Stereocontrolled synthesis of a prototype library of enantiopure 2,4-disubstituted 4-aryl-6-piperidinones and piperidines

Article abstract of DOI:10.1016/S0040-4039(02)00184-3

Addition of a set of aryl cuprates to N-Boc O-TBDPS 2-hydroxymethyl 3,4-unsaturated 6-piperidinones affords syn-adducts in preference to anti when mixed Grignard-cuprates are used. Aryllithio cuprates give more of the anti-isomer in some cases. A library of 2-hydroxymethyl carbamates (27 compounds) and 2-hydroxymethyl aryl ethers and thioethers (19 compounds) was generated from a selection of 4-aryl-6-piperidinones, and some were further reduced to the corresponding piperidines (9 compounds).

Full text of DOI:10.1016/S0040-4039(02)00184-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1995–1998
Stereocontrolled synthesis of a prototype library of enantiopure
2,4-disubstituted 4-aryl-6-piperidinones and piperidines
Stephen Hanessian,a,* Willem A. L. van Otterlo,a Ingemar Nilssonb,* and Udo Bauerb
aDepartment of Chemistry, Universite´ de Montre´al, C. P. 6128, Succ. Centre-Ville, Montre´al, P.Q., Canada H3C 3J7
bAstraZeneca, Mo¨lndal, Sweden
Received 17 December 2001; revised 21 January 2002; accepted 22 January 2002
Abstract—Addition of a set of aryl cuprates to N-Boc O-TBDPS 2-hydroxymethyl 3,4-unsaturated 6-piperidinones affords
syn-adducts in preference to anti when mixed Grignard-cuprates are used. Aryllithio cuprates give more of the anti-isomer in some
cases. A library of 2-hydroxymethyl carbamates (27 compounds) and 2-hydroxymethyl aryl ethers and thioethers (19 compounds)
was generated from a selection of 4-aryl-6-piperidinones, and some were further reduced to the corresponding piperidines (9
compounds). © 2002 Elsevier Science Ltd. All rights reserved.
Substituted piperidines and their piperidinone precur-
sors are considered as versatile molecular frameworks
because they allow the deployment of diverse ligands
for interactions with receptors and enzymes.1 One of
the largest categories of such structures include an
4-aryl piperidine motif which is found in a number of
therapeutically important drugs.2 Substituted piperidi-
nes containing 4-aryl appendages and related analogs
are also targets for pharmacological studies.3 In the
preceding paper,4 we described methods for the stere-
ocontrolled introduction of nitromethyl and related
nitroalkyl groups in a 4,5-unsaturated 2-substituted-6-
oxo-piperidine nucleus via conjugate additions. Herein
we report the synthesis of a group of 2,4-disubstituted
4-aryl-6-piperidinones and piperidines, leading to a pro-
totypical library of 46 enantiopure analogs bearing
seven different carbamate, ether and thioether groups
for each aryl analog.
aryl halide to the 4,5-unsaturated lactam 1,5 in the
presence of TMSCl followed by treatment with TFA,
and chromatographic separation led to the 4-aryl
adducts in excellent yields (Scheme 1, Table 1).6,7 When
the cuprate reagent was prepared from the correspond-
ing aryl Grignard, the major products had a syn dispo-
sition (Table 1, entries 1–4, 6, 8). The phenyl reagent
led to a ꢀ1:1 mixture of syn- and anti-adducts regard-
less of the nature of the cuprate. Surprisingly, the
4-OTBS phenyl cuprate, prepared from the mixed aryl
cuprate and the diaryl lithiocuprate gave opposite
selectivities8 (Table 1, entries 6, 7). The same trend was
observed with the dimethyllithio cuprate and the Grig-
nard variant (Table 1, entries 8, 9). Mann, Wermuth
and co-workers9 have found stereochemical differences
in related conjugate additions of alkyl and phenyl
cuprates in ether. In the latter case, the anti-isomers
were predominant, contrary to our case. In order to
evaluate the influence of an ester and TBDPS ether
substituents in the starting a,b-unsaturated lactams, we
reacted the Mann/Wermuth methyl ester 4 with the
Conjugate addition of mixed aryl Grignard cuprates, or
diaryl lithiocuprates prepared from the corresponding
R
R
R
R2CuLib or
i) TFA
ii) Separation
R2CuMgBra,
+
TMSCl
O
N
O
N
H
N
O
N
H
Boc OTBDPS
OTBDPS
Boc OTBDPS
OTBDPS
(1)
(2)
(3a)
(3b)
Scheme 1.
Keywords: piperidine; conjugate cuprate addition.
* Corresponding authors.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00184-3

1996
S. Hanessian et al. / Tetrahedron Letters 43 (2002) 1995–1998
Yield 2 (%) (ratio syn/anti)c
Table 1.
Entry
R=
Yield 3a and 3b (ratio 3a/3b)d
1
2
3
4
5
6
7
8
9
4-OMe-Pha
4-F-Pha
4-Me-Pha
Pha
82 (3:1)
93 (3.2:1)
89 (2:1)
87 (1.4:1)
87 (1:2)
91 (4:1)
71 (1:3)
72 (9:1)
74 (1:5)
99 (4.5:1)
66 (5:1)
64 (1.8:1)
e
Phb
65 (1:2.1)
4-OTBS-Pha
4-OTBS-Phb
Mea
e
e
81 (11:1)
80 (1:5)
Meb
a Cuprate prepared from corresponding Grignard reagent.
b Cuprate prepared from corresponding lithio reagent.
c syn/anti Ratio determined from NMR spectra.
d syn/anti Ratio determined from isolated yields of 3a and 3b.
e Reaction not carried out.
We then proceeded with the preparation of a represen-
tative library of 27 4-aryl 2-O-carbamoyl-2-hydroxy-
methyl 6-piperidinones, and 19 ethers and thioethers
(Scheme 3, Table 2). For the former group, we chose a
set of commercially available isocyanates to be reacted
with some of the syn- and anti-4-aryl-2-hydroxymethyl
6-piperidinones 7, depending on their availability and
quantity in hand. In general, yields were excellent and
the products 8 were isolated as chromatographically
homogeneous enantiopure compounds (13C, mass spec.,
HPLC). The ether and thioether analogs were prepared
under the conditions of the Mitsunobu12 reaction
(Table 2). Finally, nine piperidine analogs 9 were pre-
pared from some of the piperidinone compounds 8 by
reduction of the lactam group with borane
dimethylsulfide13 (Table 2, % in parentheses).
mixed diarylmagnesio cuprate in the presence of
TMSCl. The resulting major anti-product 5 (>10:1) was
then converted to the same product 6 (see Table 1,
entry 5) obtained from the 6-OTBDPS analog 1
(Scheme 2) using the mixed reagent.
The preponderance of syn-isomers 3a can be rational-
ized on the basis of A1,3 strain10 in a preferred con-
former of 1 in which the bulky OTBDPS group adopts
an axial orientation.3d,9 This was in fact confirmed by
decoupling experiments (JH2,H3 ax=<1 Hz; JH2,H3
eq. ꢀ6.2 Hz). It is possible that the dimethylmagnesio
cuprate reagent coordinates in part to the ether
oxygen8,11 and delivers the nucleophile from the same
side affording the syn-product 3a as a major isomer. As
the reagent gets bulkier the complex is less favored and
more anti-attack can occur. The substituent effects on
the aryl portion may play a subtle role which is more
difficult to rationalize.
With the 4-OTBS analog 10 in hand, we explored
functionalizations based on the Suzuki15 and Pd-cata-
lyzed aryl triflate16 substitution reactions as shown in
a) LiOH, H2O/MeOH
b) ClCO2Et, Pri2NEt
Ph2CuMgBr
O
N
CO2Me
TMSCl
(60%)
c) NaBH4, MeOH
CO2Me
O
N
O
N
Boc
Boc
Boc OTBDPS
d) TBDPSCl, NEt3,
DMAP (36%, 4 steps)
(syn / anti 1 : 10)
(4)
(5)
(6)
Scheme 2.
R
R
R
R
a or b or c
TBAF
(72-100%)
BH3.SMe2
(Yields in
parenthesis,
Table 2)
(See Table 2
for yields)
O
N
H
O
N
O
N
H
N
OTBDPS
H
OH
X
H
X
(3a) or (3b)
(8)
(7)
(9)
Scheme 3.

S. Hanessian et al. / Tetrahedron Letters 43 (2002) 1995–1998
1997
Table 2.
Reaction conditions: (a) ArNCO, pyridine, heat; (b) Ar%OH, DEAD, Ph2P(Ph-4-NMe2); (c) Ph2S2, nBu3P; * PPh3 used instead of Ph2P(C6H4-4-
NMe2);14 - refers to reactions not carried out.
Scheme 4. Thus, treatment of the triflate ester 11 with
phenylboronic acid and phenylacetylene individually,
in the presence of palladium catalysts afforded the
corresponding 4-phenyl 12a and 4-phenyl acetylenic
12b derivatives in excellent yields.
nones and piperidines in enantiopure form. A total of
27 4-aryl-2-hydroxymethyl O-carbamoyl and 19 ether
and thioether analogs were prepared by standard
methodology. A selected set of nine original ether
and thioether adducts were converted into their
piperidine counterparts. The methodology developed
in this work should prove useful in the design of
larger libraries of substituted enantiopure 4-aryl piper-
idines.
In conclusion, we have investigated methods for the
stereocontrolled synthesis of 4-aryl piperidines, and
the generation a set of 4-aryl-2-substituted 6-piperidi-
Scheme 4.

1998
S. Hanessian et al. / Tetrahedron Letters 43 (2002) 1995–1998
at −78°C for a further 3 h before being allowed to warm
Acknowledgements
up to room temperature over a period of 2 h. Saturated
NH4Cl (200 mL) was added and the mixture was
extracted with Et2O. The combined organic fractions
were dried (Na2SO4) and removed in vacuo to afford a
yellow oil which was purified by silica gel flash chro-
matography (10% AcOEt/hexane) to give compounds 2
(2.76 g, 89%) as an inseparable mixture of diastereomers.
These were then dissolved in CH2Cl2 (50 mL) and cooled
to 0°C. TFA (5.0 mL, 0.1 volume equiv.) was added and
the reaction mixture was stirred under argon for a further
2 h. Excess TFA was removed by evaporation with
toluene and careful silica gel flash chromatography (10%
MeOH/AcOEt) subsequently afforded compounds 3a
(0.92 g, 41%) and 3b (0.52 g, 23%) as pale yellow oils
We thank NSERC of Canada and AstraZeneca (Mo¨ln-
dal, Sweden) for financial assistance through the
Medicinal Chemistry Chair program. W.A.L.v.O.
thanks the NRF (South Africa) for partial post-doc-
toral support. The authors also acknowledge collabora-
tion with Mr. Mehran Seid of the Universite´ de
Montre´al.
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6. Typical procedure for cuprate addition and diastereomer
separation: To a cooled solution (−40°C) of CuBr·SMe2
(5.7 g, 2.8×10−2 mol, 5 mol. equiv.) in THF (30 mL), was
added tolylmagnesium bromide (56 mL, 5.6×10−2 mol, 10
mol. equiv.). The reaction mixture was then stirred, under
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cooling bath was lowered to −78°C and the a,b-unsatu-
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with vigorous stirring of the reaction mixture. TMSCl
(10.6 mL, 8.4×10−2 mol, 15 mol. equiv.) was added
dropwise over 1 min and the reaction mixture was stirred