Stereodivergent diversity oriented synthesis of piperidine alkaloids

Article abstract of DOI:10.1002/ejoc.200600744

Alkylidenetitanium reagents enable the reagent-controlled high throughput asymmetric synthesis of 2-substituted piperidines and rapid access to multiple cyclic imines using solid phase synthesis (SPS). The Schrock carbenes, generated by reduction of thioacetals, convert resin-bound esters into enol ethers. Treatment with acid releases amino ketones that are cyclized with TMSCl to give iminium salts. Reduction introduces a chiral centre at C-2, whose absolute stereochemistry is determined by a phenethylamine (PEA) chiral auxiliary. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600744

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600744
Stereodivergent Diversity Oriented Synthesis of Piperidine Alkaloids[‡]
Louis V. Adriaenssens,[a] Carolyn A. Austin,[a] Mairi Gibson,[a] David Smith,[b] and
Richard C. Hartley*[a]
Dedicated to Dr Stuart Warren on the occasion of his retirement
Keywords: Amines / Asymmetric synthesis / Combinatorial chemistry / Solid-phase synthesis / Titanium complexes
Alkylidenetitanium reagents enable the reagent-controlled
high throughput asymmetric synthesis of 2-substituted piper-
idines and rapid access to multiple cyclic imines using solid
phase synthesis (SPS). The Schrock carbenes, generated by
reduction of thioacetals, convert resin-bound esters into enol
ethers. Treatment with acid releases amino ketones that are
cyclized with TMSCl to give iminium salts. Reduction intro-
duces a chiral centre at C-2, whose absolute stereochemistry
is determined by a phenethylamine (PEA) chiral auxiliary.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
The generation of libraries of pure structurally-diverse
compounds is key to the discovery of new medicines and
to the elucidation of biological pathways through chemical
genetics.[1] While relatively simple molecules can interact
well with enzymes and receptors a degree of complexity is
often required for selectivity, and so it is important to con-
struct three dimensional chiral structures. This requires the
generation of stereodiverse libraries where the relative and
absolute configuration of stereocentres is controlled, so that
mixtures of compounds are avoided and detecting the biod-
iscrimination of enantiomers is straightforward. Since
chemical space is so large, the inclusion of structural motifs
that are known to interact with biological systems is impor-
tant. A good way of identifying such privileged structures[2]
is from natural products,[3] as by their very nature these
must interact with biological machinery. The piperidine al-
kaloids[4] have excellent pedigree in this respect with com-
pounds such as γ-coniceine 1a and (S)-coniine (S)-2a re-
sponsible for the effects of hemlock used to execute the
ancient Greek philosopher Socrates (Figure 1). The drug
Ritalin®[5] that treats attention-deficit-hyperactivity-disor-
der and the insect repellent Bayrepel®[6] also contain a 2-
substituted piperidine core.
Figure 1. Piperidine alkaloids from hemlock.
Results and Discussion
We envisaged two approaches for the sterodivergent syn-
thesis of 2-substituted piperidines. In the first approach, we
would develop a route to cyclic imines[7] that could serve as
useful substrates for asymmetric reactions. There has been
a great deal of interest in the asymmetric reduction of im-
ines,[8,9] particularly using organocatalysis,[10] and easy ac-
cess to libraries of substrates would be useful to such meth-
ods. In the second approach, we would use a chiral auxil-
iary to control the absolute stereochemistry and so prepare
both enantiomeric series of piperidines having one chiral
centre. We would also control the diastereomer formed
when more than one chiral centre was present.
We had shown that alkylidenetitanium compounds bear-
ing an internal nucleophile can be generated from thioacet-
als and used on solid phase to prepare indoles,[11] benzofu-
rans,[11,12] benzothiophenes[13] and quinolines[14] in high pu-
rity. We decided to follow a similar strategy for accessing
piperidines and so prepared thioacetals 4 and 5 from dihy-
drofuran 3 by ring opening,[15] oxidation and then reductive
amination (Scheme 1). Treating each of these substrates
with 4 equiv. of low valent titanocene complex[16] 6 gave
effective alkylidenating agents, presumably having the
Schrock carbene structures 7 and 8.[17] The bulky benzylic
[‡] EPSRC, Sanofi-Aventis and the University of Glasgow for
funding.
[a] WestCHEM Department of Chemistry, University of Glasgow,
Glasgow, G12 8QQ, UK
Fax: +44-141-3304888
E-mail: richh@chem.gla.ac.uk
[b] Alnwick Research Centre, Sanofi-Aventis,
Willowburn Avenue, Alnwick, NE66 2JH, UK
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
4998
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Piperidine Alkaloids
SHORT COMMUNICATION
protecting groups do not allow the nitrogen atom to inter-
fere with alkylidene formation, and they are more stable
than the N-silyl Boc group that we used when preparing
indoles.[11]
Figure 2. Cyclic imines prepared. [a]Volatile: yield calculated on
ketone precursor.
enantiomers of 1-phenethylamine are readily available,[23]
and it had been used to prepare (S)-coniine and (2S)-phen-
ylpiperidine with high ee values through reduction of an
iminium salt generated by intramolecular N-alkylation of
a chiral imine[24] or from a diol using iridium catalysis,[25]
respectively. Alkylidenation of the resin-bound esters 9, and
acid-induced cleavage of the resulting enol ethers 12 gave
the ketones 13, which were cyclized and reduced stereose-
lectively to give the piperidines 14 (Scheme 3). Cyclization
to the iminium salt using trimethylsilyl chloride (TMSCl)
provided a chloride counterion and gave only volatile side
products. A range of reducing agents and temperatures were
tested, but a weak bulky reducing agent at room tempera-
ture proved best. Removal of the auxiliary[23] gave (R)- and
(S)-2-substituted piperidines 2a,b,g as hydrochloride salts
with high ee values (Figure 3).[26] All were obtained in excel-
lent purity following a wash with EtOAc and without
chromatography or recrystallization at any stage.
Scheme 1. Synthesis of alkylidenetitanium reagents.
To access imines, Merrifield resin-bound esters 9 were
treated with 3 equiv. of the alkylidenetitanium compound
7. The resulting enol ethers 10 were cleaved with mild acid
in the presence of Et3SiH and the solvent removed to give
ammonium salts 11 (Scheme 2). The Et3SiH reduced the
trityl cation during cleavage so that the only side product
was Ph3CH which was easily removed by washing the am-
monium salts with hexane.[18] Treatment with NaOH then
generated the selected imines 1a–f in the yields shown based
on the original loading of Merrifield resin (Figure 2). No
chromatography was necessary as any unreacted resin-
bound ester is unaffected by the mild conditions used in the
cleavage. Only imine 1e contained significant impurities, in
this case due to some unavoidable elimination of the dieth-
ylamino group.
Scheme 3. Synthesis of enantiomerically enriched piperidines.
Reagent-controlled diastereoselective synthesis was also
Scheme 2. Preparation of cyclic imines 1.
Asymmetric synthesis of piperidines[19–22] was achieved demonstrated using enantiopure resin-bound esters derived
using the enantiopure alkylidenetitanium compounds (S)-8 from (S)-(+)-2-methylbutyric acid and (R)-(+)-citronellic
and (R)-8. The 1-phenethyl auxiliary was chosen as both acid. The diastereomers 2h and 2i were produced in higher
Eur. J. Org. Chem. 2006, 4998–5001
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4999

R. C. Hartley et al.
SHORT COMMUNICATION
(TFA) (4%) and Et3SiH (1%) in DCM (5 mL) for 2 h. The solution
was removed and the reactor was washed with DCM (3×). Com-
bined organics were concentrated in vacuo. The resulting residue
was washed with cold hexane, treated with 4  NaOH and ex-
tracted into DCM. The organics were dried with Na2SO4 and the
solvent removed to give the imine 1.
Preparation of Chiral Piperidines 2: A reactor containing a resin-
bound enol ether 12 was shaken with TFA (4%) in DCM (5 mL)
for 1 h. The solution was removed and the reactor was washed
with DCM (3×). The combined organics were concentrated under
reduced pressure to give the salt of an amino ketone 13, which was
re-dissolved in DCM and washed (2×) with 1  NaOH. The or-
ganic layer was dried with MgSO4, filtered and concentrated in
vacuo. TMSCl (5 equiv.) was added to a solution of the resulting
amino ketone (1 equiv.) in dry DCM (1.5 mL) under argon. After
stirring at room temp. for 6 h, solvent was removed under vacuum
(0.3 Torr). The resulting iminium salt was dissolved in dry DCM
(1.5 mL) under argon, cooled to 0 °C and NaBH(OAc)3 (2 equiv.)
was added. After stirring for 18 h at room temp. the solution was
treated with 1  NaOH at 0 °C, washed with 1  NaOH (3×) and
then brine, dried with MgSO4, and concentrated in vacuo to give
a piperidine 14. 10% Pd/C (25 mol-%) was added to a solution of
the bisubstitued piperidine (1 equiv.) and 6  HCl (2 equiv.) in eth-
anol (1.5 mL). The atmosphere was changed to H2, and the reac-
tion was stirred at 65 °C for 5 h. The reaction mixture was centri-
fuged and the supernatant liquid was decanted through a filter.
Concentration in vacuo gave the piperidine hydrochloride salt 2 as
a solid which was then washed with EtOAc.
Figure 3. Chiral piperidines prepared,[26] yields based on resin load-
ing.
Supporting Information (see also the footnote on the first page of
this article): Spectroscopic data for compounds 1, and 2 (together
with experimental showing how enantiomeric purity was deter-
mined), experimental procedures for the preparation of 4 and 5 and
scanned 1H NMR spectra of all imines 1 and piperidines 2 (to show
purity).
diastereomeric purity as the directing effects of the auxiliary
and chiral centre are matched. As with piperidine 2g, a
branch adjacent to the iminium ion reduces selectivity by
decreasing the steric difference between the two faces.
In summary, we have developed a method for the diver-
sity-oriented generation of cyclic imines and the stereodiv-
ersity-oriented synthesis of piperidine alkaloids in high en-
antiomeric and diastereomeric purity.
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Experimental Section
Preparation of Resin-Bound Enol Ethers 10 and 12: Cp2TiCl2
(0.93 g, 12 equiv.), Mg (100 mg, 13.2 equiv., predried at 250 °C
overnight) and freshly activated 4-Å molecular sieves (0.25 g) were
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(R)-5 or (S)-5 (3 equiv.) in dry THF (5 mL) was added to the mix-
ture and stirring continued for 15 min. Resin-bound ester 9
[0.311 milliequiv./reactor from Merrifield resin with a loading of
1.83 milli-equiv. (chloride) g–1] contained in a porous polypropyl-
ene reactor (internal volume 2.4 mL, pore size 74 µ) and pre-
purged with argon was added. After 17 h the reactor was removed
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5000
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Synthesis of Piperidine Alkaloids
SHORT COMMUNICATION
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2g and 2i) derivatives eluted first on the chiral GC and chiral
HPLC used respectively to determine the ee values. For details
see Supporting Information.
Received: August 22, 2006
Published Online: September 20, 2006
Eur. J. Org. Chem. 2006, 4998–5001
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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