Synthesis of a polymer-bound galactosylamine and its application as an immobilized chiral auxiliary in stereoselective syntheses of piperidine and amino acid derivatives

Article abstract of DOI:10.1002/chem.200400253

A 2,3,4-tri-O-pivaloylated β-D-galactopyranosyl azide bearing a hydroxy-functionalized spacer unit at the C-6 position of the galactose was synthesized and immobilized on the solid phase by using a polymer-bound chlorosilane. The azide was reduced to the

Full text of DOI:10.1002/chem.200400253

FULL PAPER
Synthesis of a Polymer-Bound Galactosylamine and Its Application as an
Immobilized Chiral Auxiliary in Stereoselective Syntheses of Piperidine and
Amino Acid Derivatives
Gernot Zech and Horst Kunz*[a]
Dedicated to Professor Johann Mulzer on the occasion of his 60th birthday
Abstract: A 2,3,4-tri-O-pivaloylated b-
d-galactopyranosyl azide bearing a hy-
droxy-functionalized spacer unit at the
C-6 position of the galactose was syn-
thesized and immobilized on the solid
reaction of the immobilized galactosyl-
amine with aldehydes gave rise to the
corresponding aldimines, which under-
went a domino Mannich Michael con-
densation reaction with Danishefsky×s
diene at ambient temperature to yield
2-substituted 5,6-didehydropiperidin-4-
ones on the solid phase. Subsequent
cleavage with tetra-n-butylammonium
fluoride delivered the N-glycosylated
products in high yields, purities, and
diastereoselectivities. A chemoselective
1,4-hydride addition to the polymer-
bound dehydropiperidinones was ach-
ieved in the presence of the bulky oxy-
genophilic Lewis acid methylaluminum
[bis(2,6-di-tert-butyl-4-methylphenox-
ide)]. The conjugate addition of cyano-
modified Gilman reagents to the im-
mobilized dehydropiperidinones fur-
nished 2,6-cis-substituted piperidine de-
rivatives as the major diastereomers
that were isolated after cleavage from
the support.
phase by using
a
polymer-bound
chlorosilane. The azide was reduced to
the corresponding galactopyranosyl-
amine, which served as a versatile chiral
auxiliary in highly diastereoselective
Ugi four-component condensation re-
actions at ambient temperature. Fluo-
ride-induced cleavage from the poly-
meric support furnished N-glycosylated
N-acylated a-amino acid amides. The
Keywords: carbohydrates
¥ chiral
auxiliaries chiral piperidines
¥
¥
combinatorial chemistry
phase synthesis
¥
solid-
Introduction
Combinatorial solid-phase chemistry[1] has proven to be an
essential tool for rapid and efficient drug development. Al-
though the synthesis of enantiomerically pure compounds is
of significant importance for the medicinal industry, general-
ly applicable asymmetric solid-phase strategies are still
rare.[2] While polymer-bound chiral catalysts usually suffer
from limited applicability, several immobilized chiral auxilia-
ries have been described in the literature.[3] Auxiliaries
bound to the solid phase so far include enantiomerically
pure 1,3-oxazolidine-2-ones,[4] prolinols,[5] pseudoephedrins,[6]
or different carbohydrates;[7] these auxiliaries allow asym-
metric enolate reactions,[4] Diels Alder reactions,[8] 1,3-dipo-
lar cycloadditions,[9] conjugate additions,[4e,10] and other types
of reaction.[11]
2,3,4,6-Tetra-O-pivaloyl-b-d-galactopyranosylamine (1)[12]
was shown to be a versatile chiral auxiliary enabling, for ex-
ample, diastereoselective Strecker[13] and Ugi reactions,[14]
hetero-Diels Alder[15] and domino Mannich Michael reac-
tions.[16] Recently, we reported an immobilized version (2a)
of this chiral galactosylamine, which allows diastereoselec-
tive syntheses of piperidine derivatives on the solid phase.[7e]
Herein, we describe the preparation of this polymer-
bound galactosylamine and its employment in diastereose-
lective syntheses of piperidine and amino acid derivatives,
which are generally obtained in excellent overall yields and
high chemical and optical purities after cleavage from the
polymeric support.
[a] Dr. G. Zech, Prof. Dr. H. Kunz
Institut f¸r Organische Chemie der Universit‰t Mainz
Duesbergweg 10 14, 55128 Mainz (Germany)
Fax: ( +49)6131 39 24786
E-mail: hokunz@mail.uni-mainz.de
4136
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/chem.200400253
Chem. Eur. J. 2004, 10, 4136 4149

4136 4149
Results and Discussion
in THF, thereby furnishing the desired galactosyl azide 8
bearing a hydroxy-terminated spacer unit.
Preparation of the immobilized galactosylamine: Polymer-
bound silyl ethers, especially those substituted with bulky
groups, have been investigated extensively as reaction surfa-
ces due to the facile detachment of the reaction products by
mild fluoridolysis. Resin-bound aryl dialkylsilyl ethers have
been used in numerous syntheses of oligosaccharides,[17] gly-
copeptides,[18] polyketides,[19] and prostaglandins[20] and have
been found to be stable towards a variety of organometallic
reagents. For these reasons, we employed a sterically encum-
bered diisopropylchlorosilane as the anchor for the immobi-
lization of the galactosylamine. Coupling with a suitable hy-
droxy-functionalized galactosyl azide should furnish a pre-
cursor of the auxiliary from which the desired galactosyl-
amine can be obtained by on-bead reduction.
Polymer-bound chlorosilane 10a was obtained with a rela-
tively high loading of approximately 1.8 mmolgꢀ1 (corre-
sponding to a substitution of every fourth arene unit) by
direct lithiation of polystyrene 9a (cross-linked with 1% di-
vinylbenzene) and subsequent treatment with dichlorodiiso-
propylsilane according to a general procedure given by Far-
rall and Frÿchet (Scheme 2).[22] O-Silylation of glycosyl azide
According to preceding studies,[7c] glycosyl azide
8
(Scheme 1) bearing an w-hydroxy carboxylic acid spacer
unit at C-6 of the carbohydrate was envisioned as a suitable
Scheme 2. Synthesis of the immobilized galactosylamine. a) For 9a:
nBuLi, TMEDA, C6H12, 608C; for 9b: nBuLi, toluene, 608C (2 cycles);
b) iPr2SiCl2, THF, 208C; c) 1. imidazole, 8 (0.23 equiv), CH2Cl2, 208C,
12 h; 2. addition of MeOH, 24 h; d) 1,3-propanedithiol (10 equiv), NEt3
(10 equiv), DMF, 208C, 12 h. PS=polystyrene, TMEDA=N,N,N’,N’-
tetramethylethylenediamine.
8 with chlorosilane 10a led to the immobilized auxiliary pre-
cursor 11a with a loading of approximately 0.4 mmolgꢀ1.[23]
It should be noted that due to the high loading of 10a, 0.2
of an equivalent of 8 was sufficient to allow complete cou-
pling onto the solid phase and that there was no need to re-
isolate any potentially remaining alcohol 8 from the washing
solutions. If more than 0.2 of an equivalent of 8 was em-
ployed, the loading of 11a only slightly increased to a maxi-
mum value of 0.484 mmolgꢀ1 (with 1.0 equivalent of 8), a
result indicating that the polymeric support is saturated with
the bulky auxiliary, probably due to steric reasons.[24] Substi-
tuted polystyrene resins obtained by the lithiation procedure
described above and subsequent reaction with electrophiles
mainly show a para substitution pattern.[25] Selectively para-
substituted chlorosilane 10b was obtained when commer-
cially available para-bromopolystyrene 9b was lithiated in-
stead of polystyrene and was subsequently treated with di-
chlorodiisopropylsilane according to the procedures of Far-
rall and Frÿchet[22] and Heinze et al.,[26] respectively (load-
ing: approximately 1.437 mmolgꢀ1). Chlorosilane 10b has
been described to be advantageous with respect to reprodu-
cibility, control of the degree of functionalization, and ho-
mogeneity of the resin. However, in our hands, resin 10b
and resins 11b and 2b, obtained thereof, did not show any
noticable difference in reactivity compared to resins 11a
and 2a. Therefore, due to the lower costs of preparation,
the following transformations on the solid phase have all
been performed with silyl resins based on chlorosilane 10a.
Scheme 1. Solution-phase synthesis of 8. a) TBDPSCl, imidazole, DMF,
208C, 88%; b) CBr4, PPh3, CH2Cl2, 0!208C, 97%; c) Me2C=C(OLi)2,
THF, ꢀ20!408C, 78%; d) 1. C2O2Cl2, CH2Cl2, 208C; 2. b-d-galactopyra-
nosyl azide 5, pyridine, DMAP, 608C, 59%; e) PivCl, pyridine, 608C,
85%; f) TBAF¥3H2O, THF, 208C, 86%. TBDPS=tert-butyldiphenylsilyl,
DMF=N,N-dimethylformamide, THF=tetrahydrofuran, DMAP=4-
(N,N-dimethylamino)pyridine, Piv=pivaloyl (tBuCO), TBAF=tetra-n-
butylammonium fluoride.
precursor. Galactosyl azide 8 was readily synthesized on a
multigram scale from 1,6-hexanediol and b-d-galactopyrano-
syl azide 5 by a six-step protocol. Monoprotection of 1,6-
hexanediol with tert-butyldiphenylchlorosilane, transforma-
tion of the remaining hydroxy function to form bromide 3,
and treatment with isobutyric acid dianion delivered the
chain-extended pivalic acid derivative 4 (Scheme 1). This
was treated with oxalyl chloride and coupled to b-d-galacto-
pyranosyl azide 5[21] to give selectively 6-O-acylated galacto-
syl azide 6. The remaining carbohydrate hydroxy functions
were pivaloylated and the silyl protecting group was finally
removed by using tetra-n-butylammonium fluoride (TBAF)
Chem. Eur. J. 2004, 10, 4136 4149
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H. Kunz and G. Zech
FULL PAPER
On-bead reduction of the azide moiety was accomplished
by using 10 equivalents each of 1,3-propanedithiol and tri-
ethylamine in DMF at room temperature to give galactosyl-
amines 2 (Scheme 2). This method of reduction[27] has al-
ready been employed for the reduction of b-d-glycosyl
azides[28] on the solid phase and resulted in retention of the
b configuration at the anomeric center. Both the coupling
and the reduction reaction are favorably monitored by FT-
IR spectroscopy of KBr pellets prepared from the resins.
The spectrum obtained from resin 11a showed strong ab-
sorption for the azide (n˜azide =2116 cmꢀ1) and the ester car-
bonyl groups (n˜C O =1745 cmꢀ1), while in the spectrum of
resin 2a the azid=e absorption almost disappeared, thereby
indicating complete reduction after 22 h of vigorous shaking
(Figure 1). Galactosylamine resin 2a can be prepared on a
bient temperature without any decrease in diastereoselectiv-
ity. Shaking of the galactosylamine 2a with five equivalents
each of aldehyde, tert-butyl isocyanide, formic acid, and zinc
chloride gave rise to N-formylated N-galactosylated amino
acid derivatives 12 on the solid phase; the products were
subsequently released from the support by treatment with
fluoride (Scheme 3). Standard cleavage conditions include
1
ꢀ
Scheme 3. Diastereoselective Ugi synthesis on the solid phase. a) R
CHO (5 equiv), HCO2H (5 equiv), tBuNC (5 equiv), ZnCl2 (3 equiv),
THF, 208C; b) cleavage method A: TBAF¥3H2O (5 equiv based on silyl
units), AcOH (1.7 equiv), THF, 208C, 48 h; c) cleavage method B: 1. HF-
pyridine complex(10 equiv based on silyl units), THF, 20 8C, 2. addition
of MeOSiMe3.
stirring with five equivalents of tetra-n-butylammonium
fluoride (TBAF) in THF buffered with acetic acid (molar
ratio TBAF/AcOH 3:1). The crude products were generally
obtained with high yield, purity, and diastereoselectivity (ac-
cording to LC-MS analysis with UV and ELS detection) and
did not require any further purification.[30] In cases with
electron-deficient phenylglycine derivatives as the reaction
products 13 (see 13a, 13b, and 13d in Table 1), cleavage of
Figure 1. IR spectra of resin-bound glycosyl azide 11a (A) and amine 2a
(B).
multigram scale and stored without any loss of reactivity for
several months. Its loading was determined by elemental
analysis to be 0.414 mmolgꢀ1 (corresponding to a substitu-
tion of every eighteenth arene unit with the galactose
moiety).[29]
Table 1. Analysis of Ugi condensation products 13 after cleavage from
the polymeric support.
Compound
R1
Yield [%][a]
Purity [%][b]
d.r.[b]
ꢀ
13a
13b
13c
13d
13e
13 f
13g
13h
p-O2N C6H4
p-F3C-C6H4
Ph
66 (56)
65
58
84
67
68 (96)
70
64
92 (99)
99
98
96
98
99 (95)
95
96
76:24 (95:5)
74:26
96:4
80:20
94:6
91:9 (93:7)
91:9
90:10
With the immobilized amine 2a in hand, we first set out
to explore the use of this auxiliary in asymmetric Ugi four-
component condensation reactions on solid phase to give N-
formyl-N-galactosyl-a-amino acid derivatives. Reaction con-
ditions of the corresponding solution-phase process include
stirring of the galactosylamine 1 with a small excess of alde-
hyde, isocyanide, formic acid, and the activating Lewis acid
zinc chloride at low temperature.[14] Preliminary investiga-
tions with a similar polymer-bound galactosylamine bearing
a different spacer unit have shown that asymmetric Ugi re-
actions can be performed on the solid phase by using reac-
tion conditions similar to those reported for the solution-
phase process. In these previous studies, the N-formyl-N-ga-
lactosyl-a-amino acid derivatives were obtained after cleav-
age from the support with diastereoselectivities (d.r. 86:14
94:6)[7c] comparable to those reported for the solution-phase
process (d.r. 91:9 97:3).[14] However, to obtain sufficiently
pure reaction products purification by preparative HPLC
was necessary.
p-Cl-C6H4
p-MeO-C6H4
iPr
nPr
iBu
[a] Overall yield of crude product (3 steps, based on loading of galactosyl
azide 11a). [b] Determined by LC-MS (ELSD) of crude products; results
obtained from cleavage with HF-pyridine are given in parentheses (for
13 a and 13 f).
the silyl anchor with the nonbasic HF-pyridine complexis
recommended instead of cleavage with TBAF. Although
buffered with acetic acid, treatment with TBAF led to par-
tial epimerization of the amino acid derivatives (Table 1).
As expected from the corresponding reactions in solution,
the major diastereomers belong to the d series of a-amino
acids.[31]
Galactosyl imines prepared from 1 and aldehydes undergo
a Lewis acid promoted domino Mannich Michael reaction
with Danishefsky×s diene 16 and yield N-galactosyl-5,6-dide-
During the present work, we reinvestigated the reaction
and found that the condensation could be performed at am-
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Chem. Eur. J. 2004, 10, 4136 4149

Synthesis and Application of a Polymer-Bound Galactosylamine
4136 4149
Table 2. Diastereoselective synthesis of dehydropiperidinones on the
solid phase (after cleavage from polymeric support with TBAF).
hydropiperidin-4-ones, which represent versatile synthons
for the diastereoselective synthesis of highly functionalized
piperidine derivatives.[16,32] In a preliminary communication,
we reported on the application of galactosylamine 2a as a
highly efficient chiral matrixfor the asymmetric solid-phase
synthesis of dehydropiperidinones. As all solid-phase meth-
odologies leading to dehydropiperidinones described in the
literature so far[33] only gave racemic products, this ap-
proach, to the best of our knowledge, represents the only
asymmetric route towards a combinatorial solid-phase syn-
thesis of piperidinones.
According to this approach the primary reaction step was
the condensation of amine 2a with 5 equivalents of an aro-
matic or an aliphatic aldehyde; this was successfully ach-
ieved under optimized reaction conditions at room tempera-
ture in the presence of 10 equivalents of acetic acid
(Scheme 4). It should be noted that under these conditions
Compound R1
Yield [%][a] Purity [%][b] d.r.[b]
18a
C6H5
81
98
95:5
18b
4-F-C6H4
3-F-C6H4
4-Br-C6H4
3-Br-C6H4
4-Cl-C6H4
77
97
91
97
99:1
18c
n.d.
n.d.
57 (90[c]
77
>99:1
98:2
18d[c]
18e
)
95 (88[c]
n.d.
89
)
99:1 (95:5[c]
97:3
)
18 f
18g
2-Cl-6-F-C6H3 49
97:3
18h
18i
18j
18k
4-CN-C6H4
4-CF3-C6H4
4-NO2-C6H4
4-Me-C6H4
4-MeO-C6H4
4-pyridyl
CH2CH2-C6H5 50
CH3
CH3CH2
n-Pr
iPr
76
81
42
n.d.
84
13
93
97
80
66
98
<45
83
90
92
>99:1
98:2
93:7
91:9
98:2
18l
18m[d]
18n
n.d.
90:10
78:22
85:15
81:19
98:2
18o
50
78
90
73
61
18p[c][e]
18q[c][e]
18r
n.d.
92
88
18s
iBu
82:18
18t
tBu
n-pentyl
n-heptyl
18u[c][e]
18v
87
57
95
74
84:16
89:11
[a] Overall yield of crude product (4 steps, based on loading of galactosyl
azide 11a). [b] Determined by LC-MS (ELSD). [c] Cleavage with HF-
pyridine. [d] 15 equivalents of ZnCl2 were used. [e] Domino reaction at
ꢀ108C. n.d.=not determined.
in cases with aromatic-substituted dehydropiperidinones,
whereas an increase of reaction temperature to 608C result-
ed in significantly diminished purity of crude products after
cleavage. Obviously aliphatic dehydropiperidinones (except
for 18r where R is the bulky isopropyl group; see Table 2)
were formed with lower diastereoselectivity than their aro-
matic counterparts. As this difference was not observed in
the corresponding solution-phase reaction, it has to be as-
cribed to either reaction or cleavage conditions on the solid
phase. However, for aliphatic-substituted enaminones 17
and 18, respectively, the diastereomeric ratio could be shift-
ed towards the major diastereomer by lowering the reaction
temperature (for 18q, for example, the following diastereo-
meric ratios at different reaction temperatures have been
determined: 68:32 at 208C, 81:19 at ꢀ108C, and 81:19 at
ꢀ258C). Moreover, in contrast to the a-amino acid deriva-
tives mentioned above, the nature of the fluoride source did
not influence the chemical or optical purity of crude prod-
ucts 18 (Table 2, 18e and 18q).[35]
1
ꢀ
Scheme 4. Solid-phase synthesis of dehydropiperidinones. a) R CHO
(5 equiv), AcOH (10 equiv), toluene, 208C, 6 h; b) Danishefsky×s diene
16 (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.
anomerization was not a problem, as could be anticipated
from preceding studies on reactions of the galactosylamine 1
in solution.[13] Moreover, undesired cleavage from the sup-
port during the condensation did not occur, as was proven
by gravimetric control and analysis of the combined washing
solutions. Interestingly, imine formation cannot be per-
formed with trimethylorthoformate as the dehydrating
agent.[34] However, the imine purity and the completeness of
imine formation could only be estimated by analysis of the
products derived from polymer-bound galactosyl imines.
Subsequent Mannich Michael reactions of aldimines 15
with Danishefsky×s diene 16 to give resin-bound dehydropi-
peridinones 17 were preferably performed at room tempera-
ture as well (Scheme 4). The diastereoselectivities deter-
mined for the crude products 18 after fluoride-induced
cleavage compared well with those reported for the corre-
sponding solution-phase process,[16a,b] especially in cases of
dehydropiperidinones bearing an aromatic substituent at C-
2 (Table 2). It has to be emphasized that lowering of the re-
action temperature did not improve the diastereomeric ratio
After elaborating efficient reaction conditions for the syn-
thesis of polymer-bound dehydropiperidinones, we were
next interested in achieving transformations leading to
higher-functionalized piperidine derivatives on the solid
phase.
The first transformation envisioned by us was the chemo-
ꢀ
selective reduction of the C C double bond, to give finally
chiral 2-substituted piperidines. In solution chemistry, steri-
cally demanding borohydride reagents (for example, L-se-
lectride) have been found to be the reagents of choice for
this hydride addition. However, if polymer-bound dehydro-
piperidinones 17 were treated with varying quantities of L-
selectride, mixtures of the desired 1,4 and concurring 1,2 ad-
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4139

H. Kunz and G. Zech
FULL PAPER
dition products were isolated in all cases. In addition, the
corresponding tetrahydropyridines resulting from reduction
enhanced by employing the sterically more demanding
methyl aluminum-bis(2,4,6-tri-tert-butylphenoxide) (MAT;
Table 3, 20r).[36a]
ꢀ
of both the C C double bond and the carbonyl group and
subsequent elimination of water, probably under the condi-
tions of the fluoride-induced cleavage from the polymeric
support, have been detected as by-products. Reaction condi-
tions, as well as stoichiometry, could not be optimized in
favor of the chemoselective conjugate C=C bond reduction
of the enone moiety. Improved purities of the products were
only observed when the sterically demanding Lewis acid
methyl aluminum-bis(2,6-di-tert-butyl-4-methylphenoxide)
(MAD) was added to the reaction mixture. Beside some
other interesting synthetic applications,[36] this oxygenophilic
aluminum complexhas been shown to allow chemoselective
conjugate addition of Li organyls to a,b-unsaturated ke-
tones.[37] In the present case, the carbonyl function of dehy-
dropiperidinones 17 is activated and simultaneously effec-
tively blocked, thereby allowing selective attack of the hy-
dride at the b position (Scheme 5). Piperidinones 20 were
The conjugate addition of soft nucleophiles (for example,
organocuprates) to dehydropiperidinones generates the 2,6-
disubstitution pattern of piperidines that is a common struc-
ture motif in natural products.[38] Therefore, we were inter-
ested in the stereoselective solid-phase synthesis of 2,6-di-
substituted piperidine derivatives, which are readily available
by using the glycosyl imine strategy in solution. Due to the
vinylogous amide structure of the enone the conjugate addi-
tion requires soft nucleophiles in combination with hard
electrophiles for activation (for example, Yamamoto-type[39]
mono-organocuprates RCu¥BF3¥OEt2 or Gilman reagents ac-
tivated with trimethylsilylchloride (TMSCl)[40]). However,
all attempts to apply these cuprate reagents to the corre-
sponding reaction on the solid phase failed to give selective-
ly 2,6-disubstituted piperidines. In most cases either no reac-
tion or an unselective cuprate addition took place. The rea-
sons for this unexpected outcome probably lie in processes
that occur upon slowly warming up the reaction mixtures.
Therefore, it was necessary to investigate other cuprate re-
agents which show sufficient reactivity and especially stabili-
ty–even at the higher temperatures that are obviously
needed for cuprate addition on the solid phase to occur.
After several attempts with different donor-stabilized cup-
rate reagents and b-silyl cuprates,[41] cyano-modified Gilman
cuprates[42] proved to be the reagents of choice for this
transformation on the solid phase. When resin-bound dehy-
dropiperidinones were subjected to an excess of cuprate re-
agent R2Cu(CN)Li2 in the presence of BF3¥OEt2, conjugate
addition took place and furnished piperidine derivatives 21
(Scheme 6, Table 4). Crude 2,6-disubstituted piperidinones
Scheme 5. Conjugate hydride addition to polymer-bound enones 17. a) L-
Selectride (10 equiv), MAD (20 equiv), THF/toluene, ꢀ208C, 4 h;
b) TBAF¥3H2O (5 equiv based on silyl units), AcOH (1.7 equiv), THF,
208C, 48 h. MAD=methylaluminum bis(2,6-di-tert-butyl-4-methylphen-
oxide).
obtained after fluoridolytic detachment from the resins 19 in
satisfactory yields and purities. The major impurities either
arose from unreduced dehydropiperidinones 18 or from pi-
peridin-4-ols formed by double reduction (Scheme 5,
Table 3). It has to be noted that product purity could not be
Table 3. Conjugate hydride addition on the solid phase in the presence
of MAD (after cleavage from the polymeric support).
Scheme 6. Conjugate cuprate addition to polymer-bound enones 17.
a) (R2)2Cu(CN)Li2 (30 equiv), BF3¥OEt2 (30 equiv), THF, ꢀ60!ꢀ158C,
14 h, then washing with ammonium pyrrolidine dithiocarbamate solution;
b) TBAF¥3H2O (5 equiv based on silyl units), AcOH (1.7 equiv), THF,
208C, 48 h.
Compound
R1
Yield [%][a]
Purity [%][b]
20c
20d
20e
3-F-C6H4
53
34
99
4-Br-C6H4
3-Br-C6H4
4-Cl-C6H4
2-Cl-6-F-C6H3
4-F3C-C6H4
4-MeO-C6H4
iPr
82[f]
51
n.d.
50
n.d.
n.d.
n.d.
28 (32)
20 f
65[f]
47
83
21
74 (77)
22 were obtained in satisfactory yields and purities after re-
lease from the polymeric support. However, it has to be
noted that there was a distinct relationship between the re-
action temperature and the purity and diastereomeric ratio
of crude products 22. The lower the temperature chosen for
the cuprate addition and the longer this temperature was
kept, the higher was the diastereomeric ratio observed for
the piperidinones in most cases. As anticipated from preced-
ing studies carried out on reactions in solution, the major di-
astereomer was the cis-configured form (Scheme 6, Table 4).
20g
20i[c]
20l[d]
20r[e]
[a] Overall yield of crude product (5 steps, based on loading of galactosyl
azide 11a). [b] Determined by LC-MS (ELS detection unless otherwise
stated). [c] 40 equivalents of MAD and 15 equivalents of L-selectride
were used. [d] 10 equivalents of MAD and 5 equivalents of L-selectride
were used at ꢀ408C. [e] Numbers in parentheses show results when
MAT was used instead of MAD. [f] UV detection at l=215 nm. n.d.=
not determined.
4140
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4136 4149

Synthesis and Application of a Polymer-Bound Galactosylamine
4136 4149
Table 4. Addition of cyano-modified Gilman reagents to polymer-bound
enones 17 (after cleavage from the polymeric support).
Experimental Section
Compound R1
R2
Temp.
grad.[a]
Yield [%][b] Purity [%][c] d.r.[d]
General procedures: 1H NMR and 13C NMR spectra were recorded on
Bruker AC-200, AC-300, AM-400, or DRX-600 spectrometers. LC-MS
spectra were measured with an assembly consisting of a Knauer Maxi-
Star K-1001 gradient pump, a PhenomenexLuna C-18 (2) column (3 m,
75î4.6 mm), an LKB 2140 diode array detector, a PL-ELS 1000 ELS de-
tector (Polymer Laboratories), and a Navigator-1 ESI mass spectrometer
(ThermoQuest). Unless otherwise noted, all analytical HPLC runs were
performed with a flow rate of 0.75 mLminꢀ1 and a gradient of MeCN/
H2O (80:20!100:0 (v/v) within 10 min). Preparative and semi-prepara-
tive HPLC was performed with Luna C-18 (2) columns (10 m, 250î
50 mm and 250î21.2 mm, respectively), 2 Knauer Mini-Star K-500 gradi-
ent pumps, and a variable wavelength detector (Knauer). Flow rates
were 20 mLminꢀ1 for preparative and 10 mLminꢀ1 for semi-preparative
separations. IR spectra were measured on a Perkin Elmer FT-1760X ap-
paratus by using KBr pellets (5 mg of resin with 120 mg of KBr).
22ac
22ca
Ph
3-F-
nBu
nBu
A
B
38
75
33 (61)
49 (40)
n.d.
98:2
C6H4
3-F-
C6H4
3-F-
C6H4
3-Br-
C6H4
3-Br-
C6H4
2-Cl-6- Ph
F-C6H3
2-Cl-6- Me
F-C6H3
4-F3C-
C6H4
4-F3C-
C6H4
4-F3C-
C6H4
iPr
22ca
22ca
22ea
22ea
22gc
22gb
22ia
22ia
22ia
22rc
nBu
nBu[e]
nBu
nBu
C
D
B
E
D
D
B
C
E
A
47
n.d.
71
44
48
67
76
47
62
39
99
90:10
67:33
95:5
52 (47)
78 (22)
90
74:26
78:22
96:4
68
81 (12)
61 (27)
85 (15)
99
Solid-phase reactions were either run in standard glassware or in fritted
glass cylinders being shaken in a Miniblock apparatus (Bohdan). All re-
actions involving organometallic species were carried out under an argon
atmosphere with oven-dried glassware.
nBu
nBu
nBu
Ph
93:7
72:28
84:16
n.d.
Materials: TLC was performed on Merck silica gel 60 F254 aluminum
sheets. Silica gel was used for flash chromatography (40 63 mm) and for
filtrations (63 200 mm). The resins were purchased from Acros and Nova-
Biochem, washed successively with water, ethanol, THF, CH2Cl2, and di-
ethyl ether, dried under high vacuum at 608C for 12 h, and stored in a
desiccator over P2O5. THF was distilled over potassium benzophenone
ketyl, toluene over sodium benzophenone ketyl, and CH2Cl2 over calci-
um hydride immediately prior to use. Aldehydes used for imine forma-
tion were distilled und stored under argon at 48C. A solution of zinc
chloride in THF was prepared by melting ZnCl2 (3.41 g, 25 mmol) with
3 drops of conc. HCl under high vacuum and dissolving it in dry THF
(25 mL) after recooling. Diene 16 was prepared from 4-methoxybut-3-
ene-2-one by the silylation procedure given by Danishefsky and Kitahara
followed by repeated careful distillation at moderate temperature (oil
bath temperature has to be kept below 708C).[43]
30 (30)
[a] Temperature gradients used: A: ꢀ408C for 18 h; B: ꢀ788C!ꢀ608C
over 2 h, then ꢀ608C!ꢀ158C over 12 h; C: ꢀ608C for 2 h, then ꢀ558C
for 12 h; D: ꢀ208C for 16 h; E: ꢀ408C for 2 h, then ꢀ408C!ꢀ158C
over 14 h. [b] Overall yield of crude product (5 steps, based on loading of
galactosyl azide 11a). [c] Determined by LC-MS (ELSD), percentage of
reisolated dehydropiperidinone is given in parentheses. [d] Determined
by LC-MS (ELSD). [e] TMSCl was used instead of BF3¥OEt2. n.d=not
determined.
6-(tert-Butyldiphenylsilyloxy)hexylbromide (3): tert-Butyldiphenylchloro-
silane (36.3 mL, 0.140 mol) was added to a solution of 1,6-hexanediol
(50.0 g, 0.423 mol) and imidazole (15.3 g, 0.224 mol) in DMF (700 mL) at
room temperature. After 36 h the solvent was removed and the residue
was dissolved in dichloromethane (400 mL) and washed twice with 1n
HCl and water. The organic layer was dried with MgSO4. Silica gel flash
chromatography (petroleum ether/ethyl acetate (4:1)) enabled separation
of excess 1,6-hexanediol and of bissilylated by-product from the monosi-
lylated product 6-(tert-butyldiphenylsilyloxy)hexanol (44.2 g, 88%),
which was obtained as a colorless oil; Rf =0.43 (petroleum ether/ethyl
acetate (2:1)); 1H NMR (CDCl3, 200 MHz): d=7.68 7.63 (m, 4H, aryl);
7.41 7.32 (m, 6H, aryl); 3.61 (pq, 4H, 3J=6.6 Hz, CH2OH, CH2OSi);
1.56 1.50 (m, 4H, 2îCH2); 1.38 1.24 (m, 4H, 2îCH2); 1.04 (s, 9H,
tBu) ppm; MS (FD): m/z: 356.4 [M]+; elemental analysis: calcd (%) for
C22H32O2Si (356.57): C 74.10, H 9.05; found: C 73.83, H 9.26.
Conclusion
Herein, we have described the fluoride-labile linking strat-
egy of a galactosylamine as a polymer-bound chiral auxiliary
and its employment in Ugi four-component and domino
Mannich Michael condensation reactions. In both types of
transformations stereodifferentiation was readily and effi-
ciently achieved at room temperature. The reaction products
were usually obtained in high yield and good chemical and
optical purity. It has to be emphasized that the analogous
solution-phase reactions leading to the corresponding prod-
ucts with comparable diastereoselectivities had to be con-
ducted at ꢀ258C or even at lower temperatures. Dehydropi-
peridinones arising from the domino Mannich Michael con-
densation reaction were further functionalized by conjugate
addition reactions, thereby enabling an efficient access to pi-
peridine derivatives of higher structural diversity. As the
presented methodology delivered the glycosylated diastereo-
meric reaction products and allowed a direct analysis of the
diastereomeric ratio, the optimization of reaction sequences
was achieved in a time-efficient manner. However, to obtain
enantiomerically pure amino acid and piperidine derivatives,
respectively, the N-glycosidic bond has to be cleaved. Strat-
egies towards the selective cleavage of the N-glycosidic
bond of immobilized reaction products with the chiral auxil-
iary left on the polymeric support will be reported in due
course.
Transformation into bromide 3:
A solution of tetrabromomethane
(43.11 g, 0.130 mol) in dry dichloromethane (150 mL) was added to a sol-
ution of the silyl ether prepared as described above (36.64 g, 0.103 mol)
in dichloromethane (700 mL). At 08C, a solution of triphenylphosphine
(39.34 g, 0.150 mol) in dichloromethane (100 mL) was added dropwise.
The reaction mixture was stirred for 3 h at 08C and for 12 h at room tem-
perature. After evaporation of the solvent, the residue was suspended in
diethyl ether (700 mL) and filtered. The filter cake was washed several
times with diethyl ether. The combined filtrates were concentrated in
vacuo und the remaining yellowish oil was purified by silica gel flash
chromatography (petroleum ether/ethyl acetate (15:1)) to give 3 (41.86 g,
97%) as colorless oil; Rf =0.84 (petroleum ether/ethyl acetate (15:1));
1H NMR (CDCl3, 200 MHz): d=7.67 7.63 (m, 4H, aryl); 7.41 7.36 (m,
6H, aryl); 3.64 (t, 2H, 3J=6.1 Hz, CH2OSi); 3.37 (t, 2H, 3J=6.8 Hz,
CH2Br); 1.86 1.79 (m, 2H, 1îCH2); 1.58 1.53 (m, 2H, 1îCH2); 1.39
1.36 (m, 4H, 2îCH2); 1.03 (s, 9H, tBu) ppm; 13C NMR (CDCl3,
50.3 MHz): d=135.6, 129.5, 127.6 (phenyl); 134.1 (ipso-phenyl); 63.7
(CH2O); 33.9 (CH2Br); 32.8, 32.3, 27.9, 25.0 (4îCH2); 26.9 (3îMe); 19.3
(CMe3) ppm; MS (FD): m/z: 418.2 [M]+, 340.3 [MꢀBr]+; elemental anal-
Chem. Eur. J. 2004, 10, 4136 4149
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4141

H. Kunz and G. Zech
FULL PAPER
ysis: calcd (%) for C22H31BrOSi (419.47): C 62.99, H 7.45; found: C
62.25, H 7.35.
Me); 1.02 (s, 9H, tBu) ppm; 13C NMR (CDCl3, 50.3 MHz): d=177.4,
177.1, 176.7 (C=O); 135.5, 134.2, 129.5, 127.6 (aryl); 88.5 (C-1); 73.2,
70.8, 67.8, 66.6 (C-2, C-3, C-4, C-5); 64.0, 61.0 (C-6, CH2OR); 42.3
(CMe2); 40.5 (CH2); 39.1, 38.8, 38.8 (Piv CMe3); 32.6, 29.8 (2îCH2);
27.2, 27.0, 26.9 (Piv Me, tBu Me); 25.7 (CH2); 25.1, 25.1, 24.9 (CH2, 2î
Me); 19.2 (tBu CMe3) ppm; MS (FD): m/z: 809.1 [MꢀtBu]+; MS (ES+):
m/z: 888.7 [M+Na]+; elemental analysis: calcd (%) for C47H71N3O10Si
(866.17): C 65.17, H 8.26, N 4.85; found: C 65.16, H 8.11, N 4.96.
2,2-Dimethyl-8-(tert-butyldiphenylsilyloxy)-octanoic acid (4): Lithium di-
isopropylamide was prepared by adding nBuLi (1.6m in n-hexane;
235.1 mL, 0.376 mol) dropwise to
a solution of diisopropylamine
(52.7 mL, 0.376 mol) in dry THF (400 mL) at ꢀ208C. The solution was
stirred for an additional 20 min and subsequently treated with isobutano-
ic acid (15.9 mL, 0.171 mol). The mixture was slowly warmed to 508C
(2 h) and recooled to ꢀ208C. A solution of hexylbromide 3 (35.86 g,
0.086 mol) in THF (50 mL) was added dropwise to the solution of the
dianion at ꢀ208C, then the mixture was warmed to 408C and kept at this
temperature for 1 h. The reaction mixture was hydrolyzed with cold 2n
HCl (220 mL) and the organic solvents were removed to a great extent.
The aqueous layer was extracted twice with dichloromethane (each
500 mL) and the organic solutions were washed with 1n HCl and water
and dried over MgSO4. Purification of the crude product by silica gel
2,3,4-Tri-O-pivaloyl-6-O-(2,2-dimethyl-8-hydroxy-octanoyl)-b-d-galacto-
pyranosyl azide (8): A solution of silyl ether 7 (16.57 g, 18.8 mmol) in
THF (250 mL) was treated with TBAF¥3H2O in THF (1m, 24.9 mL,
24.9 mmol) and stirred at room temperature until desilylation was com-
plete (24 h). The solvent was evaporated in vacuo and the residue was
dissolved in dichloromethane (400 mL), extracted twice with water
(200 mL), and dried with MgSO4. The crude product was purified by
silica gel flash chromatography (petroleum ether/ethyl acetate (5:1)) to
give 8 (10.19 g, 86%) as colorless needles; Rf =0.24 (petroleum ether/
ethyl acetate (4:1)); m.p. 748C; [a]2D5 =ꢀ9.91 (c=1, CHCl3); 1H NMR
(CDCl3, 200 MHz): d=5.39 (d, 1H, 3J=2.4 Hz, H-4); 5.17 (dd, 1H, 3J=
10.2, 3J=7.8 Hz, H-2); 5.07 (dd, 1H, 3J=10.0, 3J=2.7 Hz, H-3); 4.60 (d,
1H, 3J=7.8 Hz, H-1); 4.21 3.92 (m, 3H, H-5, H-6a, H-6b); 3.59 (t, 2H,
3J=6.3 Hz, CH2OH); 1.85 (brs, 1H, OH); 1.50 1.39 (m, 4H, 2îCH2);
1.32 1.23 (m, 13H, 2îCH2, 1îPiv tBu); 1.14, 1.07 (2s, 18H, Piv tBu);
1.11 (s, 6H, 2îMe) ppm; 13C NMR (CDCl3, 50.3 MHz): d=177.4, 177.3,
176.7 (C=O); 88.5 (C-1); 73.1, 70.8, 67.9, 66.6 (C-2, C-3, C-4, C-5); 62.8,
61.0 (C-6, CH2OH); 42.3 (CMe2); 40.4 (CH2); 39.1, 38.8 (Piv CMe3);
32.7, 29.7 (2îCH2); 27.1, 27.0 (Piv Me); 25.5 (CH2); 25.1, 25.0, 24.9
(CH2, 2îMe) ppm; MS (ES+): m/z=622.0 [M+NaꢀN2]+; 650.1
[M+Na]+; elemental analysis: calcd (%) for C31H53N3O10 (627.77): C
59.31, H 8.51, N 6.69; found: C 59.44, H 8.64, N 6.70.
flash chromatography (petroleum ether/ethyl acetate (8:1)) gave
4
(38.78 g, 78%) as colorless oil; Rf =0.65 (petroleum ether/ethyl acetate
(6:1)); 1H NMR (CDCl3, 200 MHz): d=7.67 7.62 (m, 4H, aryl); 7.38
7.35 (m, 6H, aryl); 3.63 (t, 2H, 3J=6.3 Hz, CH2OSi); 1.53 1.46 (m, 4H,
2îCH2); 1.32 1.20 (m, 6H, 3îCH2); 1.17 (s, 6H, 2îMe); 1.03 (s, 9H,
tBu) ppm; 13C NMR (CDCl3, 50.3 MHz): d=184.9 (COOH); 135.6, 129.5,
127.6 (phenyl); 134.2 (ipso-phenyl); 64.0 (CH2O); 42.1 (CMe2COOH);
40.5, 32.5, 29.9, 25.7, 24.8 (5îCH2); 26.9 (3îMe); 25.0 (2îMe); 19.3
(CMe3) ppm; MS (ESꢀ): m/z: 425.4 [MꢀH]ꢀ; 255.2 [OTBDPS]ꢀ; elemen-
tal analysis: calcd (%) for C26H38O3Si (426.66): C 73.19, H 8.98; found: C
73.17, H 8.73.
6-O-[2,2-Dimethyl-8-(tert-butyldiphenylsilyloxy)-octanoyl]-b-d-galacto-
pyranosyl azide (6): a,a-Branched carboxylic acid 4 (28.24 g, 66.2 mmol)
was dissolved in dry dichloromethane (200 mL) and treated with oxalyl
chloride (7.2 mL, 86.1 mmol). When gas evolution had ceased, the sol-
vent was evaporated and the crude acid chloride was dried under high
vacuum. The acid chloride was taken up in dry pyridine (150 mL) and
added dropwise to a solution of b-d-galactopyranosyl azide 5[21] (9.05 g,
44.1 mmol) in pyridine (60 mL). After addition of catalytic amounts of
DMAP, the mixture was stirred for 20 h at 708C. After concentration in
vacuo the residue was dissolved in ethyl acetate (500 mL) and extracted
twice with 1n HCl (300 mL), saturated NaHCO3, and water. The organic
solution was dried with MgSO4 and the residue obtained after evapora-
tion of the solvent was purified by silica gel flash chromatography (ethyl
acetate) to furnish 6 (15.90 g, 59%) as a yellowish oil; Rf =0.62 (ethyl
Polymer-bound diisopropylchlorosilane (10a): In a solid-phase reaction
vessel fitted with frit and heating jacket, washed and dried polystyrene
(4.00 g, 38.3 mmol, 100 200 mesh, cross-linked with 1% divinylbenzene)
was suspended in dry cyclohexane (40 mL). After addition of TMEDA
(7.52 mL, 49.8 mmol) and n-BuLi (1.6m in n-hexane; 31.1 mL,
49.8 mmol) the suspension was shaken at 608C for 4 h. After being
cooled to room temperature, the deeply red colored resin was washed
with dry cyclohexane (2î20 mL) and dry THF (3î20 mL) and swollen
in dry THF (60 mL). Upon addition of dichlorodiisopropylsilane
(11.8 mL, 65.1 mmol), an instantaneous decolorization was observed.
After 1.5 h of shaking the resin was washed successively with dry THF
and diethyl ether (3 cycles) and dried under high vacuum for 12 h to fur-
nish 10a (5.66 g, colorless beads; (DM=+1.66 g, which corresponds to
8.73 mmol chlorosilane units or approximately 1.542 mmolgꢀ1): FT-IR
(KBr): n˜ =3025 (w); 2923 (m); 2850 (w); 1602 (s); 1493 (s); 1452 (s);
1115 (br); 1029 (w); 883 (m); 757 (s); 730 (m); 697 (s) cmꢀ1; elemental
analysis: {[(C8H8)x(C10H10)y]1[C8H7SiCl(iPr)2]0.32} with x=0.959 and y=
0.013; found: C 80.27, H 8.37, equal to (C+H)=88.6%, (Si+Cl)=
11.4%; the loading (l) was calculated by using Equation 1, where w(Si in
SiCl)=44.2%.
1
acetate); [a]2D5 =0.43 (c=1, CHCl3); H NMR (CDCl3, 400 MHz): d=7.64
(dd, 4H, 3J=7.8, 4J=1.6 Hz, 4îaryl); 7.41 7.32 (m, 6H, 6îaryl); 4.51
(brd, 1H, H-1); 4.36 4.27 (m, 2H, H-6a, H-6b); 3.88 (brs, 1H, H-4);
3
3.74 (t, 1H, J=6.3 Hz, H-5); 3.63 3.58 (m, 4H, CH2OSi, H-2, H-3); 3.52
(brs, 3H, 3îOH); 1.53 1.45 (m, 4H, 2îCH2); 1.33 1.27 (m, 2H,
1îCH2); 1.26 1.18 (m, 4H, 2îCH2); 1.14 (s, 6H, 2îMe); 1.02 (s, 9H,
tBu) ppm; 13C NMR (CDCl3, 50.3 MHz): d=178.5 (C=O); 134.1 (ipso-
aryl); 135.6, 129.5, 127.6 (aryl); 90.6 (C-1); 74.6, 73.4, 70.9, 68.5 (C-2, C-3,
C-4, C-5); 64.0, 62.5 (C-6, CH2OR); 42.4 (CMe2); 40.4, 32.5, 29.8, 25.6,
24.8 (5îCH2); 26.9 (Me); 25.0 (CMe2); 19.2 (CMe3) ppm; MS (ES+):
m/z: 608.0 [M+NaꢀN2]+; 636.0 [M+Na]+; elemental analysis: calcd (%)
for C32H47N3O7Si (613.82): C 62.62, H 7.72, N 6.85; found: C 63.41,
H 7.65, N 6.95.
wðSi þ ClÞ Â wðSi in SiClÞ
ð1Þ
l10 a
¼
¼ 1:794 mmol gꢀ1
MðSiÞ
2,3,4-Tri-O-pivaloyl-6-O-[2,2-dimethyl-8-(tert-butyldiphenylsilyloxy)-octa-
noyl]-b-d-galactopyranosyl azide (7): A solution of linker-conjugated gal-
actosyl azide 6 (5.25 g, 8.6 mmol) in dry pyridine (100 mL) was treated
with pivaloyl chloride (5.3 mL, 42.8 mmol) and stirred at 608C for 6 days.
After filtration of precipitated pyridine hydrochloride and washing, the
solution was concentrated in vacuo and the residue was taken up with
ethyl acetate (500 mL) and extracted twice with 1n HCl (300 mL), satu-
rated NaHCO3, and water. The organic layer was dried with MgSO4 and
evaporated and the residue was purified by silica gel flash chromatogra-
phy (petroleum ether/ethyl acetate (12:1)) to give 7 (6.33 g, 85%) as a
Polymer-bound 2,3,4-tri-O-pivaloyl-6-O-(2,2-dimethyl-8-hydroxy-octano-
yl)-b-d-galactopyranosyl azide (11a)–Immobilization of galactosyl
azide: Polymer-bound chlorosilane 10a (5.59 g, approximately
9.67 mmol) was swollen in dry dichloromethane (40 mL). This was fol-
lowed by addition of galactosyl azide 8 (1.40 g, 2.23 mmol) and imidazole
(1.14 g, 1.81 mmol), each dissolved in dichloromethane (10 mL), and the
suspension was shaken at room temperature for 24 h. After addition of
dry MeOH (3.6 mL, 89.1 mmol) the suspension was shaken for a further
24 h. After filtration, the resin was washed successively with dichlorome-
thane and diethyl ether (3 cycles), with DMF (4î), and with dichlorome-
thane and diethyl ether (3 cycles). For gravimetric analysis the resin was
dried under high vacuum for 12 h. The polymer-bound galactosyl azide
was obtained as approximately 7 g of colorless beads: FT-IR (KBr): n˜ =
3026 (w); 2925 (br); 2864 (m); 2117 (m); 1745 (s); 1602 (m); 1494 (s);
1453 (s); 1384 (w); 1277 (m); 1111 (br); 883 (m); 759 (s) cmꢀ1; elemental
analysis: Calcd. (%) for (C8H8)0.959(C10H10)0.013(C8H7Si(iPr)2OXc)0.074(C8H7-
Si(iPr)2OMe)0.246 (wherein Xc =C31H52N3O10): C 78.7, H 8.5, N 1.4; found:
colorless oil; Rf =0.56 (petroleum ether/ethyl acetate (10:1)); [a]D25
=
ꢀ6.34 (c=1, CHCl3); 1H NMR (CDCl3, 200 MHz): d=7.67 7.62 (m, 4H,
aryl); 7.40 7.32 (m, 6H, aryl); 5.41 (d, 1H, 3J=2.9 Hz, H-4); 5.19 (dd,
1H, 3J=10.2, 3J=8.3 Hz, H-2); 5.09 (dd, 1H, 3J=10.3, 3J=2.9 Hz, H-3);
4.59 (d, 1H, 3J=8.3 Hz, H-1); 4.24 3.95 (m, 3H, H-5, H-6a, H-6b); 3.62
(t, 2H, 3J=6.6 Hz, CH2OR); 1.56 1.40 (m, 4H, 2îCH2); 1.36 1.25 (m,
13H, 2îCH2, 1îPiv tBu); 1.16, 1.09 (2 s, 18H, Piv tBu); 1.12 (s, 6H, 2î
4142
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4136 4149

Synthesis and Application of a Polymer-Bound Galactosylamine
4136 4149
C 80.02, H 9.21, N 1.54; loading based on nitrogen content: l11a
=
amounts from 10 mg up to 1 g. For analytical purposes the miniscale
cleavage (10 mg) easily allowed quantification of the purity of reaction
products. However, due to the small amount of product expected in these
cases the corresponding yield is not given (n.d.=not determined).
0.366 mmolgꢀ1 (calculated from [Eq. (2)], where w≈ (N) is the mean value
of nitrogen content of a sample of resin 11a). Coupling was nearly quan-
titative as only traces of galactosyl azide 8 could be detected in the com-
bined wash solutions.
General procedure for the synthesis of polymer-bound Ugi condensation
products (12) by using galactosylamine 2a: A suspension of galactosyl-
amine resin 2a in dry THF (1 mL per 100 mg resin) was mixed with alde-
hyde (5 equiv), formic acid (5 equiv), tert-butyl isocyanide (5 equiv), and
ZnCl2 (3 equiv, 1m in THF) and shaken for 24 h at room temperature.
After filtration the resin was washed with dichloromethane, THF, and di-
ethyl ether and dried under high vacuum. Fluoridolytic cleavage from the
support by using either method A or B (see above) gave N-formyl-N-gal-
actopyranosyl-a-amino acid tert-butyl amides 13. (Due to amide rotamer-
ism partial signal doubling was observed in NMR spectra. This is indicat-
ed by the superscript R.}
ꢀ1
l11a ½mmol gꢀ1ꢁ ¼ 10 wðNÞ ½%ꢁ=½3 Â 14:007 g mmol
ꢁ
ð2Þ
ꢀ
Polymer-bound 2,3,4-tri-O-pivaloyl-6-O-(2,2-dimethyl-8-hydroxy-octano-
yl)-b-d-galactopyranosylamine (2a)–Reduction of galactosyl azide: Pol-
ymer-bound azide 11a (approximately 7 g, corresponding to about
2.24 mmol) was swollen in dry DMF (70 mL) and treated with triethyl-
amine (3.10 mL, 22.4 mmol) and 1,3-propanedithiol (2.24 mL, 22.4 mmol).
The suspension was shaken at room temperature for 24 h, then filtered.
The resin was successively washed with dichloromethane and diethyl
ether (3 cycles) and with dichloromethane und methanol (3 cycles). A
yield of 6.74 g of colorless beads was obtained: FT-IR (KBr): n˜ =3027
(m); 2926 (s); 2864 (s); 1741 (s); 1601 (m); 1494 (s); 1453 (s); 1384 (w);
1280 (m); 1110 (br); 1029 (w); 994 (w); 883 (m); 759 (s) cmꢀ1; elemental
analysis: found: C 81.66, H 8.48, N 0.58; loading based on nitrogen con-
tent: l2a =0.414 mmolgꢀ1 (calculated from [Eq. (3)], where w≈ (N) is the
mean value of nitrogen content of a sample of resin 2a).
N-Formyl-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4,-tri-O-pivaloyl-
b-d-galacto-pyranosyl]-4-nitrophenylglycine-tert-butyl amide (13a): Clea-
vage A: Yield: 2.3 mg (66%); colorless oil; LC-MS: tR =4.71 (minor);
6.20 (major) min; d.r. 24:76 (ELSD), purity 92% (ELSD). Cleavage B:
LC-MS: tR =4.67 (minor); 6.17 (major) min; d.r. 5:95 (ELSD), purity
99% (ELSD). Isolation of both stereoisomers by preparative HPLC
(Luna C-18, MeCN (80%!100%), 60 min, l=215 nm); S isomer: tR =
50.0 min; yield: 14.8 mg (8%); colorless, amorphous solid; [a]2D5 =5.70
(c=1, CDCl3); Rf =0.30 (petroleum ether/ethyl acetate (4:1)); 1H NMR
(CDCl3, 400 MHz): d=8.38R, 8.16 (s, 1H, CHO); 8.38, 8.20R (d, 2H, 3J=
ꢀ1
l2a ½mmol gꢀ1ꢁ ¼ 10 wðNÞ ½%ꢁ=14:007 g mmol
ð3Þ
ꢀ
3
8.6 Hz, aryl); 7.52 (d, 2H, J=7.8 Hz, aryl); 6.01R, 5.50 (s, 1H, NH); 6.02,
Polymer-bound, para-selective diisopropylchlorosilane (10b): The prepa-
ration of resin 10b from para-bromopolystyrene was performed accord-
ing to the procedure given by Heintze et al.,[26] except that the lithiation
procedure was carried out twice before the resin was treated with di-
3
3
5.05R (d, 1H, J=9.4 Hz, H-1); 5.48, 5.45R (d, 1H, J=2.9 Hz, H-4); 5.44,
5.35R (t, 1H, 3J=9.6 Hz, H-2); 5.21, 5.09R (dd, 1H, 3J=9.8, 3J=3.1 Hz,
H-3); 5.11R, 4.92 (s, 1H, a-CH); 4.17 3.95 (m, 3H, H-5, H-6a, H-6b);
3.62 (t, 2H, 3J=6.4 Hz, CH2OH); 1.58 1.46, 1.32 1.20, 1.36, 1.31, 1.29,
1.23, 1.10, 1.05, 1.00, 0.91 (m, 52H, 3îPiv tBu, tBu, 2îMe, 5îCH2) ppm;
MS (ES+): C44H69N3O12 (864.03): m/z: 886.7 [M+Na]+; R isomer: tR =
57.9 min; yield: 84 mg (48%); yellowish, crystalline solid; m.p. 918C;
[a]2D5 =ꢀ32.03 (c=1, CDCl3); Rf =0.47 (petroleum ether/ethyl acetate
(4:1)); elemental analysis: calcd. (%) for C44H69N3O14 (864.03): C 61.16,
H 8.05, N 4.86; found: C 60.68, H 7.92, N 4.75; 1H NMR (CDCl3,
400 MHz): d=8.31R, 8.20 (s, 1H, CHO); 8.13 8.10 (m, 2H, aryl); 7.56R,
chlorodiisopropylsilane. Loading determined by elemental analysis: l10b
=
1.437 mmolgꢀ1
.
Polymer-bound 2,3,4-tri-O-pivaloyl-6-O-(2,2-dimethyl-8-hydroxy-octano-
yl)-b-d-galactopyranosyl azide (11b)–Immobilization of galactosyl
azide: Coupling of 10b with 8 was carried out under analogous condi-
tions to those described above for glycosyl azide 11a; elemental analysis:
found: C 78.96, H 10.10, N 1.76; loading based on nitrogen content: l11b
=
0.414 mmolgꢀ1 [Eq. (2)].
3
7.50 (d, 2H, J=8.6 Hz, aryl); 6.42R, 5.71 (s, 1H, NH); 5.93, 5.12R (d, 1H,
3J=9.4 Hz, H-1); 5.49R, 5.23 (t, 1H, 3J=9.2 Hz, H-2); 5.42, 5.35R (d, 1H,
3J=2.5 Hz, H-4); 5.33, 5.10R (s, 1H, a-CH); 5.16 5.12 (m, 1H, H-3);
4.15 4.08, 3.93 3.77 (m, 3H, H-5, H-6a, H-6b); 3.56R, 3.54 (t, 2H, 3J=
6.7 Hz, CH2OH); 1.49 1.37, 1.28 1.17, 1.36, 1.29, 1.28, 1.22, 1.12, 1.10,
1.08, 1.05 (m, 52H, 3îPiv tBu, tBu, 2îMe, 5îCH2) ppm; 13C NMR
Polymer-bound 2,3,4-tri-O-pivaloyl-6-O-(2,2-dimethyl-8-hydroxy-octano-
yl)-b-d-galactopyranosylamine (2b)–Reduction of galactosyl azide: Re-
duction was carried out as described above for resin 2a; elemental analy-
sis: found: C 80.23, H 10.71, N 0.61; loading based on nitrogen content:
l
2b =0.436 mmolgꢀ1 [Eq. (3)].
ꢀ
(CDCl3, 100.6 MHz): d=177.3, 177.2, 177.1, 176.7, 176.5, 176.1 (Piv C=
General procedure for TBAF-induced cleavage from the polymeric sup-
port (method A): Resin (50 mg; loading: approximately 0.4 mmolgꢀ1 car-
bohydrate, approximately 2 mmolgꢀ1 Si units, approximately 0.10 mmol
Si units) was swollen in dry THF (2 mL), mixed with acetic acid (10 mL,
0.17 mmol) and tetra-n-butylammonium fluoride trihydrate (1m in dry
THF, 0.5 mL, 0.5 mmol) and shaken for 48 h at room temperature. The
suspension was filtered and the resin was washed successively with di-
chloromethane, THF, and methanol (each 2 mL, 6 cycles), then dried
under high vacuum. The filtrate was evaporated either under reduced
pressure or in a nitrogen stream and the remaining residue was filtered
through a short plug of silica (5 cm, È1 cm, conditioned with petroleum
ether/ethyl acetate (1:1)). Elution with petroleum ether/ethyl acetate
(1:1, 15 mL) and evaporation of the solvents delivered the crude reaction
products. For LC-MS and gravimetric analysis the crude product was dis-
solved in CH3CN and the solution filtered through an Optiflow mem-
brane filter (0.45 mm pore size). The filter was then washed twice with
CH3CN and the solution was evaporated to dryness.
O); 165.9R, 165.6 (CONHtBu); 163.7, 162.9R (CHO); 147.6, 147.5R (C
ꢀ
NO2); 144.9, 142.9R (ipso-aryl); 129.2, 123.9, 123.5 (aryl); 86.3R, 78.5,
73.6, 73.1R, 72.0, 71.9R, 67.2, 66.4R, 65.8R, 65.4, 61.3R, 58.8 (C-1, C-2, C-3,
C-4, C-5, a-C); 62.7 (CH2OH); 61.2, 60.5R (C-6); 52.6, 51.9R (CMe3);
42.3, 42.2R (CMe2); 40.4, 40.3R (CH2); 39.1, 38.8, 38.7 (Piv CMe3); 32.6,
29.6 (2îCH2); 28.6, 28.5R (tBu Me); 27.3, 27.2, 27.0 (Piv Me); 25.5, 25.5,
24.8 (CH2); 25.1, 25.0, 24.9 (CMe2) ppm; MS (ES+): m/z: 585.3 [Msugar]+;
864.4 [M+H]+; 886.5 [M+Na]+.
N-Formyl-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-
b-d-galacto-pyranosyl]-(4-trifluoromethyl)phenylglycine-tert-butyl amide
(13b): Cleavage A: Yield: 4.6 mg (65%), colorless oil; Rf =0.45 (petrole-
um ether/ethyl acetate (5:1)); LC-MS: tR =6.23 (minor); 7.57 (major)
min; d.r. 26:74 (ELSD), purity: 99% (ELSD). Separation of diastereo-
mers by semi-preparative HPLC (Luna C-18, MeCN (90%!100%),
40 min): S isomer: tR =29.7 min; 1H NMR (CDCl3, 400 MHz): d=8.40R,
8.16 (s, 1H, CHO); 7.63 7.47 (m, 4H, aryl); 6.21R, 5.40 (s, 1H, NH);
6.01, 4.99R (d, 1H, 3J=9.4 Hz, H-1); 5.51 5.42 (m, 2H, H-2, H-4); 5.14R,
General procedure for the HF-induced cleavage from polymeric support
(method B): In a fritted polypropylene syringe the resin (50 mg, loading:
approximately 0.4 mmolgꢀ1 carbohydrate, approximately 2 mmolgꢀ1 Si
units, approximately 0.1 mmol Si units) was swollen in dry THF (0.5 mL)
and treated with HF-pyridine complex(70%, 26 mL, 1.0 mmol). After
16 h of shaking, methoxytrimethylsilane (414 mL, 3.0 mmol) was added
and the suspension was shaken for an additional 5 h. It was filtered, then
the resin was washed successively with dichloromethane, THF, and meth-
anol (each 2 mL, 6 cycles) and dried under high vacuum. The residue ob-
tained after thorough evaporation of the wash solutions generally needed
no further purification. Both cleavage protocols are viable for resin
4.87 (s, 1H, a-CH); 5.21, 5.06R (dd, 1H, J=10.0, J=2.9 Hz, H-3); 4.14
3.94 (m, 3H, H-5, H-6a, H-6b); 3.62 (t, 2H, 3J=6.4 Hz, CH2OH); 1.37,
1.31, 1.30, 1.27, 1.12, 1.11, 1.07, 0.99, 0.87 (m, 52H, 3îPiv tBu, tBu, 2î
Me, 5îCH2) ppm; MS (ES+): C45H69F3N2O12 (887.03): m/z: 909.7
[M+Na]+; R isomer: tR =34.7 min; 1H NMR (CDCl3, 400 MHz): d=
8.35R, 8.23 (s, 1H, CHO); 7.61 7.49 (m, 4H, aryl); 6.11R, 5.37 (s, 1H,
NH); 5.95 (d, 1H, 3J=9.4 Hz, H-1); 5.53R, 5.25 (t, 1H, 3J=9.6 Hz, H-2);
5.45, 5.28R (d, 1H, 3J=2.6 Hz, H-4); 5.36R, 5.08 (s, 1H, a-CH); 5.16 5.11
(m, 1H, H-3); 4.20, 3.78R (dd, 1H, 2J=11.0, 3J=7.4 Hz, H-6a); 4.13,
3.81R (dd, 1H, 3J=7.4, 3J=5.1 Hz, H-5); 3.93, 3.70R (dd, 1H, 2J=11.0,
3
3
Chem. Eur. J. 2004, 10, 4136 4149
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4143

H. Kunz and G. Zech
FULL PAPER
3J=4.9 Hz, H-6b); 3.60, 3.57R (t, 1H, 3J=6.6 Hz, CH2OH); 1.39, 1.30,
1.25, 1.15, 1.13, 1.11, 1.07 (m, 52H, 3îPiv tBu, tBu, 2îMe, 5îCH2) ppm;
MS (ES+): m/z: 909.7 [M+Na]+.
(2R)-N-Formyl-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-piv-
aloyl-b-d-galactopyranosyl]-valine-tert-butyl amide (13 f): Cleavage A:
Yield: 2.1 mg (68%), colorless oil; Rf =0.43 (petroleum ether/ethyl ace-
tate (4:1)); LC-MS: tR =5.72 (minor); 6.22 (major) min; d.r. 9:91
(ELSD), purity: 99% (ELSD). Cleavage B: Yield: 6 mg (96%), colorless
oil; LC-MS: tR =5.60; 6.13 min; d.r. 7:93 (ELSD), purity: 95% (ELSD).
Separation of diastereomers by semi-preparative HPLC (Luna C-18,
MeCN (80%!100%), 30 min): S isomer: Yield: <1 mg, tR =18.9 min;
1H NMR (CDCl3, 400 MHz): d=8.54, 8.48R (s, 1H, CHO); 6.16 (s, 1H,
N-Formyl-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-
b-d-galacto-pyranosyl]-phenylglycine-tert-butyl amide (13c): Cleavage A:
Yield: 3.8 mg (58%), colorless oil; Rf =0.27 (cyclohexane/ethyl acetate
(4:1)); LC-MS: tR =5.17 (minor); 6.55 (major) min; d.r. 4:96 (ELSD),
purity 98% (ELSD); MS (ES+): m/z: 841.6 [M+Na]+. On a larger scale
(12c: 540 mg, approximately 0.216 mmol) cleavage allows the separation
of the diastereomers by preparative HPLC (Luna C-18, MeCN (80%!
100%), 60 min, l=215 nm): S isomer: tR =54.0 min; yield: 13 mg (7%);
3
3
NH); 6.01, 4.99R (d, 1H, J=9.0 Hz, H-1); 5.59 (t, 1H, J=10.0 Hz, H-2);
3
5.41 (d, 1H, J=2.8 Hz, H-4); 5.32 5.13 (m, 1H, H-3); 4.10 3.83 (m, 3H,
H-5, H-6a, H-6b); 3.62 (t, 2H, 3J=6.3 Hz, CH2OH); 3.06 (d, 1H, 3J=
10.2 Hz, a-CH); 2.25 2.15, 2.03 1.95R (m, 1H, CHMe2); 1.33, 1.30, 1.29,
1.26, 1.12, 1.11, 1.10, 1.09 (m, 52H, 3îPiv tBu, tBu, 2îMe, 5îCH2);
1.03, 0.80R (d, 3J=6.3 Hz, Me); 0.96, 0.85R (d, 3J=6.7 Hz, Me) ppm; R
isomer: Yield: 4 mg, tR =20.1 min; 1H NMR (CDCl3, 400 MHz): d=
8.66R, 8.32 (s, 1H, CHO); 6.55 (s, 1H, NH); 5.96 (d, 1H, 3J=9.0 Hz, H-
1
colorless, amorphous solid; [a]2D5 =25.14 (c=1, CDCl3); H NMR (CDCl3,
400 MHz): d=8.44R, 8.15 (s, 1H, CHO); 7.36 7.34 (m, 5H, aryl); 6.08R,
3
5.31 (s, 1H, NH); 6.00, 4.76R (d, 1H, J=9.4 Hz, H-1); 5.52, 5.40R (t, 1H,
3J=9.8 Hz, H-2); 5.47, 5.39R (d, 1H, 3J=2.4 Hz, H-4); 5.24R, 4.84 (s, 1H,
a-CH); 5.19, 4.95R (dd, 1H, 3J=9.8, 3J=2.8 Hz, H-3); 4.14 3.94 (m, 3H,
H-5, H-6a, H-6b); 3.62, 3.61R (t, 2H, 3J=6.4 Hz, CH2OH); 1.87 (s, 1H,
OH); 1.57 1.18 (m, 10H, 5îCH2); 1.35, 1.30, 1.29, 1.28, 1.12, 1.11, 1.04,
1.00, 0.96 (several singlets, 42H, 3îPiv tBu, tBu, 2îMe) ppm; MS (ES+):
C44H70N2O12 (819.03): m/z: 838.6 [2M+Ca]+/2; 841.6 [M+Na]+; 857.6
[M+K]+; R isomer: tR =61.9 min; yield: 85 mg (48%); colorless, amor-
phous solid; [a]2D5 =ꢀ28.31 (c=1, CDCl3); elemental analysis: calcd (%):
C 64.52, H 8.61, N 3.42; found: C 63.04, H 8.89, N 3.24; 1H NMR
(CDCl3, 400 MHz): d=8.39R, 8.15 (s, 1H, CHO); 7.33 7.29 (m, 5H,
3
3
1); 5.53 (t, 1H, J=9.6 Hz, H-2); 5.42 (d, 1H, J=3.1 Hz, H-4); 5.17 (dd,
1H, 3J=9.8, 3J=2.8 Hz, H-3); 4.08 3.80 (m, 3H, H-5, H-6a, H-6b); 3.62
(t, 2H, 3J=6.3 Hz, CH2OH); 3.26 (d, 1H, J=10.1 Hz, a-CH); 2.46 2.35,
3
2.24 2.16R (m, 1H, CHMe2); 1.35, 1.30, 1.29, 1.11, 1.10, 1.09, 1.06 (m,
52H, 3îPiv tBu, tBu, 2îMe, 5îCH2); 1.01R, 0.97, 0.93R, 0.87 (d, 6H,
3J=6.6 Hz, 2îMe) ppm; MS (ES+): C41H72N2O12 (785.02): m/z: 807.7
[M+Na]+.
3
aryl); 5.87R, 5.30 (s, 1H, NH); 5.92, 5.10R (d, 1H, J=9.4 Hz, H-1); 5.55R,
(2R)-N-Formyl-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-piv-
aloyl-b-d-galactopyranosyl]-norvaline-tert-butyl amide (13 g): Cleav-
age A: Yield: 4.4 mg (70%), colorless oil; Rf =0.33 (cyclohexane/ethyl
acetate (4:1)); LC-MS: tR =5.70 (minor); 6.05 (major) min; d.r. 9:91
(ELSD), purity: 95% (ELSD); MS (ES+): C41H72N2O12 (785.02): m/z:
807.7 [M+Na]+.
5.21 (t, 1H, 3J=9.8 Hz, H-2); 5.52R, 5.07 (s, 1H, a-CH); 5.43, 5.29R (d,
1H, 3J=2.3 Hz, H-4); 5.10 (dd, 1H, 3J=10.2, 3J=2.7 Hz, H-3); 4.20,
2
3
3
3.58R (dd, 1H, J=10.6, J=7.2 Hz, H-6a); 4.13, 3.58R (t, 1H, J=6.3 Hz,
H-5); 4.13, 3.58R (dd, 1H, 2J=10.9, J=5.3 Hz, H-6b); 3.59R, 3.53 (t, 1H,
3
3J=6.4 Hz, CH2OH); 2.10 (s, 1H, OH); 1.50 1.20 (m, 10H, 5îCH2);
1.34, 1.27, 1.20, 1.13, 1.11, 1.08, 1.07, 1.04 (several singlets, 42H, 3îPiv
tBu, tBu, 2îMe) ppm; 13C NMR (CDCl3, 100.6 MHz): d=177.4, 177.3,
(2R)-N-Formyl-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-piv-
aloyl-b-d-galactopyranosyl]-leucine-tert-butyl amide (13h): Cleavage A:
Yield: 4.1 mg (64%), colorless oil; Rf =0.31 (cyclohexane/ethyl acetate
(4:1)); LC-MS: tR =6.77 (major); 7.13 (minor) min; d.r. 90:10 (ELSD),
purity: 96% (ELSD); MS (ES+): C42H74N2O12 (799.04): m/z: 821.7
[M+Na]+.
R
R
R
ꢀ
177.1 , 176.8 , 176.5 , 176.2, 176.1 (Piv C=O) ppm; 166.9 (CONHtBu);
164.7, 162.6R (CHO); 137.4, 135.5R (ipso-phenyl); 129.0, 128.8, 128.6,
128.4 (phenyl); 85.7R, 72.3 (C-3); 78.3 (C-1); 73.2 (C-5); 67.4 (C-4); 65.4
(C-2); 62.7 (CH2OH); 61.3 (C-6); 58.9 (a-C); 52.3, 51.6R (CMe3); 42.3
(CMe2); 40.4 (CH2); 39.1, 38.9R, 38.7, 38.6 (Piv CMe3); 32.7, 29.7 (2î
CH2); 28.8, 28.6R (tBu Me); 27.3, 27.2, 27.1 (Piv Me); 25.5, 25.1, 25.0,
24.8 (CH2, CMe2) ppm; MS (ES+): m/z: 838.6 [2M+Ca]+/2; 841.6
[M+Na]+; 857.6 [M+K]+.
General procedure for the formation of N-galactosyl aldimines (15) on
the solid phase: Galactosylamine resin 2a (75 mg, 0.03 mmol) was swol-
len in toluene (0.5 mL), the suspension was combined with the aldehyde
(5 equivalents, 0.15 mmol) in toluene (0.3 mL) and acetic acid (10 equiva-
lents, 18 mL, 0.30 mmol), and the mixture was shaken at room tempera-
ture for 6 h. After filtration and successive washing with dichloromethane
and methanol (6 cycles), the resin was dried in vacuo to constant weight
(approximately 2 h).
(2R)-N-Formyl-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-piv-
aloyl-b-d-galactopyranosyl]-4-chlorophenylglycine-tert-butyl
amide
(13d): Cleavage A: Yield: 14.4 mg (84%), colorless oil; Rf =0.66 (petrole-
um ether/ethyl acetate (4:1)); LC-MS: tR =6.25 (minor); 7.53 (major)
min; d.r. 20:80 (ELSD), purity: 96% (ELSD). Isolation of the major dia-
stereomer by semi-preparative HPLC (Spherisorb C-18, MeCN (80%!
100%), 120 min): tR =20.1 min; 1H NMR (CDCl3, 400 MHz): d=8.35R,
8.19 (s, 1H, CHO); 7.37 7.21 (m, 4H, 4îaryl); 5.96R, 5.30 (s, 1H, NH);
5.93, 5.06R (d, 1H, 3J=9.4 Hz, H-1); 5.53R, 5.22 (t, 1H, 3J=9.7 Hz, H-2);
5.44, 5.35R (d, 1H, 3J=2.6 Hz, H-4); 5.31R, 5.02 (s, 1H, a-CH); 5.14,
5.12R (dd, 1H, 3J=10.1, 3J=2.6 Hz, H-3); 4.22 (dd, 1H, 2J=11.1, 3J=
7.4 Hz, H-6a); 4.13 (dd, 1H, 3J=7.0, 3J=5.6 Hz, H-5); 3.94 (dd, 1H, 2J=
11.1, 3J=5.3 Hz, H-6b); 3.60, 3.57R (t, 1H, 3J=6.4 Hz, CH2OH); 1.49
1.43, 1.36, 1.29, 1.24, 1.14, 1.12, 1.10 (m, 52H, 3îPiv tBu, tBu, 2îMe, 5î
CH2) ppm; MS (ES+): C44H69ClN2O12 (853.48): m/z: 875.6 [M(35Cl)+Na]+;
877.6 [M(37Cl)+Na]+.
General procedure for the tandem Mannich Michael reaction on the
solid phase–Synthesis of dehydropiperidinones 18: Galactosyl aldimine
resin 15 (75 mg, 0.03 mmol) was swollen in dry THF (1 mL), then zinc
chloride (1m in THF; 0.15 mL, 0.15 mmol) and diene 16 (59 mL,
0.30 mmol) were added at room temperature. The suspension was shaken
for 48 h, treated with 1n HCl (0.1 mL), shaken for a further 10 minutes,
and filtered, then the resin was washed with dichloromethane, THF, and
methanol (6 cycles). Subsequent cleavage from the support by using
either cleavage method A or B (see above) delivered dehydropiperidi-
nones 18.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-phenyl-5,6-didehydro-piperidin-4-one (18a): Cleav-
age A: Yield: 19.1 mg (81%); colorless oil; Rf =0.41 (petroleum ether/
ethyl acetate (1:1)); LC-MS: tR =3.85 (minor); 4.20 (major) min; d.r. 5:95
(ELSD), purity: 98% (ELSD); 1H NMR (CDCl3, 200 MHz): d=7.37
7.28 (m, 6H, 5îaryl, NCH=CH); 5.56 (t, 1H, 3J=9.8 Hz, H-2); 5.29 (d,
1H, 3J=2.9 Hz, H-4); 5.25 (d, 1H, 3J=8.4 Hz, NCH=CH); 4.93 (dd, 1H,
3J=9.8, 3J=2.9 Hz, H-3); 4.80 (dd, 1H, 3J=9.0, 3J=7.1 Hz, NCHPh);
4.27 (d, 1H, 3J=9.3 Hz, H-1); 3.97 (dd, 1H, 3J=6.8, 2J=10.7 Hz, H-6a);
3.81 3.56 (m, 4H, H-5, H-6b, CH2OH); 2.83 2.70 (m, 2H, CH2C=O);
1.51 1.20 (m, 10H, 5îCH2); 1.25, 1.16, 1.08 (3 s, 27H, Piv tBu); 1.12 (s,
6H, 2îMe) ppm; MS (ES+): C42H63NO11 (757.95): m/z: 758.6 [M+H]+;
780.6 [M+Na]+.
(2R)-N-Formyl-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-piv-
aloyl-b-d-galactopyranosyl]-4-methoxyphenylglycine-tert-butyl
amide
(13e): Cleavage A: Yield: 17 mg (67%), colorless oil; Rf =0.53 (cyclohex-
ane/ethyl acetate (1:1)); [a]D25 =ꢀ26.91 (c=0.5, CDCl3); LC-MS: tR =4.78
(minor); 6.25 (major) min; d.r. 6:94 (ELSD), purity 98% (ELSD);
1H NMR (CDCl3, 400 MHz): d=8.39R, 8.18 (s, 1H, CHO); 7.34R, 7.27 (d,
3
3
2H, J=8.8 Hz, 2îaryl); 6.84 (d, 2H, J=8.6 Hz, 2îaryl); 5.93, 5.01R (d,
1H, 3J=9.4 Hz, H-1); 5.72R, 5.21 (s, 1H, NH); 5.56R, 5.22 (t, 1H, 3J=
9.6 Hz, H-2); 5.45, 5.31R (d, 1H, 3J=2.4 Hz, H-4); 5.42R, 5.03 (s, 1H, a-
3
3
2
3
CH); 5.11 (dd, 1H, J=9.8, J=2.7 Hz, H-3); 4.25 (dd, 1H, J=11.0, J=
7.4 Hz, H-6a); 4.14 (t, 1H, 3J=6.6 Hz, H-5); 3.98 (dd, 1H, 2J=11.3, 3J=
5.7 Hz, H-6b); 3.78 (s, 3H, OMe); 3.61R, 3.57 (t, 1H, 3J=6.6 Hz,
CH2OH); 1.53 1.21, 1.35, 1.29, 1.28R, 1.23R, 1.15R, 1.13, 1.09, 1.06R (m,
52H, 3îPiv tBu, tBu, 2îMe, 5îCH2) ppm; MS (ES+): C45H72N2O13
(849.06): m/z: 871.6 [M+Na]+.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-fluorophenyl)-5,6-didehydro-piperidin-4-one
(18b): Cleavage A: Yield: 18.2 mg (77%); colorless oil; Rf =0.37 (petro-
4144
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4136 4149

Synthesis and Application of a Polymer-Bound Galactosylamine
4136 4149
leum ether/ethyl acetate (1:1)); [a]2D5 =13.64 (c=1, CHCl3); LC-MS: tR =
3.83 (minor); 4.12 (major) min; d.r. 1:99 (ELSD), purity: 97% (ELSD);
MS (ES+): C42H62FNO11 (775.94): m/z: 798.7 [M+Na]+.
100%), 20 min): tR =12.3 (minor); 13.6 (major) min; d.r. 7:93, purity:
97% (ELSD); MS (ES+): C43H62F3NO11 (825.95): m/z: 848.6 [M+Na]+.
(2S)-N-[6-O-(8-hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-nitrophenyl)-5,6-didehydro-piperidin-4-one (18j):
Cleavage A: Yield: 10.1 mg (42%); yellowish oil; Rf =0.43 (petroleum
ether/ethyl acetate (1:1)); LC-MS: tR =3.45 (minor); 3.65 (major) min;
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(3-fluorophenyl)-5,6-didehydro-piperidin-4-one
(18c): Cleavage A: Yield: n.d.; colorless oil; Rf =0.56 (petroleum ether/
ethyl acetate (1:1)); LC-MS: tR =4.32 min; d.r. >99:1, purity: 91%
(ELSD); MS (ES+): C42H62FNO11 (775.94): m/z: 798.5 [M+Na]+.
1
d.r. 7:93 (ELSD), purity: 80% (ELSD); H NMR (CDCl3, 200 MHz): d=
3
3
8.15 (d, H, J=8.8 Hz, 2îaryl); 7.46 (d, 2H, J=8.8 Hz, 2îaryl); 7.24 (d,
1H, 3J=7.4 Hz, NCH=CH); 5.56 (t, 1H, 3J=9.5 Hz, H-2); 5.32 (d, 1H,
3J=2.9 Hz, H-4); 5.15 (d, 1H, 3J=7.8 Hz, NCH=CH); 5.11 (dd, 1H, 3J=
9.8, 3J=2.7 Hz, H-3); 5.00 (dd, 1H, 3J=6.1, 3J=8.6 Hz, NCHAryl); 4.36
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-bromophenyl)-5,6-didehydro-piperidin-4-one
(18d): Cleavage B: Yield: n.d.; colorless oil; Rf =0.58 (petroleum ether/
ethyl acetate (1:1)); LC-MS: tR =4.42 (minor); 4.85 (major) min; d.r. 2:98
(ELSD), purity: 97% (ELSD); MS (ES+): C42H62BrNO11 (836.85): m/z:
585.4 [Msugar]+; 836.3 [M(79Br)+H]+; 838.3 [M(81Br)+H]+; 858.3
[M(79Br)+Na]+; 860.3 [M(81Br)+Na]+.
3
3
2
(d, 1H, J=9.3 Hz, H-1); 3.94 (dd, 1H, J=9.1, J=12.7 Hz, H-6a); 3.78
3
3.69 (m, 2H, H-5, H-6b); 3.60 (t, 2H, J=6.3 Hz, CH2OH); 2.78 (dd, 1H,
3J=5.9, 2J=16.1 Hz, CH2C=O); 2.62 (dd, 1H, 3J=8.6, 2J=16.4 Hz,
CH2C=O); 1.87 1.21 (m, 10H, 5îCH2); 1.23, 1.15, 1.08 (3 s, 27H, Piv
tBu); 1.10 (s, 6H, 2îMe) ppm; MS (ES+): C42H62N2O13 (802.95): m/z:
825.7 [M+Na]+.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(3-bromophenyl)-5,6-didehydro-piperidin-4-one
(18e): Cleavage A: Yield: 14.3 mg (57%); colorless oil; Rf =0.52 (petrole-
um ether/ethyl acetate (1:1)); LC-MS: tR =4.60 (minor); 5.02 (major)
min; d.r. 1:99 (ELSD), purity: 95% (ELSD). Cleavage B: Yield: 30 mg
(90%); colorless oil; [a]2D5 =13.38 (c=1, CHCl3); LC-MS: d.r. 5:95
(ELSD), 2:98 (l=215 218 nm), purity: 88% (ELSD), 99% (l=215
218 nm); 1H NMR (CDCl3, 400 MHz): d=7.44 7.38, 7.28 7.16 (m, 5H,
4îaryl, NCH=CH); 5.56 (t, 1H, 3J=9.6 Hz, H-2); 5.32 (d, 1H, 3J=
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-methylphenyl)-5,6-didehydro-piperidin-4-one
(18k): Cleavage A: Yield: n.d.; colorless oil; Rf =0.13 (petroleum ether/
ethyl acetate (2:1)); LC-MS: tR =4.23 (minor); 4.76 (major); 8.45 (imine,
30%, m/z: 726.4 [Mimine+Na]+) min; d.r. 9:91 (ELSD), purity: 66%
(ELSD); MS (ES+): C43H65NO11 (771.98): m/z: 585.4 [Msugar]+; 772.4
[M+H]+; 794.4 [M+Na]+.
3
3
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-methoxyphenyl)-5,6-didehydro-piperidin-4-one
(18 l): Cleavage A: Yield: 20.9 mg (84%); colorless oil; Rf =0.27 (petrole-
um ether/ethyl acetate (1:1)); LC-MS: tR =3.65 (minor); 3.98 (major)
min; d.r. 2:98 (ELSD), purity: 98% (ELSD); 1H NMR (CDCl3,
200 MHz): d=7.29 (d, 1H, 3J=8.3 Hz, NCH=CH); 7.22 (d, 2H, 3J=
2.8 Hz, H-4); 5.23 (d, 1H, J=7.8 Hz, NCH=CH); 5.04 (dd, 1H, J=10.0,
3J=3.0 Hz, H-3); 4.80 (t, 1H, 3J=6.9 Hz, NCHAryl); 4.41 (d, 1H, 3J=
9.0 Hz, H-1); 3.90 (dd, 1H, 3J=5.3, 2J=10.2 Hz, H-6a); 3.79 3.71 (m,
3
3
2H, H-5, H-6b); 3.60 (t, 2H, J=6.4 Hz, CH2OH); 2.83 (dd, 1H, J=6.1,
2J=16.6 Hz, CH2C=O); 2.64 (dd, 1H, 3J=7.8, 2J=16.8 Hz, CH2C=O);
1.74 1.20 (m, 10H, 5îCH2); 1.24, 1.16, 1.09 (3 s, 27H, Piv tBu); 1.10 (s,
6H, 2îMe) ppm; MS (ES+): C42H62BrNO11 (836.85): m/z: 858.3
[M(79Br)+Na]+; 860.3 [M(81Br)+Na]+.
3
3
8.1 Hz, 2îaryl); 6.89 (d, 2H, J=8.8 Hz, 2îaryl); 5.54 (t, 1H, J=9.8 Hz,
3
3
H-2); 5.28 (d, 1H, J=2.9 Hz, H-4); 5.27 (d, 1H, J=8.3 Hz, NCH=CH);
4.92 (dd, 1H, 3J=9.8, 3J=2.9 Hz, H-3); 4.73 (dd, 1H, 3J=5.4, 3J=
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-chlorophenyl)-5,6-didehydro-piperidin-4-one
(18 f): Cleavage A: Yield: 60.9 mg (77%); colorless oil; Rf =0.48 (petrole-
um ether/ethyl acetate (1:1)); [a]2D5 =10.15 (c=1, CHCl3); HPLC (Luna
C-18, MeCN (80%!100%), 20 min): tR =11.7 (minor); 12.6 (major) min;
3
3
12.2 Hz, NCHAryl); 4.20 (d, 1H, J=9.8 Hz, H-1); 4.03 (dd, 1H, J=7.3,
2J=11.2 Hz, H-6a); 3.85 3.76 (m, 4H, OMe, H-6b); 3.66 (m, 3H,
CH2OH, H-5); 2.76 (dd, 1H, 3J=11.7, 2J=16.6 Hz, CH2C=O); 2.61 (dd,
1H, 3J=5.4, 2J=16.6 Hz, CH2C=O); 1.56 1.22 (m, 10H, 5îCH2); 1.25,
1.15, 1.07 (3 s, 27H, Piv tBu); 1.13 (s, 6H, 2îMe) ppm; 13C NMR
(CDCl3, 50.3 MHz): d=192.5 (keto C=O); 177.3, 176.9, 176.6 (Piv C=O);
160.0 (MeOC); 149.8 (NCH=CH); 129.5 (ipso-aryl); 128.9, 114.5 (aryl);
104.0 (NCH=CH); 86.8 (C-1); 72.6, 71.7, 66.9, 65.9 (C-2, C-3, C-4, C-5);
62.8, 61.3, 60.9 (NCHAryl, C-6, CH2OH); 55.3 (OMe); 43.9 (CH2C=O);
1
d.r. 3:97 (l=215 nm); H NMR (CDCl3, 200 MHz): d=7.33 7.21 (m, 5H,
4îaryl, NCH=CH); 5.55 (t, 1H, 3J=9.5 Hz, H-2); 5.31 (d, 1H, 3J=
3
3
2.9 Hz, H-4); 5.20 (d, 1H, J=7.8 Hz, NCH=CH); 5.01 (dd, 1H, J=10.0,
3J=3.2 Hz, H-3); 4.80 (dd, 1H, 3J=6.1, 3J=8.6 Hz, NCHAryl); 4.36 (d,
1H, 3J=9.3 Hz, H-1); 3.94 (dd, 1H, 3J=9.1, 2J=12.7 Hz, H-6a); 3.78
ꢀ
42.3 (CMe2 COOR); 40.6 (CH2); 39.1, 38.9, 38.8 (Piv CMe3); 32.8, 29.8,
3
3.69 (m, 2H, H-5, H-6b); 3.60 (t, 2H, J=6.3 Hz, CH2OH); 2.78 (dd, 1H,
29.7 (3îCH2); 27.2, 27.1 (Piv Me); 25.6 (CH2); 25.1, 24.9 (2îMe) ppm;
3J=5.9, 2J=16.1 Hz, CH2C=O); 2.62 (dd, 1H, 3J=8.6, 2J=16.4 Hz,
CH2C=O); 1.87 1.21 (m, 10H, 5îCH2); 1.23, 1.15, 1.08 (3 s, 27H, Piv
tBu); 1.10 (s, 6H, 2îMe) ppm; 13C NMR (CDCl3, 50.3 MHz): d=191.3
(keto C=O); 177.3, 177.2, 177.1, 176.5 (Piv C=O); 149.8 (NCH=CH);
137.2, 134.4 (ipso-aryl); 129.1, 128.5 (aryl); 103.3 (NCH=CH); 88.7 (C-1);
72.7, 71.4, 66.7, 65.2 (C-2, C-3, C-4, C-5); 62.8, 61.0 (C-6, CH2OH); 59.1
MS (ES+): C43H65NO12 (787.98): m/z: 810.7 [M+Na]+.
(2R)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(2-phenylethyl)-5,6-didehydro-piperidin-4-one
(18n): Cleavage A: Yield: 11.9 mg (50%); colorless oil; Rf =0.13 (petro-
leum ether/ethyl acetate (2:1)); LC-MS: tR =4.55 (minor); 4.93 (major)
min; d.r. 10:90 (ELSD), purity: 83% (ELSD); MS (ES+): C44H67NO11
(786.00): m/z: 786.4 [M+H]+; 808.4 [M+Na]+.
ꢀ
(NCHAryl); 43.6 (CH2C=O); 42.3 (CMe2 COOR); 40.5 (CH2); 39.1,
38.9, 38.8 (Piv CMe3); 32.7, 29.8 (2îCH2); 27.2, 27.1 (Piv Me); 25.6, 24.9
(2îCH2); 25.0 (2îMe) ppm; MS (ES+): C42H62ClNO11 (792.39): m/z:
814.7 [M(35Cl)+Na]+; 816.7 [M(37Cl)+Na]+.
(2R)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-methyl-5,6-didehydro-piperidin-4-one (18o): Cleav-
age A: Yield: 15.3 mg (73%); colorless oil; Rf =0.37 (petroleum ether/
ethyl acetate (2:1)); HPLC (Luna C-18, MeCN (80%!100%), 20 min):
tR =8.63 (minor); 9.07 (major) min; d.r. 22:78 (l=320 nm); purity: 90%
(ELSD); MS (ES+): C37H61NO11 (695.88): m/z: 696.5 [M+H]+; 718.5
[M+Na]+.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(2-chloro-6-fluorophenyl)-5,6-didehydro-piperidin-4-
one (18g): Cleavage A: Yield: 11.9 mg (49%); colorless oil; Rf =0.48 (pe-
troleum ether/ethyl acetate (1:1)); LC-MS: tR =4.90 (minor); 6.23 (ma-
jor) min; d.r. 3:97 (ELSD), purity: 89% (ELSD); MS (ES+):
C42H61ClFNO11 (810.38): m/z: 832.4 [M(35Cl)+Na]+; 834.4 [M(37Cl)+Na]+.
(2R)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-ethyl-5,6-didehydro-piperidin-4-one (18p): Cleav-
age B: Yield from tandem condensation at ꢀ108C: 11.1 mg (78%); color-
less oil; Rf =0.37 (petroleum ether/ethyl acetate (2:1)); HPLC (Luna C-
18, MeCN (80%!100%), 20 min): tR =9.63 (major); 10.58 (minor) min;
d.r. 85:15 (l=320 nm), purity: 87% (ELSD); 1H NMR (major diaster-
eomer, CDCl3, 400 MHz): d=7.00 (d, 1H, 3J=7.4 Hz, NCH=CH); 5.63
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-cyanophenyl)-5,6-didehydro-piperidin-4-one
(18h): Cleavage A: Yield: 59 mg (76%); colorless oil; Rf =0.38 (petrole-
um ether/ethyl acetate (1:1)); LC-MS: tR =3.22 min; d.r. >99:1 (ELSD),
purity: 93% (ELSD); MS (ES+): C43H62N2O11 (782.96): m/z=805.7
[M+Na]+.
3
3
3
(t, 1H, J=9.8 Hz, H-2); 5.50 (d, 1H, J=2.7 Hz, H-4); 5.25 (dd, 1H, J=
9.8, 3J=2.9 Hz, H-3); 5.06 (d, 1H, 3J=7.8 Hz, NCH=CH); 4.63 (d, 1H,
3J=9.4 Hz, H-1); 4.29 (dd, 1H, 3J=6.6, 2J=11.0 Hz, H-6a); 4.10 (t, 1H,
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-trifluoromethylphenyl)-5,6-didehydro-piperidin-4-
one (18i): Cleavage A: Yield: 67 mg (81%); colorless oil; Rf =0.59 (pe-
troleum ether/ethyl acetate (1:1)); HPLC (Luna C-18, MeCN (80%!
3J=6.6 Hz, H-5); 3.99 (dd, 1H, J=6.6, J=11.0 Hz, H-6b); 3.72 3.69 (m,
3
2
3H, H-2, CH2OH); 2.69 (dd, 1H, 3J=7.3, 2J=16.4 Hz, CH2C=O); 2.48
Chem. Eur. J. 2004, 10, 4136 4149
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4145

H. Kunz and G. Zech
FULL PAPER
2
(brd, 1H, J=15.6 Hz, CH2C=O); 1.93 1.27 (m, 12H, 6îCH2); 1.36, 1.21
11:89 (ELSD); purity: 74% (ELSD); MS (ES+): C43H73NO11 (780.04):
(2 s, 27H, Piv tBu); 1.23 (s, 6H, 2îMe); 0.96 (t, 3H, 3J=7.6 Hz,
Me) ppm; MS (ES+): C38H63NO11 (709.91): m/z: 585.5 [Msugar]+; 710.5
[M+H]+; 732.4 [M+Na]+.
m/z: 780.4 [M+H]+; 802.5 [M+Na]+.
General procedure for conjugate hydride addition on solid phase (50 mg
resin scale): a) Preparation of methyl aluminum-bis(2,6-di-tert-butyl-4-
methylphenoxide) (MAD):[36a] At room temperature, AlMe3 (2m in tolu-
ene, 0.2 mL, 0.40 mmol) was added dropwise to a solution of 2,6-di-tert-
butyl-4-methyl-phenol (176 mg, 0.80 mmol) in dry toluene (2 mL). When
methane evolution ceased (after approximately 30 min), the clear solu-
tion of the methyl alumoxane was ready for use. b) Conjugate hydride
addition: A suspension of polymer-bound enone 17 (50 mg, approximate-
ly 0.02 mmol) in dry THF (4 mL) was cooled to ꢀ208C and treated with
MAD (approximately 2.2 mL, 0.40 mmol) prepared according to the pro-
cedure described above. After 15 min, L-selectride (1m in THF, 0.2 mL,
0.2 mmol) was added at this temperature and the mixture was shaken for
the given time period before being quenched with acetic acid (10% in
THF, 1 mL). The suspension was warmed to room temperature, then the
resin was filtered and thoroughly washed with CH2Cl2 and MeOH
(6 cycles). The following N-galactosylpiperidin-4-ones 20 were obtained
after treatment with TBAF (yields given are based on loading of galacto-
syl azide 11a).
N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-galac-
to-pyranosyl]-2-n-propyl-5,6-didehydro-piperidin-4-one (18q): Cleav-
age B: Yield from tandem condensation at ꢀ108C: 13.0 mg (90%); color-
less oil; Rf =0.39 (petroleum ether/ethyl acetate (2:1)); HPLC (Luna C-
18, MeCN (80%!100%), 20 min): tR =10.80 (minor); 12.02 (major) min;
d.r. 19:81 (l=320 nm). Separation of diastereomers by semi-preparative
HPLC (Luna C-18, MeCN (80%!90%), 30 min): tR =15.9 (minor); 17.2
1
(major) min. Major diastereomer: 8 mg; H NMR (CDCl3, 400 MHz): d=
6.89 (d, 1H, 3J=7.8 Hz, NCH=CH); 5.52 (t, 1H, 3J=9.6 Hz, H-2); 5.41
3
3
3
(d, 1H, J=2.7 Hz, H-4); 5.16 (dd, 1H, J=9.8, J=3.1 Hz, H-3); 4.95 (d,
1H, 3J=7.8 Hz, NCH=CH); 4.55 (d, 1H, 3J=9.4 Hz, H-1); 4.22 (dd, 1H,
3J=6.7, 2J=11.0 Hz, H-6a); 4.01 (t, 1H, 3J=6.9 Hz, H-5); 3.90 (dd, 1H,
3J=6.6, 2J=11.0 Hz, H-6b); 3.76 3.70 (m, 1H, NCHPr); 3.61 (t, 2H, 3J=
6.5 Hz, CH2OH); 2.60 (dd, 1H, 3J=6.6, 2J=16.8 Hz, CH2C=O); 2.34
2
(brd, 1H, J=16.4 Hz, CH2C=O); 1.92 1.83 (m, 1H, CH2); 1.64 1.13 (m,
13H, 6.5îCH2); 1.27, 1.10 (2 s, 27H, Piv tBu); 1.11 (s, 6H, 2îMe); 0.88
(t, 3H, 3J=7.2 Hz, Me) ppm; 13C NMR (CDCl3, 100.6 MHz): d=192.2
(keto C=O); 177.3, 177.0, 176.5 (Piv C=O); 149.8 (NCH=CH); 99.9
(NCH=CH); 91.5 (C-1); 72.9, 71.3, 66.6, 65.7 (C-2, C-3, C-4, C-5); 62.8
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(3-fluorophenyl)-piperidin-4-one (20c): Reaction
time: 3.5 h; Yield: 8.3 mg (53%); colorless oil; Rf =0.63 (petroleum
ether/ethyl acetate (2:1)); LC-MS: tR =6.73 min; purity: 99% (ELSD);
1H NMR (CDCl3, 400 MHz): d=7.33 (td, 1H, 3J=8.0, 4J(H,F)=5.5 Hz,
aryl-H-5); 7.07 6.99 (m, 3H, aryl); 5.45 (t, 1H, 3J=9.8 Hz, H-2); 5.25 (d,
1H, 3J=2.7 Hz, H-4); 4.89 (dd, 1H, 3J=10.2, 3J=3.1 Hz, H-3); 4.10 (dd,
1H, 3J=10.6, 3J=4.3 Hz, NCHAryl); 4.05 (dd, 1H, 3J=7.0, 2J=11.3 Hz,
H-6a); 3.90 (d, 1H, 3J=9.4 Hz, H-1); 3.85 (dd, 1H, 3J=6.3, 2J=11.4 Hz,
ꢀ
(CH2OH); 60.8 (C-6); 53.3 (NCHPr); 42.3 (CMe2 COOR); 40.3 (CH2);
39.1, 38.9, 38.8 (CH2C=O, Piv CMe3); 32.7, 29.7 (2îCH2); 27.2, 27.1, 27.0
(CH2, Piv Me); 25.5 (CH2); 25.0, 24.8 (2îMe, CH2); 18.9 (CH2CH3); 13.8
(CH2CH3) ppm; MS (ES+): C39H65NO11 (723.93): m/z: 585.5 [Msugar]+;
724.4 [M+H]+; 746.6 [M+Na]+. Minor diastereomer: 3 mg; 1H NMR
(CDCl3, 400 MHz): d=7.11 (d, 1H, 3J=9.0 Hz, NCH=CH); 5.42 (d, 1H,
3J=2.8 Hz, H-4); 5.36 (t, 1H, 3J=9.6 Hz, H-2); 5.15 (dd, 1H, 3J=10.2,
3J=3.1 Hz, H-3); 5.12 (d, 1H, 3J=8.2 Hz, NCH=CH); 4.42 (d, 1H, 3J=
9.0 Hz, H-1); 4.12 (dd, 1H, 3J=6.6, 2J=10.6 Hz, H-6a); 4.03 (t, 1H, 3J=
6.3 Hz, H-5); 3.96 (dd, 1H, 3J=5.9, 2J=10.6 Hz, H-6b); 3.61 (t, 2H, 3J=
6.4 Hz, CH2OH); 3.55 3.49 (m, 1H, NCHPr); 2.64 (dd, 1H, 3J=6.6, 2J=
3
H-6b); 3.62 3.58 (m, 3H, NCH2, CH2OH); 3.50 (t, 1H, J=6.5 Hz, H-5);
2.98 2.91 (m, 1H, NCH2); 2.61 2.45 (m, 4H, CH2C=O); 1.58 1.22 (m,
10H, 5îCH2); 1.23, 1.21, 1.07 (3 s, 27H, Piv tBu); 1.14 (s, 6H, 2î
Me) ppm;
[MꢀPivOH+Na] ; 800.6 [M Na] .
MS
(ES+):
C42H64FNO11
(777.96):
m/z:
698.6
+
+
ꢀ
2
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-bromophenyl)-piperidin-4-one (20d): Reaction
time: 7 h; Yield: 15.9 mg (34%); colorless oil; Rf =0.32 (petroleum ether/
ethyl acetate (2:1)); HPLC (Luna C-18, MeCN (80%!100%), 20 min):
tR =21.50 min; purity: 82% (l=215 nm). Isolation by preparative HPLC
(Luna C-18, MeCN (80%!100%), 60 min): tR =72.2 min; Yield: 7.9 mg;
1H NMR (CDCl3, 400 MHz): d=7.50 (d, 2H, 3J=8.6 Hz, 2îaryl); 7.16
(d, 2H, 3J=8.2 Hz, 2îaryl); 5.44 (t, 1H, 3J=9.8 Hz, H-2); 5.25 (d, 1H,
3J=2.7 Hz, H-4); 4.89 (dd, 1H, 3J=9.8, 3J=3.1 Hz, H-3); 4.08 4.03 (m,
2H, H-6a, NCHAryl); 3.86 (d, 1H, 3J=9.4 Hz, H-1); 3.84 (dd, 1H, 3J=
6.3, 2J=11.3 Hz, H-6b); 3.63 3.57 (m, 3H, NCH2, CH2OH); 3.48 (t, 1H,
3J=6.6 Hz, H-5); 2.93 (td, 1H, 3J=7.7, 2J=11.8 Hz, NCH2); 2.60 2.44
(m, 4H, CH2C=O); 1.53 1.16 (m, 10H, 5îCH2); 1.23, 1.21, 1.07 (3 s,
27H, Piv tBu); 1.14 (s, 6H, 2îMe) ppm; 13C NMR (CDCl3, 100.6 MHz):
d=207.6 (keto C=O); 177.4, 177.2 (Piv C=O); 138.8, 132.2, 129.5, 122.4
(aryl); 87.9 (C-1); 71.9, 71.7, 67.2, 65.0, 63.4, 62.8, 61.7 (C-2, C-3, C-4, C-
5, C-6, NCHAryl, CH2OH); 48.9, 43.6, 41.6 (NCH2, CH2C=O); 42.2
16.0 Hz, CH2C=O); 2.39 (brd, 1H, J=16.0 Hz, CH2C=O); 1.87 1.77 (m,
1H, CH2); 1.53 1.18 (m, 13H, 6.5îCH2); 1.28, 1.14, 1.11 (3 s, 27H, Piv
tBu); 1.12 (s, 6H, 2îMe); 0.89 (t, 3H, 3J=7.2 Hz, Me) ppm; MS (ES+):
m/z: 585.5 [Msugar]+; 724.4 [M+H]+; 746.6 [M+Na]+.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-isopropyl-5,6-didehydro-piperidin-4-one (18r): Cleav-
age A: Yield: 16.2 mg (73%); colorless oil; Rf =0.24 (petroleum ether/
ethyl acetate (1:1)); LC-MS: tR =3.57 (minor); 4.12 (major) min; d.r. 2:98
(ELSD); purity: 92% (ELSD); 1H NMR (CDCl3, 200 MHz): d=7.01 (d,
1H, 3J=7.8 Hz, NCH=CH); 5.55 (t, 1H, 3J=9.5 Hz, H-2); 5.41 (d, 1H,
3J=2.9 Hz, H-4); 5.15 (dd, 1H, 3J=10.3, 3J=3.2 Hz, H-3); 4.96 (d, 1H,
3J=7.8 Hz, NCH=CH); 4.61 (d, 1H, 3J=9.3 Hz, H-1); 4.19 (dd, 1H, 3J=
5.9, 2J=9.8 Hz, H-6a); 4.04 3.87 (m, 3H, H-5, H-6b, NCH-iPr); 3.61 (t,
2H, 3J=6.3 Hz, CH2OH); 2.60 (dd, 1H, 3J=7.3, 2J=17.1 Hz, CH2C=O);
2.41 (dd, 1H, 3J=2.9, 2J=17.1 Hz, CH2C=O); 2.30 2.18 (m, 1H,
CHMe2); 1.51 1.22 (m, 10H, 5îCH2); 1.26, 1.11, 1.10 (3 s, 33H, Piv tBu,
2îMe); 0.91 (2 d, 6H, 3J=7.2 Hz, 2îMe) ppm; MS (ES+): C39H65NO11
(723.93): m/z: 746.6 [M+Na]+.
ꢀ
(CMe2 COOR); 40.5 (CH2); 39.0, 38.8, 38.7 (Piv CMe3); 32.7, 29.8 (2î
CH2); 27.4, 27.2, 27.0 (Piv Me); 25.6 (CH2); 25.1, 25.0, 24.9 (2îMe,
CH2) ppm; MS
(ES+): C42H64BrNO11 (838.86):
m/z: 758.2
(2R)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-isobutyl-5,6-didehydro-piperidin-4-one (18 s): Cleav-
age A: Yield: 13.4 mg (61%); colorless oil; Rf =0.37 (petroleum ether/
ethyl acetate (2:1)); LC-MS: tR =4.42 (minor); 4.93 (major) min; d.r.
18:82 (ELSD); purity: 88% (ELSD); MS (ES+): C40H67NO11 (737.96):
m/z: 760.3 [M+Na]+.
[M(79Br)ꢀPivOH+Na]+;
760.2
[M(81Br)ꢀPivOH+Na]+;
860.4
[M(79Br)+Na]+; 862.4 [M(81Br)+Na]+.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(3-bromophenyl)-piperidin-4-one (20e): Reaction
time: 3.5 h; Yield: n.d.; colorless oil; Rf =0.35 (petroleum ether/ethyl ace-
tate (2:1)); LC-MS: tR =4.97 (37%, 18e); 8.12 (51%, 20e) min; MS (ES+):
(2R)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-n-pentyl-5,6-didehydro-piperidin-4-one (18u): Cleav-
age B: Yield from tandem condensation at ꢀ108C: 13.1 mg (87%); color-
less oil; Rf =0.40 (petroleum ether/ethyl acetate (2:1)); LC-MS: tR =5.25
(minor); 6.02 (major) min; d.r. 16:84 (ELSD); purity: 95% (ELSD); MS
(ES+): C41H69NO11 (751.99): m/z: 585.5 [Msugar]+; 752.4 [M+H]+; 774.4
[M+Na]+.
79
+
ꢀ
C42H64BrNO11 (838.86): m/z: 758.3 [M( Br) PivOH+Na] ; 760.3
81
+
79
+
81
+
ꢀ
[M( Br) PivOH+Na] ; 860.5 [M( Br)+Na] ; 862.5 [M( Br)+Na] .
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-chlorophenyl)-piperidin-4-one (20 f): Reaction
time: 7 h; Yield: 8.3 mg (50%); colorless oil; Rf =0.35 (petroleum ether/
ethyl acetate (2:1)); HPLC (Luna C-18, MeCN (80%!100%), 20 min):
tR =28.67 min; purity: 65% (l=215 nm). Isolation by preparative HPLC
(Luna C-18, MeCN (80%!100%), 60 min): tR =72.3 min; yield: 6.2 mg;
1H NMR (CDCl3, 400 MHz): d=7.35 (d, 2H, 3J=8.6 Hz, 2îaryl); 7.22
(d, 2H, 3J=8.6 Hz, 2îaryl); 5.44 (t, 1H, 3J=9.6 Hz, H-2); 5.25 (d, 1H,
(2R)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-n-heptyl-5,6-didehydro-piperidin-4-one (18v): Cleav-
age A: Yield: 13.3 mg (57%); colorless oil; Rf =0.42 (petroleum ether/
ethyl acetate (2:1)); LC-MS: tR =7.07 (minor); 8.07 (major) min; d.r.
4146
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 4136 4149

Synthesis and Application of a Polymer-Bound Galactosylamine
4136 4149
3
3
2
3J=3.1 Hz, H-4); 4.89 (dd, 1H, 3J=9.8, 3J=3.1 Hz, H-3); 4.09 4.04 (m,
2H, H-6a, NCHAryl); 3.87 3.81 (m, 2H, H-1, H-6b); 3.63 3.59 (m, 3H,
NCH2, CH2OH); 3.48 (t, 1H, J=6.5 Hz, H-5); 2.93 (td, 1H, J=7.8, J=
12.1 Hz, NCH2); 2.60 2.42 (m, 4H, CH2C=O); 1.53 1.16 (m, 10H, 5î
CH2); 1.23, 1.20, 1.07 (3 s, 27H, Piv tBu); 1.14 (s, 6H, 2îMe) ppm; MS
(ES+): C42H64ClNO11 (794.41): m/z: 816.6 [M(35Cl)+Na]+; 818.6
[M(37Cl)+Na]+.
3J=5.1, J=9.0 Hz, NCHAryl); 4.07 (dd, 1H, J=7.0, J=11.3 Hz, H-6a);
3
3.93 (d, 1H, J=9.4 Hz, H-1); 3.82 3.78 (m, 2H, H-6b, NCHBu); 3.60 (t,
3
3
2
2H, 3J=6.5 Hz, CH2OH); 3.30 (t, 1H, 3J=6.8 Hz, H-5); 2.51 2.46 (m,
4H, CH2C=O); 1.52 1.42, 1.38 1.20 (m, 16H, 8îCH2); 1.23, 1.22, 1.07
(3 s, 27H, Piv tBu); 1.13 (s, 6H, 2îMe); 0.88 (t, 3H, 3J=6.8 Hz,
CH2CH3) ppm; MS (ES+): C46H72FNO11 (834.06): m/z: 732.5
[MꢀPivOH+H]+; 754.5 [MꢀPivOH+Na]+; 856.6 [M+Na]+.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(2-chloro-6-fluorophenyl)-piperidin-4-one (20g): Re-
action time: 3.5 h; Yield: n.d.; colorless oil; LC-MS: tR =4.92 (32%,
18g); 7.37 (47%, 20g) min; MS (ES+): C42H63ClFNO11 (812.40): m/z:
732.4 [M(35Cl)ꢀPivOH+Na]+; 734.4 [M(37Cl)ꢀPivOH+Na]+; 834.6
[M(35Cl)+Na]+; 836.6 [M(37Cl)+Na]+.
(2S,6S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-
d-galacto-pyranosyl]-2-(3-bromophenyl)-6-n-butyl-piperidin-4-one
(22ea): (nBu)2Cu(CN)Li2 (30 equiv, cuprate formation: ꢀ608C);
BF3¥OEt2 (30 equiv); reaction time: 2 h at ꢀ 408C, then warm to ꢀ128C
for 14 h; Yield of crude product: 7.9 mg (44%); yellowish oil; LC-MS:
tR =4.93 (2%, 18e); 10.60 (71%, major); 11.30 (15%, minor) min. Purifi-
cation by preparative HPLC (Luna C-18, MeCN (80%!100%), 60 min):
tR =60.47 (74%, major); 64.50 (26%, minor) min. Major diastereomer:
1H NMR (CDCl3, 400 MHz): d=7.52 7.45 (m, 2H, 2îaryl); 7.28 7.20
(m, 2H, 2îaryl); 5.50 (t, 1H, 3J=9.4 Hz, H-2); 5.24 (d, 1H, 3J=2.7 Hz,
H-4); 4.84 (dd, 1H, 3J=9.8, 3J=3.1 Hz, H-3); 4.45 (dd, 1H, 3J=4.7, 3J=
9.8 Hz, NCHAryl); 4.09 (dd, 1H, 3J=6.7, 2J=11.0 Hz, H-6a); 3.90 (d,
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-trifluoromethylphenyl)-piperidin-4-one (20i): Re-
action time: 4 h (40 equivalents of MAD and 15 equivalents of L-selec-
tride were used); yield: n.d.; colorless oil; LC-MS: tR =7.63 (83%,
20i) min; MS (ES+): C43H64F3NO11 (827.96): m/z: 748.5 [MꢀPivOH+
Na]+; 850.7 [M+Na]+.
3
3
1H, J=9.8 Hz, H-1); 3.82 3.77 (m, 2H, H-6b, NCHBu); 3.60 (t, 2H, J=
6.6 Hz, CH2OH); 3.32 (t, 1H, 3J=6.6 Hz, H-5); 2.52 2.46 (m, 4H,
CH2C=O); 1.57 1.16 (m, 16H, 8îCH2); 1.23, 1.22, 1.07 (3 s, 27H, Piv
tBu); 1.13 (s, 6H, 2îMe); 0.88 (t, 3H, 3J=6.8 Hz, CH2CH3) ppm. Minor
diastereomer: 1H NMR (CDCl3, 400 MHz): d=7.49 7.42 (m, 2H, 2î
aryl); 7.25 7.18 (m, 2H, 2îaryl); 5.49 (t, 1H, 3J=9.8 Hz, H-2); 5.29 (d,
1H, 3J=2.7 Hz, H-4); 4.85 (dd, 1H, 3J=9.8, 3J=2.8 Hz, H-3); 4.55 (dd,
1H, 3J=3.5, 3J=12.5 Hz, NCHAryl); 4.17 (dd, 1H, 3J=7.0, 2J=11.0 Hz,
H-6a); 4.15 (d, 1H, 3J=9.8 Hz, H-1); 3.89 (dd, 1H, 3J=6.4, 2J=11.4 Hz,
H-6b); 3.78 (t, 1H, 3J=6.6 Hz, H-5); 3.62 3.57 (m, 3H, CH2OH,
NCHBu); 2.87 (dd, 1H, 3J=5.5, 2J=16.4 Hz), 2.63 2.44 (m, 3H, CH2C=
O); 1.56 1.46, 1.35 1.23 (m, 16H, 8îCH2); 1.27, 1.18, 1.08 (3 s, 27H, Piv
tBu); 1.14 (s, 6H, 2îMe); 0.87 (t, 3H, 3J=7.0 Hz, CH2CH3) ppm; MS
(ES+): C46H72BrNO11 (894.97): m/z: 814.4 [M(79Br)ꢀPivOH+Na]+; 816.4
[M(81Br)ꢀPivOH+Na]+; 916.6 [M(79Br)+Na]+; 918.6 [M(81Br)+Na]+.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-(4-methoxyphenyl)-piperidin-4-one (20l): Reaction
time: 4 h at ꢀ408C (40 equivalents of MAD and 15 equivalents of L-se-
lectride were used); yield: n.d.; colorless oil; Rf =0.42 (petroleum ether/
ethyl acetate (2:1)); LC-MS: Rt =3.93 (64%, 18l); 6.70 (21%, 20l) min;
MS (ES+): C43H67NO12 (789.99): m/z: 710.4 [MꢀPivOH+Na]+; 812.5
[M+Na]+.
(2S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-d-
galacto-pyranosyl]-2-isopropyl-piperidin-4-one (20r): Reaction time: 7 h;
yield: 4.1 mg (28%); colorless oil; Rf =0.49 (petroleum ether/ethyl ace-
tate (2:1)); LC-MS: tR =7.07 (74%, 20r). Isolation by semi-preparative
HPLC (Luna C-18, MeCN (80%!100%), 30 min): tR =22.3 min;
1H NMR (CDCl3, 600 MHz): d=5.50 (t, 1H, 3J=9.7 Hz, H-2); 5.36 (d,
1H, 3J=2.9 Hz, H-4); 5.15 (dd, 1H, 3J=10.0, 3J=2.9 Hz, H-3); 4.41 (d,
3
3
2
1H, J=9.1 Hz, H-1); 4.05 (dd, 1H, J=7.0, J=11.2 Hz, H-6a); 3.93 (dd,
1H, 3J=6.2, 2J=10.9 Hz, H-6b); 3.87 (t, 1H, 3J=6.5 Hz, H-5); 3.61 (t,
(2S,6S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-
d-galacto-pyranosyl]-2-(2-chloro-6-fluorophenyl)-6-methyl-piperidin-4-
one (22gb): Me2Cu(CN)Li2 (30 equiv, cuprate formation: ꢀ308C);
BF3¥OEt2 (30 equiv); reaction time: 16 h at ꢀ208C; Yield of crude prod-
uct: 11 mg (67%); yellowish oil; Rf =0.31 (petroleum ether/ethyl acetate
(2:1)); LC-MS: tR =5.10 (12%, 18g); 7.95 (3%, minor); 8.32 (78%, ma-
jor) min. Purification by preparative HPLC (Luna C-18, MeCN (80%!
100%), 60 min): tR =59.15 min; 1H NMR (CDCl3, 400 MHz): d=7.65 (d,
2H, 3J=8.2 Hz, 2îaryl); 7.03 (t, 1H, 3J=8.6 Hz, aryl); 5.52 (t, 1H, 3J=
9.6 Hz, H-2); 5.26 5.23 (m, 2H, H-4, NCHAryl); 4.89 (dd, 1H, 3J=9.8,
3
2
3
2H, J=5.6 Hz, CH2OH); 3.29 (td, 1H, J=14.1, J=5.6 Hz, NCH2); 3.14
2
3
3
3
(ddd, 1H, J=13.8, J=8.5, J=5.1 Hz, NCH2); 2.87 (pq, 1H, J=6.2 Hz,
NCH-iPr); 2.65 (dd, 1H, 2J=13.7, 3J=5.2 Hz, CHiPrCH2); 2.54 (ddd,
2
3
3
2
3
1H, J=14.3, J=6.8, J=7.6 Hz, NCH2CH2); 2.36 (dd, 1H, J=14.1, J=
5.6 Hz, CHiPrCH2); 2.21 (td, 1H, 2J=14.3, J=5.3 Hz, NCH2CH2); 1.78
3
1.73 (m, 1H, CH(Me)2); 1.53 1.16 (m, 10H, 5îCH2); 1.25, 1.13, 1.11 (3 s,
27H, Piv tBu); 1.14 (s, 6H, 2îMe); 0.87 (d, 3H, 3J=6.7 Hz, Me); 0.86
3
(d, 3H, J=6.6 Hz, Me) ppm; MS (ES+): C39H67NO11 (725.95): m/z: 585.3
[Msugar]+; 646.3 [MꢀPivOH+Na]+; 726.3 [M+H]+; 748.2 [M+Na]+.
3
3J=3.1 Hz, H-3); 4.17 4.05 (m, 2H, H-6a, H-6b); 3.96 (d, 1H, J=9.4 Hz,
General procedure for conjugate cuprate addition to polymer-bound en-
aminones (17): a) Cuprate preparation: At ꢀ788C a suspension of cop-
per(i) cyanide in dry THF (approximately 1 mL per 50 mg) was treated
with organolithium reagent (2 equiv). The suspension was slowly warmed
up until cuprate formation was complete and the solution had become
clear. Before addition to the enone, the cuprate solution was recooled to
ꢀ788C. b) Conjugate addition: BF3¥OEt2 (for amounts, see below) and
the cooled cuprate solution (for reaction times and temperatures, see
below) were added successively to a suspension of resin 17 in THF (1 mL
per 50 mg) at ꢀ788C. After the given reaction time the suspension was
treated with ammonium pyrrolidine dithiocarbamate solution (0.1% in
CH2Cl2/MeOH (5:1)), warmed to room temperature, filtered, and vigo-
rously washed with the carbamate solution several times until the resin
had reached its initial amber colour. The resin was further washed with
CH2Cl2, THF, und MeOH (6 cycles) and dried under high vacuum. Cleav-
age from support was performed by using TBAF.
H-1); 3.80 (t, 1H, 3J=10.2 Hz, H-5); 3.60 (t, 2H, 3J=6.4 Hz, CH2OH);
3.35 (brs, 1H), 2.92 (brs, 1H), 2.66 (dd, 1H, 3J=5.5, 2J=14.1 Hz), 2.52
2.47 (m, 1H), 2.23 (brd, 1H, 2J=14.5 Hz, NCHMe, CH2C=O); 1.54 1.24
(m, 10H, 5îCH2); 1.23, 1.16, 1.08 (3 s, 27H, Piv tBu); 1.08 (s, 6H, 2î
Me); 1.32 (d, 3H, 3J=6.7 Hz, Me) ppm; MS (ES+): C43H65ClFNO11
(826.43): m/z: 724.4 [MꢀPivOH+H]+; 746.3 [MꢀPivOH+Na]+; 848.5
[M+Na]+.
(2S,6R)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-
d-galacto-pyranosyl]-2-(2-chloro-6-fluorophenyl)-6-phenyl-piperidin-4-
one (22gc): Ph2Cu(CN)Li2 (30 equiv, cuprate formation: ꢀ308C);
BF3¥OEt2 (30 equiv); reaction time: 16 h at ꢀ208C; Yield of crude prod-
uct: 11 mg (48%); yellowish oil, Rf =0.28 (petroleum ether/ethyl acetate
(2:1)); LC-MS: tR =4.92 (27%, 18g); 7.75 (53%, major); 8.92 (15%, mi-
nor) min. Purification by preparative HPLC (Luna C-18, MeCN (80%!
100%), 60 min): tR =52.40 min; 1H NMR (CDCl3, 400 MHz): d=7.43 (d,
2H, 3J=7.8 Hz, 2îaryl); 7.32 7.26 (m, 4H, 4îaryl); 7.18 (t, 1H, 3J=
7.2 Hz, 1îaryl); 7.03 6.98 (m, 1H, 1îaryl); 5.50 (brd, 1H, 3J=13.3 Hz,
CHN); 5.29 (d, 1H, 3J=2.4 Hz, H-4); 5.18 (t, 1H, 3J=9.4 Hz, H-2); 5.04
(brd, 1H, 3J=4.3 Hz, CHN); 4.87 (dd, 1H, 3J=9.8, 3J=2.7 Hz, H-3);
4.26 (d, 1H, 3J=9.4 Hz, H-1); 4.24 (dd, 1H, 3J=5.9, 2J=10.6 Hz, H-6a);
3.98 (t, 1H, 3J=6.3 Hz, H-5); 3.93 (dd, 1H, 3J=6.6, 2J=10.2 Hz, H-6b);
3.61 (t, 2H, 3J=6.5 Hz, CH2OH); 3.39 (dd, 1H, 3J=6.2, 2J=16.4 Hz),
3.27 (dd, 1H, 3J=14.9, 2J=18.0 Hz), 2.94 (dd, 1H, 3J=2.0, 2J=16.8 Hz),
2.42 (dd, 1H, 3J=2.7, 2J=18.0 Hz, CH2C=O); 1.55 1.48, 1.35 1.23 (m,
10H, 5îCH2); 1.24, 0.99, 0.98 (3 s, 27H, Piv tBu); 1.15 (s, 6H, 2î
(2S,6S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-
d-galacto-pyranosyl]-2-(3-fluorophenyl)-6-n-butyl-piperidin-4-one (22ca):
(nBu)2Cu(CN)Li2 (30 equiv, cuprate formation: ꢀ608C), BF3¥OEt2
(30 equiv); reaction time: 2 h at ꢀ608C, then warm to ꢀ558C for 12 h;
Yield of crude product: 7.9 mg (47%); yellowish oil; LC-MS: tR =9.50
(90%, major); 10.07 (10%, minor) min; purification by semi-preparative
HPLC (Luna C-18, MeCN (80%!100%), 60 min): tR =48.17 min;
1H NMR (CDCl3, 400 MHz): d=7.35 (td, 1H, 3J=7.8, 4JH,F =5.9 Hz, aryl
H-5); 7.09 6.98 (m, 3H, aryl); 5.50 (t, 1H, 3J=9.6 Hz, H-2); 5.23 (d, 1H,
3J=2.3 Hz, H-4); 4.83 (dd, 1H, 3J=9.8, 3J=3.1 Hz, H-3); 4.48 (dd, 1H,
Chem. Eur. J. 2004, 10, 4136 4149
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4147

H. Kunz and G. Zech
FULL PAPER
Me) ppm; MS (ES+): C48H67ClFNO11 (888.50): m/z: 786.5
[MꢀPivOH+H]+; 808.5 [MꢀPivOH+Na]+; 910.5 [M+Na]+.
cati, P. Seneci, Tetrahedron 2001, 57, 8313 8322; c) S. N. Savinov,
D. J. Austin, Org. Lett. 2002, 4, 1419 1422.
[10] S. Nakamura, Y. Uchiyama, S. Ishikawa, R. Fukinbara, Y. Watanabe,
T. Toru, Tetrahedron Lett. 2002, 43, 2381 2383.
(2S,6S)-N-[6-O-(8-Hydroxy-2,2-dimethyloctanoyl)-2,3,4-tri-O-pivaloyl-b-
d-galacto-pyranosyl]-2-(4-trifluoromethylphenyl)-6-n-butyl-piperidin-4-
one (22ia): (nBu)2Cu(CN)Li2 (30 equiv, cuprate formation: ꢀ608C);
BF3¥OEt2 (30 equiv); reaction time: 2 h at ꢀ608C, then warm to ꢀ558C
for 12 h; Yield of crude product: 8.3 mg (47%); yellowish oil; LC-MS:
tR =4.82 (15%, 18i); 10.22 (61%, major); 10.87 (24%, minor) min. Puri-
fication by semi-preparative HPLC (Luna C-18, MeCN (90%!100%),
60 min): tR =approximately 23.3 (diastereomeric mixture) min. Major dia-
stereomer: 1H NMR (CDCl3, 400 MHz): d=7.65 (d, 2H, 3J=8.2 Hz, 2î
aryl); 7.44 (d, 2H, 3J=7.8 Hz, 2îaryl); 5.52 (t, 1H, 3J=9.8 Hz, H-2);
5.23 (d, 1H, 3J=3.1 Hz, H-4); 4.84 (dd, 1H, 3J=9.6, 3J=2.9 Hz, H-3);
4.56 (dd, 1H, 3J=4.7, 3J=9.4 Hz, NCHAryl); 4.08 (dd, 1H, 3J=6.6, 2J=
11.3 Hz, H-6a); 3.90 (d, 1H, 3J=9.4 Hz, H-1); 3.81 3.77 (m, 2H, H-6b,
NCHBu); 3.60 (t, 2H, 3J=6.2 Hz, CH2OH); 3.27 (t, 1H, 3J=6.6 Hz, H-
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ꢀ
ꢀ
5); 2.55 2.48, 2.14 2.04 (m, 5H, CH2C=O, NCH CH2 Pr); 1.57 1.17 (m,
15H, 7.5îCH2); 1.24, 1.22, 1.07 (3 s, 27H, Piv tBu); 1.13 (s, 6H, 2îMe);
0.89 (t, 3H, 3J=6.8 Hz, CH2CH3) ppm; MS (ES+): C47H72F3NO11
(884.07): m/z: 804.6 [MꢀPivOH+Na]+; 906.6 [M+Na]+.
[17] a) S. J. Danishefsky, K. F. McClure, J. T. Randolph, R. B. Ruggeri,
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Acknowledgement
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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tetraacetate). See, for example: a) Z. Gyˆrgydÿak, L. Szil‡gyi, Lie-
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The loading of 10a was determined by gravimetric and elemental
analysis, but can only serve as rough estimate as LiCl could not be
removed completely from the resin.
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis and Application of a Polymer-Bound Galactosylamine
4136 4149
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Received: March 16, 2004
Published online: July 12, 2004
Chem. Eur. J. 2004, 10, 4136 4149
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4149