaction,2h,3l,4b Ni-catalyzed
intramolecular arylcyanation,2d Pd-catalyzed intramo-
lecular cyano-amidation,2e Mo-catalyzed intermolecular
(1) Reviews on pyrrolidinoindolines and their biological activities:
(a) Anthoni, U.; Christophersen, C.; Nielsen, P. H. InAlkaloids: Chemical
and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1999;
Vol. 13, pp 163ꢀ236. (b) Takano, S.; Ogasawara, K. In The Alkaloids;
Brossi, A., Ed.; Academic: San Diego, CA, 1989; Vol. 36, pp 225ꢀ251.
(c) Greig, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.; Brossi, A.
Med. Res. Rev. 1995, 15, 3.
Figure 1. Medicinally important molecules containing an all-
carbon benzylic quaternary center.
r
10.1021/ol203052y
Published on Web 11/21/2011
2011 American Chemical Society

enantioselectivity (Scheme 1).6 Thus, under optimized
conditions, with as little as 1ꢀ4 mol % of a Ni(II) catalyst
prepared from [(allyl)NiBr]2, a phosphoramidite ligand 8
and a highly dissociated counteranion (BARFꢀ), proto-
typical substrates 9 and 10 gave the respective adducts 11
and 12 in >98% ee. Despite the modest yield in one of
these reactions [11 (82%), the rest rearranged starting
material, 1-methyl-7-methoxy-3,4-dihydronaphthalene)6a],
this two-step procedure from a ketone represents a major
improvement over the best routes previously reported for
the synthesis of this important class of compounds. For
example, 11 has been previously synthesized via stoichio-
metric oxazoline-directed alkylation (12 steps, 35% overall
yield, 99% ee)3k or an enzyme-catalyzed desymmetrization
of an R,R-disubstituted meso-dimethylmalonate (13 steps,
31% overall yield, 97% ee).3i Shibasaki et al. prepared a
closely related compound using an asymmetric intramole-
cular Heck reaction (∼10 steps, 37% yield, 93% ee).3l The
compound 12 has been prepared in ∼51% yield (92% ee)
from acetophenone in 4 steps using an enantioselective Cu-
catalyzed allylic alkylation, which uses 5 mol % of a
catalyst and 3 equivalents of Et2Zn.7 As a logical extension
of our work, we have been exploring applications of this
chemistry for the synthesis of biologically relevant targets,
and here we describe an approach to pyrrolidinoindolines.
Further applications for the syntheses of benzomorphan
analogs (ꢀ)-eptazocine and (þ)-aphanorphine are also
discussed.
Scheme 1. All Carbon Quaternary Centers via Catalytic Asym-
metric Hydrovinylation
allylation,2f Pd-catalyzed intramolecular allylation,4d
thiourea-2b,c or quaternary ammonium-2i catalyzed alky-
lation of an oxindole anion, (R)-BINOL-SnCl4-catalyzed
[3 þ 2]-cycloaddition,2a intramolecular FriedelꢀCrafts
alkylation,3a and Pd-catalyzed R-arylation of an enolate.4e
Recently our group reported highly enantioselective
Ni-catalyzed asymmetric hydrovinylation of R-alkylviny-
larenes in which a benzylic, all-carbon quaternary center
is generated in high yield and exceptionally high
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(9) See the Supporting Information for the details of the X-ray
crystallographic analysis of 21 and 27. An ORTEP of 21 and 27 with
more legible atom-numbering is also included there.
Org. Lett., Vol. 13, No. 24, 2011
6597

Scheme 2. Synthesis of Pyrrolidinoindolines via Asymmetric
Hydrovinylation
Figure 2. Solid-state structures of 21 and 2710.
Predictably, the corresponding Schmidt reaction,11 which
relies on the intermediacy of a hydroxy-azide, where no
such stereochemical constraint is possible, is a much less
selective reaction, giving a mixture of benzazepinones 20
and 28 (eq 1).12
The azepinone 21 undergoes facile acid-induced re-
arrangement to a more stable oxindole carboxylic acid 22
in excellent yield. 3,3-Disubstituted oxindoles have been
used extensively for enantioselective synthesis of pyrroli-
dinoindolines and several other natural products.2bꢀf,h,i,n
Besides, this class of compounds are important in their
own right, and, considerable effort has been expended on
their syththeses.13,14 Curtius rearrangement using diphe-
nylphosphorylazide (DPPA) in the presence of ethanol
gives a urethane 23, which upon reduction with LAH
gives, the natural product (ꢀ)-desoxyeseroline.15 This
(10) Initially we resorted to the Beckmann rearrangement of the
oxime 25, which was readily prepared from the hydrovinylation product
15 in two steps. Beckmann rearrangement of the δ-alkenyloxime 25 did
not lead to the expected product 26; it presumably underwent a deep-
seated rearrangement to give a benzopyrrolizidine 27 in racemic form as
determined by X-ray crystallography (space group P2(1)/n). See Sup-
porting Information for details of the crystallographic analysis and a
possible mechanism for the formation of this racemic product from a
nearly enantio-pure starting material.
An enantioselective synthesis of pyrrolidinoindolines
starting from the hydrovinylation product 15 is shown in
Scheme 2. This product can be prepared in gram quantities
in enantiomerically pure form from 2-tetralone in two
steps.6b,c The alkene 15 was oxidized with RuCl3/NaIO4,8
and the resulting carboxylic acid 16 was protected as a
methyl ester (17). Subsequent benzylic oxidation with
CrO3 gave the ketone 18. Beckman ring expansion of the
corresponding oxime 19 and methylation proceeded in
excellent yield to give a tetrahydroazepinone 21, a highly
crystalline compound, whose structure was unequivocally
established by X-ray crystallography (Figure 2).9,10
Attempted Beckmann Rearrangement of a δ-Alkenyloxime:
The high regioselectivity of the successful Beckmann
rearrangement of the oxime 21 can be understood in terms
of the configuration of the corresponding oxime. At room
temperature only one stereoisomer of the oxime, presum-
1
ably the (E)-form, is seen in both H and 13C NMR.
6598
Org. Lett., Vol. 13, No. 24, 2011

(>98% ee) 1-methyl-1-vinyl-tetrahydronaphthalenes in
moderate to high yield (70ꢀ82%). This intermolecular
CꢀC bond-forming process delivers these valuable inter-
mediates in a significantly fewer number of steps compared
to the more classical routes. Conversion of the terminal
alkene to a carboxylic acid followed by benzylic oxidation
gives 4,4-disubstituted tetralones. Regioselective Beckmann
rearrangement of the corresponding oximes gives 4,4-
dialkyl benzazepinones, which serve as intermediates for
the syntheses of highly valuable 3,3-dialkylated oxi-
ndoles. Use of such oxindoles for the syntheses of pyrroli-
dinoindolines is illustrated. Finally it should be noted
that the chemistry outlined in Scheme 3 should be compa-
tible with a MeO-susbstituent on the aromatic ring, and if so,
specific targets such as (ꢀ)-esermethole could be prepared
more directly starting with the HV-product 11 (Scheme 1) in
∼<10 steps from commercially available precursors.
Scheme 3. Synthesis of Benzomorphans from Products of
Asymmetric Hydrovinylation
Acknowledgment. Financial assistance for this re-
search provided by US National Institutes of Health
(General Medical Sciences, R01 GM075107) is grate-
fully acknowledged. We also thank Dr. Judith C.
Gallucci for the X-ray crystallography of 21 and 27.
compound is a key intermediate in the synthesis of a
number of pyrrolidinoindolines including (ꢀ)-esermethole.2r
Esermethole has been converted into (ꢀ)-physostig-
mine2s,16a,b and (ꢀ)-phenserine.16b
Finally, we anticipate the intermediates such as 11
(Scheme 1) and 15 (Scheme 2), synthesized in two steps
from the corresponding tetralones in nearly enantio-
merically pure form, to have broad applicability in the
synthesis of benzomorphan analogs. For example, the
alkene 11 has been converted into (ꢀ)-eptazocine by
Meyers3k using chemistry developed earlier by Shibasaki.3l
Likewise, the aldehyde 29 (previous bezst: 11 steps
from 7-methoxytetralone3k), easily obtained by oxidative
degradation of 11, intercepts the synthesis of aphanor-
phine by Shiotani.3j
Supporting Information Available. Details of the ex-
perimental procedures, spectroscopic and chromato-
graphic data for key compounds. Crystallographic Infor-
mation Files. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) For additional examples of enantioselective syntheses of of 3,
3-disubstituted oxindoles, see the following references and others cited
therein:(a) Luan, X.; Wu, L.; Drinkel, E.; Mariz, R.; Gatti, M.; Dorta,
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€
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€
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M. W.; Krapcho., J.; White, R. E.; Ridgewell, R. E.; Obermeier, M. T.;
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€
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