Stereoselective solid-phase synthesis of chiral piperidine derivatives by using an immobilized galactose auxiliary

Article abstract of DOI:10.1002/anie.200390208

The fluoride-labile anchoring of a galactosylamine enabled the first stereoselective solid-phase combinatorial synthesis of didehydropiperidinones 1. The piperidine derivatives formed by asymmetric domino Mannich-Michael condensation at ambient temperatur

Full text of DOI:10.1002/anie.200390208

Angewandte
Chemie
Chiral Piperidine Derivatives
Stereoselective Solid-Phase Synthesis of Chiral
Piperidine Derivatives by Using an Immobilized
Galactose Auxiliary**
Gernot Zech and Horst Kunz*
Drug development[1] has significantly been accelerated by
exploiting combinatorial solid-phase synthetic methodolo-
gies.[2] Although enantiomerically pure compounds[3] are of
major interest for the pharmaceutical industry only few
stereoselective syntheses on the solid-phase have been
reported so far. Besides polymer-bound chiral ligands and
catalysts[4] some immobilized chiral auxiliaries and their
application in aldol condensations,[5] conjugate additions,[6]
1,3-dipolar cycloadditions,[7] or radical allylations[8] have been
described.
Recently, we reported on the synthesis of an immobilized
galactosylamine as auxiliary and its employment in stereo-
selective Ugi reactions on the solid-phase.[9] Within this
approach a galactosyl azide as precursor was coupled to
hydroxyfunctionalized polymers, for example Wang resin,
through the sterically demanding a,a,a’,a’-tetramethyl aze-
laic acid and subsequently reduced to the galactosylamine on
the solid-phase. Major disadvantages of this anchoring for
application in other solid-phase reactions lay in the acid
lability of the Wang anchor and in the lowloading of the
polymer with the galactosylamine.
Herein, we report diastereoselective domino Mannich–
Michael condensations[10] performed with an immobilized
glycosylamine as the auxiliary, allowing reactions with Lewis
acids and organometallic reagents. Thus, a polymer-bound
chlorodiisopropylsilane[11,12] was attached to the carbohydrate
auxiliary through a hydroxyfunctionalized spacer unit, which
enabled facile cleavage of reaction products from the solid-
phase by mild fluoridolysis.[13] Linkages of substrates through
sterically demanding silyl ethers have proven stable towards a
variety of organometallic reagents. Similar strategies have
been applied for the synthesis of oligosaccharides,[14] poly-
ketides,[15] and prostaglandins.[16]
For the assembly of the galactose auxiliary 1,6-hexanediol
was monosilylated with tert-butyldiphenylsilyl chloride, the
remaining hydroxy function was transformed to bromide to
give 1 under Appel conditions. Compound 1 was then allowed
to react with isobutyric acid dianion to give a,a-branched
octanoic acid 2 (Scheme 1). The acid chloride obtained from 2
was regioselectively esterified with the primary hydroxy
function of galactosyl azide 3. After pivaloylation[17] of the
[*] Prof. Dr. H. Kunz, Dipl.-Chem. G. Zech
Institut für Organische Chemie der Universität Mainz
Duesbergweg 10-14, 55128 Mainz (Germany)
Fax: (+49)6131-39-24786
E-mail: hokunz@mail.uni-mainz.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie (FCI). G.Z. is grateful to
the FCI for a Doktorandenstipendium.
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To optimize reaction and cleavage conditions with this
system we initially performed model Ugi reactions using the
galactosylamine 7. Fluoridolysis with tetra-n-butylammonium
fluoride (TBAF) gave the corresponding Ugi condensation
products in high yields and in diastereomeric ratios (80–
92% de) comparable to those obtained for analogous syn-
theses in solution[19] and on the solid-phase.[9]
Encouraged by these results we employed galactosyl-
amine 7 for the stereoselective synthesis of heterocycles. The
domino Mannich–Michael condensation of glycosyl imines
with the electron-rich Danishefsky's diene opens up a stereo-
selective access to 2-substituted N-galactosyl-5,6-dehydropi-
peridin-4-ones,[10] which are valuable synthons for the syn-
thesis of nitrogen heterocycles.[20]
So far, only three combinatorial syntheses of didehydro-
piperidin-4-ones have been reported, all of them based on
different methodologies, but all giving racemic products.[21]
Herein we describe the first stereoselective synthesis of chiral
dehydropiperidinones on the solid-phase. The immobilized
galactosylamine auxiliary 7 was transformed to the corre-
sponding galactosyl imines 8 with high E-isomeric and b-
anomeric purity by acid-catalyzed condensation (Scheme 3).
Scheme 1. Solution synthesis of 4. a) TBDPSCl, imidazole, DMF, 208C,
¼
88%; b) CBr4, PPh3, CH2Cl2, 08C!208C, 85%; c) Me2C C(OLi)2, THF,
ꢀ20!408C, 77%; d) 1. C2O2Cl2, CH2Cl2, 208C, 2. b-d-galactopyranosyl
azide (3), pyridine, DMAP, 608C, 49%; e) PivCl, pyridine, 608C, 85%;
f) TBAF·3H2O, THF, 208C, 85%. TBDPS=tert-butyldiphenylsilyl,
DMAP=4-(N,N-dimethylamino)pyridine, Piv=pivaloyl (tBuCO),
TBAF=tetra-n-butylammonium fluoride, DMF=dimethylformamide.
remaining hydroxy groups and removal of the silyl protecting
groups, galactosyl azide 4 was coupled to the polymer-bound
chlorosilane 5 through a hexamethylene spacer (Scheme 2).
Owing to the high loading (ca. 2 mmolgꢀ1) of 5 (see ref. [11]
for synthesis) almost complete coupling was observed when
0.25 equivalents of galactosyl azide 4 were subjected to
etherification. Methanolysis of the unreacted chlorosilane
groups furnished polymer-bound galactosyl azide 6 with a
loading of about 0.38 mmolgꢀ1, which corresponds to an
average substitution of every tenth styrene unit with the
carbohydrate moiety (Scheme 2).[18] Reduction of the galac-
tosyl azide with ten equivalents each of 1,3-propanedithiol
and triethylamine in DMF gave immobilized galactosylamine
7 quantitatively and without anomerization. Both the cou-
pling with the glycosyl azide (n˜C=O = 1742 cmꢀ1, n˜azide
=
Scheme 3. Solid-phase synthesis of didehydropiperidinones. a) R1CHO
(5 equiv), AcOH (10 equiv), toluene, 208C, 6 h; b) Danishefsky's diene
9 (10 equiv), ZnCl2 (5 equiv), THF, 208C, 48 h; c) TBAF·3H2O (5 equiv
based on silyl units), AcOH (1.7 equiv), THF, 208C, 48 h.
2116 cmꢀ1) and the azide reduction were monitored by IR
spectroscopy.
It is noteworthy that analogous conditions applied to the
solution process led to an irreversible anomerization giving
the thermodynamically more stable and less reactive a-
imines. According to IR spectroscopy trimethyl orthofor-
mate[22] was found to be an unsuitable dehydrating agent.
Subsequent domino Mannich–Michael condensation at room
temperature with Danishefsky's diene 9 gave resin-bound
didehydropiperidinones 10, which could be cleaved from the
polymeric support with TBAF (1m solution in THF, buffered
with AcOH). The LC-MS analysis of the resulting crude
products 11[23] showed that they were formed in high purity,
yield, and diastereoselectivity (Table 1), despite the relatively
high temperature (228C). The diastereomeric excesses of the
2-alkyl didehydropiperidinones 11l–o and 11q were found to
be lower than those of the 2-aryl analogues. Only a slight
increase of the diastereomeric ratio was observed when the
reaction was performed at lower temperature.
Scheme 2. Synthesis of the immobilized galactosylamine. a) 1. imida-
zole, 4 (0.25 equiv), CH2Cl2, 208C, 12 h, 2. addition of MeOH, 24 h;
b) 1,3-propanedithiol, NEt3 (each 10 equiv), DMF, 208C, 12 h.
PS=polystyrene.
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Table 1: Diastereoselective synthesis of didehydropiperidinones on the
solid-phase accordingto Scheme 3.
Table 2: Conjugate hydride and cuprate addition to polymer-bound
enones accordingto Scheme 4.
Compound
R
Yield [%][a]
Purity [%][b]
d.r.[b]
Compound R1 R2
Yield [%][a] Purity [%][b] cis/trans[b]
11a
11b
11c
11d
11e
11 f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
11q
C6H5
77
77
40
73
n.d.
75
81
49
57
n.d.
80
50
57
76
61
70
73
98
92
80
97
91
93
97
89
95
97
98
83
74
95
88
92
90
97:3
97:3
94:6
98:2
100:0
99:1
98:2
93:7
99:1
96:4
p-Cl-C6H4
p-O2N-C6H4
p-F-C6H4
13a
13b
13c
13d
13e
13 f
13g
13h
13i
p-Cl-C6H4
H
H
H
H
H
34
53
n.d.
38
60
65
95
83
82
70
49
61
78
78
–
–
–
–
m-F-C6H4
p-F3C-C6H4
p-Br-C6H4
CH(CH3)2
m-F-C6H4
p-F3C-C6H4
m-Br-C6H4
m-F-C6H4
p-NC-C6H4
p-F3C-C6H4
2-Cl-6-F-C6H3
m-Br-C6H4
p-Br-C6H4
p-MeO-C6H4
CH2CH2-C6H5
n-C7H15
–
nBu 75
nBu 76
nBu 71
98:2
93:7
95:5
96:4
2-Cl-6-F-C6H3 Me 67
98:2
[a] Yield of crude product (five steps); based on initial loadingof 6.
[b] Determined by LC-MS (ELS/UV detection). n.d. not determined.
90:10
89:11
87:13
84:16
98:2
n-C5H11
CH2-CH(CH3)2
CH(CH3)2
CH3
As 2,6-disubstituted piperidines are a widespread struc-
tural motif in natural products we are also interested in a
stereoselective solid-phase approach to this class of com-
pounds. Among many cuprate reagents tested cyano-modi-
fied Gilman reagents (Lipshutz cuprates)[25] in the presence of
BF3·OEt2 were found to be the reagents of choice for the
conjugate cuprate addition to polymer-bound enones 10.
Cleavage from the polymeric support gave N-galactosylated
2,6-disubstituted piperidinones 13 f–i in high yields and
excellent cis selectivity (Scheme 4, Table 2).
The fluoride-labile anchoring strategy of the galactosyl-
amine as immobilized auxiliary described herein and its
application in domino Mannich–Michael condensations leads
to almost diastereomerically pure products even at room
temperature. The products are obtained in high purity
without the necessity for tedious separation procedures. The
dehydropiperidinones formed stereoselectively on the solid-
phase can be subjected to further functionalization as was
shown by conjugate addition reactions. Consequently, the
methodology presented herein enables rapid combinatorial
access to structurally diverse chiral piperidine derivatives.
80:20
[a] Yield of crude product (four steps); based on initial loadingof 6.
[b] Determined by LC-MS (evaporative light scattering (ELS) /UV
detection). n.d. not determined.
For further functionalization resin-bound enaminones 10
were subjected to conjugate addition reactions. The reaction
with l-selectride as hydride donor under different reaction
conditions only gave mixtures of 1,2- and 1,4-reduced
products. The reduction in the presence of the oxygenophilic
Lewis acid methylaluminum bis[2,6-di-tert-butyl-4-methyl-
phenoxide] (MAD),[24] however, after cleavage from resins
12a–e yielded the chemoselectively 1,4-reduced piperidi-
nones 13a–e (Scheme 4, Table 2). As shown for the release of
Received: August 27, 2002 [Z50054]
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Scheme 4. Conjugate hydride and cuprate addition to polymer-bound
enones 10. a) For R2 =H: l-Selectride (10 equiv), MAD (20 equiv),
THF/toluene, ꢀ208C, 4 h; for R2 =alkyl: (R2)2Cu(CN)Li2 (15 equiv),
BF3·OEt2 (15 equiv), THF, ꢀ608C!ꢀ158C, 14 h; b) TBAF·3H2O
(5 equiv based on silyl units), AcOH (1.7 equiv), THF, 208C, 48 h.
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the polymer-bound auxiliary can be accomplished by treat-
ment with dilute trifluoroacetic acid in the presence of
dimethyl sulfide and water giving rise to the corresponding
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Communications
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790
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