Stereocontrolled synthesis of enantiopure diversely functionalized prototypical piperidinone libraries, and constrained analogs of 4-substituted 2-amino adipic acid

Article abstract of DOI:10.1016/S0040-4039(02)00183-1

Enantiopure 2-substituted 4,5-unsaturated piperidinones were subjected to stereocontrolled nitroalkane additions and the corresponding products were further manipulated to produce 4-aminomethyl derivatives. Diverse substitution led to a set of 4-arylsulfo

Full text of DOI:10.1016/S0040-4039(02)00183-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1991–1994
Stereocontrolled synthesis of enantiopure diversely functionalized
prototypical piperidinone libraries, and constrained analogs of
4-substituted 2-amino adipic acid
Stephen Hanessian,a,* Mehran Seida and Ingemar Nilssona,b,
*
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—Enantiopure 2-substituted 4,5-unsaturated piperidinones were subjected to stereocontrolled nitroalkane additions and
the corresponding products were further manipulated to produce 4-aminomethyl derivatives. Diverse substitution led to a set of
4-arylsulfonamides and O-carbamates as examples of prototypical piperidinone libraries with two sites of diversity. © 2002
Elsevier Science Ltd. All rights reserved.
Piperidine rings with one or more substituents are
abundant in nature, and their stereocontrolled synthe-
sis has been the subject of many reports.1 Substituted
piperidines are key structural elements in compounds
possessing CNS activity inhibitors2 and they are also
known enzyme inhibitors.3,4 The availability of enan-
tiopure 2,4-disubstituted piperidines and their 6-oxo
derivatives, with the option to functionally differenti-
ate the appendages would be very useful in the con-
text of spacially defined scaffolds.5 For example,
SB204070, an ester of hydroxymethyl N-butylpiper-
idine was identified as a potent and selective 5-HT4
receptor antagonist6 originating from a library of 4-
hydroxymethyl piperidines.
Conjugate addition of nitromethane in the presence
of DBU9 led to an equimolar mixture of the two
diastereomers 3 and 4, which could be easily sepa-
rated by flash chromatography. The stereochemical
assignments were based on NOE measurements and
by analogy to a related reaction (see below). Catalytic
hydrogenation led to the corresponding 4-
aminomethyl analogs 5 and 6, respectively, which
were individually subjected to a three-step sequence
involving reaction with arylsulfonyl halides, removal
of the TBDPS group, and formation of carbamates
with a set of arylisocyanates. Thus, a set of mixed
sulfonamide/carbamates corresponding to 7 and 8 and
totaling 32 compounds was produced with excellent
purities (13C, mass spec., HPLC). Addition of 2-nitro-
propane to 2 afforded a single adduct 9, which upon
catalytic hydrogenation led to the 4-(2-aminopropyl)
analog 10 (Scheme 1).
Scheme 1 illustrates our synthesis of enantiopure 4-
aminomethyl
2-hydroxymethyl-6-oxo
piperidines.
Thus, 2-hydroxymethyl piperidine 1 readily available
via enzymatic resolution7 or by chemical transforma-
tion from L
-lysine8 was protected as the N-Boc/OTB-
Treatment of the readily available a,b-unsaturated
lactam 1210 with nitromethane in DBU gave a 3:1
mixture of the syn and anti 4-nitromethyl adducts 13
and 14, respectively, in excellent yield after chromato-
graphic separation (Scheme 2). The structure of the
4-(2-nitropropyl) adduct 15 was ascertained by X-ray
crystallography. Removal of the N-Boc protective
group afforded the 4-nitroalkyl lactams 16 and 17
which were hydrogenated to the corresponding 4-
DPS derivative, then oxidized to the corresponding
6-oxo derivative. Formation of the a,b-unsaturated
lactam 2 proceeded uneventfully in good overall yield.
Keywords: sulfonamide; carbamate; piperidine; rigid analogs.
* Corresponding authors.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00183-1

1992
S. Hanessian et al. / Tetrahedron Letters 43 (2002) 1991–1994
O2N
O2N
O
(c)
(a, b)
OH
OR
OR
OR
+
N
O
N
O
N
N
Boc
Boc
Boc
Boc
4
3
1
2, R = TBDPS
(e, f)
(e, f)
(d)
H2N
H2N
O
O2N
H2N
O
(e, f)
OR
OTBDPS
OR
OTBDPS
O
N
H
N
H
O
N
N
H
Boc
10
5
6
9
R1O2SHN
R1O2SHN
or
a) Aryl Sulfonyl Chloride
b) TBAF
c) Aryl NCO
5 or 6
OCONHR2
OCONHR2
O
N
H
O
N
H
7
8
Me
CF3
CF3
S
R1 =
R2 =
OMe
Scheme 1. (a) i. TBDPSCl, DMAP, CH2Cl2, ii. RuO2×H2O, NaIO4, H2O–EtOAc, 80% (two steps); (b) i. LiHMDS, PhSeBr, THF,
ii. H2O2, pyridine, CH2Cl2, 75% (two steps); (c) CH3NO2, DBU, 85%, 1 to 1; (d) 2-nitropropane, DBU, 85%; (e) TFA, CH2Cl2,
90%; (f) H2, Pd–C, MeOH 95%.
Scheme 2. (a) i. LiHMDS, PhSeBr, THF, ii. H2O2, 75% (two steps); (b) CH3NO2, DBU, 85%, 3 to 1(anti to syn); (c)
2-nitropropane, DBU, 85%; (d) TFA, CH2Cl2, 90%; (e) H2, Pd–C, MeOH 95%; (f) nitrocyclohexyl or nitrocyclopentyl, K2CO3,
MeCN, 65%.

S. Hanessian et al. / Tetrahedron Letters 43 (2002) 1991–1994
1993
aminoalkyl 6-oxo-2-pipecolate esters 18 and 19, respec-
tively, in excellent yield. Finally, the Michael additions
were also successfully realized with nitrocyclopentane
and nitrocyclohexane to give 20 and 21, respectively, as
single isomers. In these cases, the reactions were run in
acetonitrile in the presence of potassium carbonate
(Scheme 2).
product resulted from an intramolecular attack of the
initially formed amino group on the activated lactam
carbonyl. A more efficient two-step process was devel-
oped whereby, the lactam was first converted to the
ester 22, which upon heating in toluene in the presence
of
a
catalytic quantity of pyridine underwent
intramolecular cyclization to 23 in 60% overall yield.
Removal of the protective group and oxidation13 of the
primary alcohol to the carboxylic acid gave a b-(3R-5-
It is surprising that the stereochemical outcome in the
reaction of 2 and 12 is different vis-a`-vis nitromethane,
but not the bulkier homologs. Based on steric factors
alone, one would have predicted a lesser amount of the
syn-isomer 3 compared to 4 (Scheme 1). A1,3 strain11
can play an important role in deciding the conformer
population of 2-substituted lactams related 12, where a
pseudoaxial orientation is favored by 5 kcal mol−1 in a
chair-like conformation.12 With bulkier nitroalkanes 15,
20 and 21 are formed quasi exclusively. The X-ray
crystal structure of 15 depicts the ester group in an
axial orientation (Scheme 2).
oxo-pyrrolidinyl)
L
-alanine analog 24. An analogous
sequence led to the 4-S-diastereomer 25. These 3-substi-
tuted-5-oxo-pyrrolidines can be considered as con-
strained analogs of branched L
-2-amino adipic acids.14
Finally, we prepared a versatile vinylic bromide analog
26 by a sequence of standard reactions, while ensuring
the stereochemical integrity of the product. Treatment
of 26 with nitromethane as solvent in the presence of
DBU led to a 3:1 mixture of syn and anti 4,5-
nitromethano 6-oxo-pipecolates 28 and 29, respectively
(Scheme 4).15 The minor isomer 29 afforded X-ray
quality crystals in which the pseudo axial disposition of
the ester group is noteworthy (Scheme 4). It is also of
interest that the nitro group in both products 28 and 29
When the 4-nitromethyl adduct 4 was subjected to
hydrogenation, the rearranged pyrrolidinone 23 was
obtained in ꢀ30% yield (Scheme 3). Clearly, this
O2N
O2N
O
OTBDPS
NHBoc
NHBoc
OTBDPS
(b)
(a)
OTBDPS
O
O
N
H
O
N
MeO
Boc
23
4
22
(c)
O2N
O
O
OH
NHBoc
OH
NHBoc
(a, b, c)
OTBDPS
O
O
N
N
H
N
H
Boc
3
25
24
Scheme 3. (a) NaOMe, THF, 95%; (b) i. H2, Pd–C, MeOH, ii. toluene, pyridine (cat.) 110°C, 60% (two steps); (c) i. TBAF, THF,
ii. TEMPO, NaClO2, NaOCl, MeCN, 35°C, 80%.
Scheme 4. (a) i. LiHMDS, PhSeBr, THF, ii. Br2, iii. H2O2, 65%; (b) CH3NO2, DBU, 60%.

1994
S. Hanessian et al. / Tetrahedron Letters 43 (2002) 1991–1994
adopts an exo-orientation vis-a`-vis the piperidinone
ring.
D. R.; Bonner, M. P.; Bos, M.; Cook, C. M.; Fry, D.
C.; Graves, B. J.; Hatada, M.; Hill, D. E.; Kahn, M.;
Madison, V. S.; Rusiecki, V. K. Sarabu, R.; Sepinwall,
J.; Vincent, G. P.; Voss, M. E. J. Med. Chem. 1993,
36, 3041; (e) Rizo, J.; Giersach, L.-M. Annu. Rev.
Biochem. 1992, 61, 387.
In conclusion, we have described methodology for the
stereocontrolled syntheses of 4-substituted 6-oxo-pipe-
ridine-2-carboxylic acids and the corresponding 2-
hydroxymethyl analogs.16 These were used as versatile
scaffolds to construct a small library encompassing a
4×4 (or potentially larger) combination of sulfonamides
and carbamates. The synthesis of b-(3R- and 3S-5-oxo-
6. Gaster, L. M.; Joiner, G. F.; King, F. D.; Wyman, P.
A.; Sutton, J. M.; Bingham, S.; Ellis, E. S.; Sanger, G.
J.; Wardle, K. A. J. Med. Chem. 1995, 38, 4760.
7. Sanchez-Sancho, F.; Herradon, B. Tetrahedron: Asym-
metry 1998, 9, 1951.
8. Davies, C. E.; Heightman, T. D.; Hermitage, S. A.;
Moloney, M. G. Synth. Commun. 1996, 26, 687.
9. See for example: Ono, N.; Kamimura, A.; Miyake, H.;
Hamamoto, I.; Kaji, A. J. Org. Chem. 1985, 50, 3692.
10. Muller, M.; Schoenfelder, A.; Didier, B.; Mann, A.;
Wermuth, C.-G. J. Chem. Soc., Chem. Commun. 1999,
683.
11. Hoffmann, R. W. Chem. Rev. 1989, 89, 1841; see also
following paper, Refs. 9–11.
12. (a) Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am.
Chem. Soc. 1988, 110, 7445; (b) Beak, P.; Zajdel, W. J.
J. Am. Chem. Soc. 1984, 106, 1010 and references cited
therein.
pyrrolidinyl
constrained
L-alanine could be useful as examples of
-2-amino adipic acids.
L
Acknowledgements
We thank NSERC of Canada and AstraZeneca (Mo¨ln-
dal, Sweden) for financial assistance through the
Medicinal Chemistry Chair program. We acknowledge
the services of Dr. Michel Simard in determining X-ray
crystal structures. The authors also acknowledge col-
laboration with Dr Willem A. L. van Otterlo of the
Universite´ de Montre´al.
13. Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 1999,
64, 2564.
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16. Experimental procedures available upon request. Data
for selected compounds: 16: [h]D +20.0° (c 1.3, CHCl3);
1H NMR (400 MHz, CDCl3): l (ppm) 6.50 (b, 1H),
4.38–4.37 (d, J=7.01 Hz, 2H), 4.24–4.22 (m, 1H), 3.80
(s, 3H), 2.80–2.75 (m, 1H), 2.64–2.57 (m, 1H), 2.33–
2.29 (d, J=13.58 Hz, 1H); 13C NMR (400 MHz,
CDCl3): l (ppm) 171.07(0), 168.95(0), 78.43(−), 52.92(+),
34.18(−), 29.08(+), 27.53(−); HRMS: C8H12N2O5.
Calcd: 216.0746; found: 217.0820 (m+1). 24: [h]D −27.6°
1
(c 1.2, CHCl3); H NMR (400 MHz, CD3OD): l (ppm)
4.23–4.26 (dd, J=15.0 Hz, 7.2 Hz, 1H), 3.52–3.46 (m,
1H), 3.12–3.08 (dd, J=6.17 Hz, 8.90 Hz, 1H), 2.57–
2.49 (m, 1H), 2.45–2.38 (dd, J=8.01 Hz, 15.37 Hz,
1H), 2.25–2.29 (m, 1H), 1.75–1.78 (m, 1H), 1.45 (m+s,
10H); 13C NMR (100 MHz, CD3OD):
l (ppm)
177.06(0), 174.72(0), 157.57(0), 70.62(0), 55.86(+),
43.17(−), 40.05(−), 37.04(−), 28.75(+), 23.14(+); HRMS:
C12H20N2O5. Calcd: 272.1372; found: 273.13952 (m+1).
28: [h]D −22.3° (c 15, CHCl3); 1H NMR (400 MHz,
CDCl3); l (ppm) 4.76–474 (dd, J=3.03 Hz, 1H), 4.44–
4.43 (t, J=2.89 Hz, 1H), 3.82 (s, 3H), 2.87–2.84 (dd,
J=2.84 Hz, 9.98 Hz, 1H), 2.76–2.69 (m, 1H), 2.60–2.56
(m, 1H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3): l
(ppm) 168.20(0), 161.57(0), 149.32(0), 82.29(0), 62.49(+),
54.62, 50.71(+), 26.27(+), 25.29(+), 22.86(−), 20.24(+);
HRMS: C13H18N2O7. Calcd: 314.1114; found: 315.1185
(m+1).
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