Tandem overman rearrangement and intramolecular amidomercuration reactions. Stereocontrolled synthesis of cis- and frans-2,6-dialkylpiperidines

Article abstract of DOI:10.1021/ol048961w

(Chemical Equation Presented) Hg(II)-mediated tandem Overman rearrangement and intramolecular amidomercuration reactions were proven to provide a convenient tool for the stereoselective synthesis of cis- and frans-2,6-disubstituted piperidines. Thus, upon treatment with Hg(OTFA) ₂ in THF, the trichloroacetimidate 1 directly transformed into the 2,6-dialkyl piperidine 2 with almost exclusive trans selectivity. The amiodomercuration reaction of the carbamate 7 by Hg(OTFA)₂ in nitromethane showed an excellent cis selectivity. Also reported is the stereoselective synthesis of solenopsin A and isosolenopsin A.

Full text of DOI:10.1021/ol048961w

ORGANIC
LETTERS
2004
Vol. 6, No. 18
3067-3070
Tandem Overman Rearrangement and
Intramolecular Amidomercuration
Reactions. Stereocontrolled Synthesis of
cis- and trans-2,6-Dialkylpiperidines
Om V. Singh and Hyunsoo Han*
Department of Chemistry, The UniVersity of Texas at San Antonio,
6900 N. Loop 1604 West, San Antonio, Texas 78249
hhan@utsa.edu
Received June 4, 2004
ABSTRACT
Hg(II)-mediated tandem Overman rearrangement and intramolecular amidomercuration reactions were proven to provide a convenient tool for
the stereoselective synthesis of cis- and trans-2,6-disubstituted piperidines. Thus, upon treatment with Hg(OTFA)2 in THF, the trichloroacetimidate
1 directly transformed into the 2,6-dialkyl piperidine 2 with almost exclusive trans selectivity. The amiodomercuration reaction of the carbamate
7 by Hg(OTFA)2 in nitromethane showed an excellent cis selectivity. Also reported is the stereoselective synthesis of solenopsin A and
isosolenopsin A.
Substituted piperidine ring compounds are abundant in
nature, and their therapeutic potential has been a subject of
intensive research.1,2 Particularly, 2,6-disubstituted pip-
eridines have attracted much attention in both academia and
the pharmaceutical industry because they are one of the most
common piperidine skeletons and are found in many
pharmaceutically interesting compounds. They appear in
various ring forms (Figure 1) and exhibit a broad range of
biological activitites. For examples, solenopsin A and iso-
solenopsin A, which are active ingredients in the venom of
fire ants, showed cytotoxic, haemolytic, necrotic, insecticidal,
antibacterial, antifungal, and anti-HIV properties, as well as
activities as neuronal nitric oxide synthase inhibitors.3
Clavepictines have cytotoxic activities against various cancer
cell lines,4 and precoccinelline is one of defense alkaloids
in ladybird beetles.5 As a consequence, numerous synthetic
methods have been developed for the stereoselective syn-
thesis of 2,6-disubstituted piperidines.2 However, most of
them were directed toward the synthesis of either trans-2,6-
dialkylpiperidines7 or cis-2,6-dialkylpiperidines.8 Methodolo-
gies for the stereoselective synthesis of both cis- and trans-
(1) (a) Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S.
W., Ed.; Wiley: New York, 1985; Vol. 3. (b) Alkaloids: Chemical and
Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon: Oxford, UK, 1996;
Vol. 10. (c) Michael, J. P. Nat. Prod. Rep. 2001, 18, 520-542.
Figure 1. Three widely found structures containing a 2,6-
disubstituted piperidine framework.
(2) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681.
10.1021/ol048961w CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/31/2004

2,6-dialkylpiperidines from a common intermediate have
been sporadic in the literature.9 Therefore, there is still
considerable interest in developing methodologies that not
only allow the stereoselective synthesis of 2,6-dialkylpip-
eridines but also are efficient and amenable to synthetic
manipulation.
Scheme 1. Tandem Overman Rearrangement and
Amidomercuration Strategy for Construction of
2,6-Disubstituted Piperidine Rings
During the course of our recent studies on developing new
methodologies for the asymmetric synthesis of bioactive five-
and six-membered nitrogen heterocycles, especially poly-
hydroxylated pyrrolidines and piperidines,10 it was noticed
that Hg(II) could mediate the Overman rearrangement
reaction11 of allylic imidates to allylic amine derivatives, as
well as the intramolecular amidomercuration reaction12 of
ꢀ-alkenylcarbamate/amides to form piperidine rings. Also
known is that the stereochemistry of the intramolecular
amino-/amido-mercuration reactions is often dependent upon
the structure of substrates and reaction conditions used.12 As
shown in Scheme 1, these findings strongly suggest that 2,6-
disubstituted piperidine rings can be stereoselectively syn-
thesized from an allylic imidate such as IV by the Hg(II)-
mediated tandem Overman rearrangement and intramolecular
amidomercuration reactions. Furthermore, considering that
allylic alcohols required for the synthesis of the requisite
allylic imidates are readily available, the Hg(II)-mediated
tandem Overman rearrangement and intramolecular ami-
domercuration reactions can provide an efficient and general
solution for the stereoselective synthesis of 2,6-disubstituted
piperidine rings from the relatively simple allylic alcohols.
Despite such possibility, as well as the efficiency and
versatility of the reactions, the Hg(II)-mediated tandem
Overman rearrangement and intramolecular amidomercura-
tion reactions have never been realized so far. Herein, we
report that the above strategy indeed enables the stereose-
lective synthesis of cis- and trans-2,6-disubstituted pip-
eridines from commercially available 2,7-octadienol. Appli-
cation of the developed methodology to the stereoselective
synthesis of solenopsin A and isosolenopsin A is also
described.
The tandem Overman rearrangement and intramolecular
amidomercuration reactions were accessed with the allylic
imidate 1 (see Supporting Information for the synthesis of
1) by screening various Hg(II) salts at room temperature,
and the results are summarized in Table 1. Only the reactive
Hg(II) salts (entries 1-3) enabled the tandem reactions to
generate the desired piperidine 2. Interestingly, mercuric
acetate (entry 4) gave the oxazoline product 3 as a sole
identifiable product, which formed probably through the Hg-
(II)-mediated 5-exo cyclization of 1.11c,d The reactions did
not take place with mercuric bromide and mercuric chloride
(entries 5 and 6).
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To establish relative stereochemistry of the 2,6-substituents
of the piperidine 2, conversion to the known 2,6-disubstituted
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3068
Org. Lett., Vol. 6, No. 18, 2004

To study effects of different N-protection groups on the
stereochemistry of the intramolecular amidomercuration
reactions, the compounds 7-9 were synthesized from 6,
which was prepared by the thermal Overman rearrangement
reaction of 1 (Scheme 3). Basic hydrolysis of 6 followed by
Table 1. Effects of Hg(II) Reagents on the Overman
Rearrangement and Amidomercuration Reactions of
Trichloroacetimidate 1a
Scheme 3. Stereoselective Synthesis of
cis-2-Ethyl-6-methylpiperidine
entry
HgX2
products (yield)
1
2
3
4
5
6
Hg(ClO4)2
Hg(OCOCF3)2
Hg(NO3)2
Hg(OAc)2
HgCl2
2 (90)
2 (90)
2 (90)
3 (75)
no reaction
no reaction
HgBr2
a All reactions were carried out with 1 (1.0 mmol) and HgX2 (1.2 mmol)
in THF (10 mL) at room temperature. After 1 disappeared on TLC, the
reaction mixture was quenched with aqueous KBr solution.
piperidines was accomplished (Scheme 2). The organomer-
curial 2 was reductively demercurated with sodium amal-
gam13 in aqueous THF, and deprotection of the N-trichlo-
roacetyl group also took place under the reaction conditions.
protection of the resulting amine with benzyl chloroformate,
acetic anhydride, and tosyl chloride produced the differently
N-protected amidomercuration substrates 7, 8, and 9 respec-
tively. As expected, the amidomercuration reaction of 6 with
Hg(OTFA)2 in THF at room temperature led to the formation
of trans-2 (>20:1). Interestingly, the amidomercuration
reaction of 7 under similar conditions gave an inseparable
mixture of the cis and trans mercuric bromides 10, favoring
the cis isomer in a ratio of 7:3. Varying temperature and
reaction time had little effects on the stereochemical outcome
of the amidomercuration reaction of 6 and 7. No reaction
was observed with 8 and 9 under the similar amidomercu-
ration conditions (this remains to be explained).
Scheme 2. Conversion of Organomercurial 2 to Known
2-Methyl-6-ethylpiperidine
Thus, the demercurated product was isolated in the Cbz-
protected form 4 by adding benzyl chloroformate to the
reaction mixture. It is worthwhile to mention that reductive
demercuration of 2 by the more popular NaBH4 in DMF
produced the desired demercurated product without depro-
tection of the trichloroacetyl group but in a low reaction yield
(20-25%). This may be attributed to the fact that such
reductive demercuration reactions are believed to proceed
through radical intermediates,14 and the trichloroacetyl groups
are susceptible to react under radical conditions.15 Hydro-
genation of 4 under atmospheric pressure of H2 over Pd-C
followed by treatment with 1 N HCl furnished 2-ethyl-6-
methylpiperidine hydrochloride (5), the stereochemistry of
Although the origin of the contrasting stereochemical
outcomes in the amidomercuration reaction of 6 and 7 is
not clear yet, they can be rationalized by considering the
equilibrium between two chair conformers VII and VIII
where the vinyl group at C3 and the N-protection group
occupy equatorial positions (Figure 2). According to the
Dreiding models of VII and VIII, the trichloroacetyl group
(R ) CCl3) favors VII and thus formation of the trans
isomer, whereas the Cbz-group prefers VIII and thus
formation of the cis isomer. With the trichloroacetyl group
(R ) CCl3), the severe steric repulsion between the CCl3
group and the terminal CH2 group (C8) in VIII can shift
the equilibrium far toward VII. On the other hand, with the
Cbz group (R ) OBn), the quasi 1,3-diaxial interactions
between the two axial C-H bonds (at C3 and C5) and the
terminal CH2 group in VII could become more unfavorable
relative to steric hindrance between the OBn group and the
terminal CH2 group in VIII, making VIII the predominant
conformer in the equilibrium.
1
which was determined to be trans by comparing its H and
13C NMR data with those reported in the literature.16
(13) Quirk, R. P.; Lea, R. E. J. Am. Chem. Soc. 1976, 98, 5973-5978.
(14) Barluenga, J.; Yus, M. Chem. ReV. 1988, 88, 487-509.
(15) (a) Cassayre, J.; Dauge, D.; Zard, S. Z. Synlett 2000, 471-474. (b)
Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K. J.
Org. Chem. 1993, 58, 464-470.
(16) Bowen, J. P.; Furness, M. S., Whitmire, D. U.S. Patent 6369078,
2002.
Org. Lett., Vol. 6, No. 18, 2004
3069

Scheme 4. Synthesis of Solenopsin A and Isosolenopsin A
Figure 2. A plausible explanation for the contrasting stereochem-
ical outcomes in the amidomercuration reaction of 6 and 7.
Compound 7 was also subjected to the equilibrating
amidomercuration conditions [Hg(OTFA)2 in CH3NO2 at
room temperature], under which the thermodynamically more
stable cis isomer of 10 was expected to form predominantly.12m
Gratifyingly, under these conditions, the amidomercuration
reaction of 7 indeed proceeded with an excellent cis
selectivity (>20:1). Such an exceptional cis selectivity of
the reaction is a result of the equilibrium between the cis
and trans isomers of 10 and thermodynamic control. The
equilibrium is catalyzed by trifluoroacetic acid produced
during the reaction. Neutralization of trifluoroacetic acid by
K2CO3 reduced the steteroselectivity of the amidomercuration
reaction significantly to cis:trans ) 7:3. As with 5, 10 was
converted to cis-2-ethyl-6-methylpiperidine hydrochloride
(12) by a reaction sequence of reductive demercuration and
hydrogenation (Scheme 3).
of 13 gave solenopsin A, which was isolated and character-
ized as its HCl salt by treating the hydrogenation product
with 1 N HCl.9d Similarly, isosolenopsin A was prepared
from 11.9d
In summary, it has been shown that the Hg(II)-mediated
tandem Overman rearrangement and intramolecular ami-
domercuration reactions can provide an efficient and general
route for the stereoselective synthesis of trans- and cis-2,6-
dialkylpiperidines from the readily available starting allylic
imidate 1. The catalytic asymmetric version of the present
strategy using neutral chiral Pd(II) catalysts11f is currently
under investigation.
Acknowledgment. Financial support from National In-
stitute of Health (GM 08194) and The Welch Foundation
(AX-1534) is gratefully acknowledged.
With the efficient routes for the stereoselective formation
of cis- and trans-2,6-disubstituted piperidines established,
the stereoselective synthesis of solenopsin A (14) and
isosolenopsin A (15) was pursued (Scheme 4). Cross
metathesis reaction of the olefin 4 with 1-undecene using
the 2nd generation Grubbs’ catalyst IX in refluxing CH2Cl2
afforded 13 as a mixture of E and Z isomers. Hydrogenation
Supporting Information Available: Complete experi-
mental procedures for all new compounds and copies of 1H
and 13C NMR spectra of the compounds 1, 3-7, and 10-
15. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL048961W
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Org. Lett., Vol. 6, No. 18, 2004