Three-component sequential Aza[4+2] cycloaddition/allylboration/retro- sulfinyl-ene reaction: A new stereocontrolled entry to palustrine alkaloids and other 2,6-disubstituted piperidines

Article abstract of DOI:10.1002/anie.200353152

Step-economy and stereocontrol are highlighted in a novel three-component sequential reaction to access substituted piperidines (see scheme). Through combining boronate-substituted hydrazonobutadienes, chiral sulfinimide dienophiles, and aldehydes in a hi

Full text of DOI:10.1002/anie.200353152

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Chemie
Piperidine Synthesis
Three-Component Sequential Aza[4+2]
Cycloaddition/Allylboration/Retro-Sulfinyl-Ene
Reaction:A New Stereocontrolled Entry to
Palustrine Alkaloids and Other 2,6-Disubstituted
Piperidines**
Barry B. TourØ and Dennis G. Hall*
Multicomponent reactions[1] that generate complex, function-
alized structures from simple substrates are very attractive
step-economical strategies in target-oriented synthesis.[2] We
have recently reported on the three-component hetero[4+2]
cycloaddition/allylboration reaction[3] for the preparation of
a-hydroxyalkylated piperidines[4] and furans[5a] (Scheme 1). In
the case of piperidines, this one-pot process is initiated by a
hetero-Diels–Alder reaction between boronate-substituted
hydrozonobutadienes (1) and electron-poor dienophiles. The
formation of the resulting cycloadduct unmasks an allylbor-
onate that adds in situ onto aldehydes to provide polysub-
stituted piperidine products in a highly stereoselective fash-
ion.
We were interested in the challenge of adapting this
process to access 2,6-disubstituted piperidine units[6] such as
those featured in the palustrine class of alkaloids exemplified
[*] B. B. TourØ, Prof. D. G. Hall
Department of Chemistry
Gunning-LemieuxChemistry Centre
University of Alberta
Edmonton, AB T6G2G2 (Canada)
Fax: ( +1)780-492-8231
E-mail: dennis.hall@ualberta.ca
[**] Financial support for this research by the Natural Sciences and
Engineering Research Council (NSERC) of Canada (Discovery Grant
to D.G.H.) and the University of Alberta is gratefully acknowledged.
B.B.T. thanks the Canadian Institutes for Health Research (CIHR)
for a graduate scholarship. The authors thank Melissa Chee for help
in the preparation of intermediates.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 2001 –2004
DOI: 10.1002/anie.200353152
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2001

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Scheme 1. Top: the three-component hetero[4+2] cycloaddition/allyl-
boration reaction strategy to access a-hydroxyalkyl-substituted six-
membered heterocycles. Bottom: the key components boronate-substi-
tuted hydrazonobutadiene 1 and the chiral sulfinimide dienophile 2
used in this study.
by palustrine itself (3), methyl palustramate (4), and the
saturated degradation product methyl dihydropalustramate
(5).[7,8] Unfortunately, in the normal electron-demand [4+2]
Scheme 2. Optimization of the aza[4+2] cycloaddition/allylboration/
retro-sulfinyl-ene sequential reaction. a) 1. Toluene, 808C, 70 h, 2. aq
NaHCO3, RT, 0.5 h; b) 1. NaOH (10 equiv), H2O/acetone (3:1), 08C,
0.5 h then RT, 6 h, 2. 10% aq HCl, 08C, 0.5 h then aq NaHCO3 up to
pH 6–6.5, 3. CHCl3. See table for reaction temperature and time.
RT=room temperature.
of our knowledge, this interesting fragmentation process has
never been employed in target-oriented synthesis, and only
one study examined cyclic substrates.[11c] In the case of
substrates 6, SO2 extrusion would be concomitant with a
migration of the C4–C5 double bond to the C3–C4 position,
which is necessary for accessing methyl palustramate (4) in
addition to the saturated analogue 5 following hydrogenation.
Model studies focused on the reaction of heterodiene 1a with
dienophiles 2a, 2b, and the chiral one 2c developed by
Waldner.[10]
To our satisfaction, with the same reaction conditions as
those employed with maleimides,[4] the corresponding cyclo-
adducts 6a–c were isolated in good yields as single regio- and
diastereomers.[12] Although the high diastereofacial selectivity
of Diels–Alder reactions with dienophile 2c had been
demonstrated,[10] the use of its cycloadducts in retro-sulfinyl-
ene reactions is unprecedented. Here, intermediates 6a–c
were subjected to hydrolytic conditions optimized to generate
the corresponding sulfinic acids. First, the intermediates were
treated with aqueous base, then the solution containing the
sulfinate salt was carefully acidified[13] to pH 6.0–6.5 and
concentrated to give the resulting sulfinic acids 7a–c, which
were stirred in chloroform.
manifold, the bulky electron-withdrawing boronate substitu-
ent exerts a strong deactivating effect on the diene. Thus, the
thermal cycloaddition works well only with very electron-
poor diactivated dienophiles such as N-substituted male-
imides. Acrylates are unreactive,[9] and since targets 3–5 are
unsubstituted in the 3-position, a new diactivated dienophile
was needed that would meet the following requirements:
1) possess the requisite electronic characteristics to react with
heterodienes 1; 2) provide high enantiofacial selectivity; and
3) lead to a cycloadduct that can be converted to both C3–C4
dehydro compounds and the corresponding saturated series.
Here, we describe how Waldner's chiral sulfinimide dieno-
philes[10] (2, Scheme 1) satisfy all these requirements in the
way of a novel three-component sequential aza[4+2] cyclo-
addition/allylboration/retro-sulfinyl-ene
reaction.
This
approach was then applied to the enantioselective synthesis
of (À)-methyl dihydropalustramate (5).
To our surprise, we found that the fragmentation propen-
sity of 7a–7c was highly dependent on the nature of the
amide's N-alkyl substituent. Thus, while the N-tert-butyl
derivative 7b fragmented at room temperature, the N-propyl
analogue 7a required high temperatures and resulted in a
lower yield of product. The chiral derivative 7c required for a
stereoselective synthesis of the palustrine alkaloids was found
Our design strategy to 2,6-disubstituted piperidines and
the palustrine alkaloids relied on the successful optimization
of a model retro-sulfinyl-ene reaction[11] involving the prod-
ucts 6 from the aza[4+2] cycloaddition/allylboration of diene
1a, dienophiles 2, and benzaldehyde (Scheme 2). To the best
2002
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to possess intermediate reactivity and provided an acceptable
yield of cis-2-carbamoyl-6-hydroxyalkyl piperidine product
8c.[12] Although the reasons for this reactivity trend remain
speculative, conformational effects may be evoked to explain
the different behavior of 7a–7c (Scheme 3). To reach the six-
Scheme 3. Suggested conformational equilibrium to explain the influ-
ence of the amide substituent (R) of intermediates 7 in the retro-sulfi-
nyl-ene rearrangement.
membered transition state for a concerted retro-sulfinyl-ene
fragmentation,[11d] the sulfinic acid substituent must assume a
pseudoaxial orientation (conformer B). This reactive con-
former also features two disfavored gauche interactions
between the bulky NMe2 hydrazine group, and the a-
hydroxyalkyl chain and the carboxamide. To minimize this
type of strain, closely related cis-2,6-disubstituted piperidines
have been shown to adopt a “diaxial” conformation of
type A.[14] In this nonreactive conformer A, the carboxamoyl
group occupies a pseudo-axial position. Thus, we hypothesize
that bulkier N-alkyl substituents on the amide may affect the
conformational equilibrium and facilitate the retro-ene
fragmentation by destabilizing conformer A to the benefit
of reactive conformer B.
We tested the applicability of the sequential aza[4+2]
cycloaddition/allylboration/retro-sulfinyl-ene reaction to the
test by first targeting (À)-methyl dihydroplustramate (5)
(Scheme 4). To this end, we employed butadiene 1b, which
was easily made from the known 3-boronoacrolein pinaco-
late[15] through simple dehydrative hydrazone formation with
1,1-dibenzylhydrazine.[12] The key one-pot three-component
reaction between equimolar amounts of 1b and 2c in the
presence of excess propanaldehyde furnished the heterobi-
cyclic adduct 9 as a single regio- and diastereomer in 62%
yield. To effect the retro-sulfinyl-ene fragmentation, 9 was
hydrolyzed and heated as described above for compounds
6a–c. The desired amide product 10 was isolated in 77%. Ra-
Ni-promoted hydrogenolysis of the hydrazine and concom-
itant reduction of the double bond was followed by protection
of the aminoalcohol to afford the carbamate intermediate 11
in high overall yield. Selective hydrolysis of the amide group
of 11 was performed through formation of the N-nitroso
derivative.[16] Unfortunately, in all conditions attempted,
epimerization occurred in this operation, and the major 2,6-
cis-configured acid product was always accompanied with
variable amounts of the trans isomer. The required homo-
logation was performed on the epimeric mixture of carboxylic
acids 12 using an Arndt–Eistert sequence. The two isomers
were readily separable at that stage, and the cis isomer 13 was
subjected to the final step of aminoalcohol deprotection. This
transformation proved difficult with a known hydrolysis
procedure,[8d] but we eventually succeeded with the method
of Weinreb and co-workers using barium hydroxide.[17]
Scheme 4. Total synthesis of (À)-methyl dihydropalustramate (5).
a) 1. Toluene, 808C, 70 h, 2. aq NaHCO3, RT, 0.5 h; b) 1. NaOH, H2O/
acetone (3:1), 08C, 0.5 h then RT, 6 h, 2. aq HCl, 08C, 0.5 h then aq
NaHCO3 up to pH 6.5, removal of solvents; 3. CHCl3, reflux, 16 h;
c) Ra-Ni, EtOH, 608C, 450 psi, 24–48 h, 85%; d) Im2CO (4 equiv),
CH2Cl2, RT, 17 h; e) 1. NaNO2, AcOH/Ac2O (1:2), 2. LiOH, THF, H2O,
08C to RT, 16 h; f) 1. (COCl)2, cat DMF, THF, RT, 3 h, 2. CH2N2, Et2O,
RT, 16 h, 3. AgOBz, Et2N, MeOH, RT, 24 h; g) 1. Ba(OH)2, DME/H2O,
2. SOCl2, MeOH, 608C, 16 h. DME=1,2-dimethoxyethane, DMF=di-
methylformamide, Im=imidazole.
Reesterification of the resulting amino acid afforded (À)-
methyl dihydropalustramate (5), the spectroscopic character-
istics and optical rotation value of which are in agreement
with reported literature data.[12,18] The entire sequence to
reach target 5 was accomplished with very few purification
steps, and in only 10 linear synthetic operations from
commercial 3,3’-diethoxypropyne.[12] Further adaptations of
À
this strategy to include chemoselective cleavage of the N N
À
bond for preserving the C3 C4unsaturation is expected to
allow access to 3 and 4.
In summary, we have described a novel three-component
sequential aza[4+2] cycloaddition/allylboration/retro-sulfi-
nyl-ene reaction to access cis-2,6-disubstituted piperidines in
a highly regio- and diastereoselective fashion. The utility of
this powerful and step-economical process was successfully
demonstrated with a concise enantioselective synthesis of the
palustrine degradation product (À)-methyl dihydropalustra-
mate (5). Few multicomponent reaction strategies demon-
strate such a high level of stereocontrol in the formation of
complex, functionalized compounds.
Received: October 24, 2003 [Z53152]
Keywords: allylation · asymmetric synthesis · cycloaddition ·
.
multicomponent reactions · nitrogen heterocycles · piperidines
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À
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