Synthesis and complexation properties of unsymmetrical sucrose-based receptors

Article abstract of DOI:10.1002/ejoc.201300427

New unsymmetrical , sucrose-based diaza-crown ethers have been designed and prepared from monosilylated hexa-O-benzylsucrose derivatives. The enantioselective complexation of phenylethylammonium cations by these receptors was evaluated. It was demonstrated that the introduction of the amino group at the 6-position (glucose moiety) in sucrose increases the association constant for the S cation, but reduces the enantioselectivity. On the other hand, introduction of the amino group at the 6′-position (fructose moiety) in sucrose increases significantly the value of K_a and at the same time the high enantioselectivity is preserved. A new approach to sucrose-based macrocyclic receptors with an unsymmetrical arrangement of heteroatoms is presented. Their complexes with the (S)-α- phenylethylammonium cation are stronger than with the corresponding R cation. The enantioselectivity of the complexation depends on the position of the nitrogen atom(s) in the macrocyclic ring. Copyright

Full text of DOI:10.1002/ejoc.201300427

FULL PAPER
DOI: 10.1002/ejoc.201300427
Synthesis and Complexation Properties of “Unsymmetrical” Sucrose-Based
Receptors
Mykhaylo A. Potopnyk[a] and Sławomir Jarosz*[a]
Keywords: Carbohydrates / Macrocyclic ligands / Receptors / Host–guest systems / Molecular recognition
New “unsymmetrical”, sucrose-based diaza-crown ethers
have been designed and prepared from monosilylated hexa-
O-benzylsucrose derivatives. The enantioselective complex-
ation of phenylethylammonium cations by these receptors
was evaluated. It was demonstrated that the introduction of
the amino group at the 6-position (glucose moiety) in sucrose
increases the association constant for the S cation, but re-
duces the enantioselectivity. On the other hand, introduction
of the amino group at the 6Ј-position (fructose moiety) in su-
crose increases significantly the value of Ka and at the same
time the high enantioselectivity is preserved.
that served as a precursor in the synthesis of various N-
substituted analogues 2b[14b] (Figure 1).
Introduction
Nitrogen-containing macrocyclic compounds occupy an
important position in supramolecular chemistry.[1] For ex-
ample, aza-crown ethers, because of their cation-complex-
ation ability, are widely used in catalysis (including in
phase-transfer catalysis, PTC),[2] for the transport of metal
cations across membranes,[3] as well as in the synthesis of
catenenes[4] and rotaxanes.[5] Chiral aza-crown ethers are
often used as catalysts in asymmetric synthesis[6] and/or as
synthetic receptors that are able to recognize chiral ammo-
nium cations with high enantioselectivity,[1a,7] in chiral
analysis and separation.[8] The design of such receptors is
based on common enantiomerically pure starting platforms,
for example, amino acids,[9] binaphthyl,[10] salen,[10b] ter-
penes,[11] or sugars.[12]
Carbohydrates, because of their structural variety, offer
a unique possibility for the preparation of various stereo-
chemically different molecules. In most cases, the monosac-
charides (or their derivatives) are used as a chiral platform,
much less common are receptors based on a disaccharide
scaffold.[12]
Recently we proposed a convenient methodology for the
preparation of macrocyclic receptors containing sucrose as
a chiral-discriminating moiety.[13] Several of these receptors
showed interesting enantioselectivity in the complexation of
α-phenylethylammonium and α-amino acid cations.[14] In
particular, we synthesized 16-membered aza-crown ethers
1a,b containing one or three nitrogen atoms. We also ob-
tained macrocycle 2a with a secondary amine functionality
Figure 1. “Symmetrical” sucrose-based macrocyclic receptors.
The receptor containing one nitrogen atom (monoaza-
crown ether 1a) complexed the (S)-phenylethylammonium
cation with high enantioselectivity but a rather moderate
association constant.[14b] On the other hand, the association
constants of the complexes of receptor 1b (with three nitro-
gen atoms in the ring) with α-phenylethylammonium cat-
ions (R and S) were substantially higher, but the enantio-
selectivities were rather low.[14a] In our opinion, 16-mem-
bered sucrose-based diaza-crown ethers might have better
complexation abilities.
Receptors prepared by us to date (1a,b or 2a,b) are “sym-
metrical”, that is, with the same heteroatom at the fructose
and glucose “end” of the molecule (X = Y = O for 1a, 2a,b;
X = Y = N-Bn for 1b). In this paper we will report the
preparation of “nonsymmetrical” (X ϶ Y) sucrose-based
receptors and some applications in enantioselective com-
plexation.
[a] Institute of Organic Chemistry, Polish Academy of Sciences,
01-224 Kasprzaka 44/52, Warsaw, Poland
Results and Discussion
E-mail: slawomir.jarosz@icho.edu.pl
Homepage: www.icho.edu.pl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300427.
An especially useful sucrose platform for the synthesis of
macrocyclic compounds is based on 1Ј,2,3,3Ј,4,4Ј-hexa-O-
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benzylsucrose (3) obtained in a rather moderate yield from Removal of both silyl protections with fluoride anion af-
di-O-tritylsucrose.[15] In this paper we propose an alterna- forded the diol 3 in good overall yield.
tive approach to 3, starting from 6,6Ј-di-O-tert-butyldi-
methylsilylsucrose 4.[16] The TBDMS protecting group was
chosen rather than tert-butyldiphenylsilyl (TBDPS) because
the latter is, as we have observed, not very stable in the
strongly basic media applied in the next step. Thus, the pro-
tection of all free hydroxy groups in 4 (five secondary and
one primary at C-1Ј) as benzyl ethers was achieved with
sodium hydride/benzyl bromide in 83% yield (5; Scheme 1).
For the synthesis of “nonsymmetrical” sucrose-based re-
ceptors, monofunctionalized derivatives of the diol 3, such
as 6 and 7, were necessary. These alcohols were prepared
by a strategy similar to that used by us[17] for the differentia-
tion of the primary positions of (partially) protected su-
crose.
The reaction of compound
5 with 1.1 equiv. of
TBAF·3H2O in THF for 6 h afforded, after flash
chromatography, the monosilylated product 6 in 57% yield
(Scheme 1). The position of the TBDMS group in com-
pound 6 was proven by spectral correlations and also by
further transformations (to product 17, see Scheme 3).
As already noted, the free sucrose as well as the diol 3
can be selectively silylated with TBDPS at 6Ј-OH (fruc-
tose).[17,18]
Also, the reaction of 1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose
(3) with 1.1 equiv. of tert-butyldimethylsilyl chloride
(TBDMSCl) in CH2Cl2 in the presence of 4-(dimeth-
ylamino)pyridine (DMAP) as catalyst and Et3N as base for
24 h afforded 6Ј-O-tert-butyldimethylsilyl-1Ј,2,3,3Ј,4,4Ј-
hexa-O-benzylsucrose (7; 56%) as the main product to-
gether with disilylated compound 5 (13%) and unreacted
dialcohol 3 (25%; Scheme 1).
The structure of regioisomer 7 was proven by spectral
correlations and further transformations (to 8, see
Scheme 2).
The synthesis of the first “nonsymmetrical” macrocycle
16 was initiated starting from the derivative with the free
hydroxy group on the glucose moiety in 7. Alkylation of
the 6-OH group with tert-butyl bromoacetate (under phase-
Scheme 1. Synthesis of the monosilylated sucrose precursor. Rea-
gents and conditions: (i) TBDMSCl (2.5 equiv.), Py, 24 h, room
temp., 59% (ref.[16]); (ii) BnBr (6.5 equiv.), NaH (6.3 equiv.), DMF,
room temp., 24 h, 83%; (iii) TBAF·3H2O (4 equiv.), THF, 12 h,
room temp., 78%; (iv) TBAF·3H2O (1.1 equiv.), THF, 6 h, room
temp., 57%; (v) TBDMSCl (1.1 equiv.), DMAP (cat.), Et3N,
CH2Cl2, 24 h, room temp., 56%.
Scheme 2. Synthesis of macrocyclic receptor 16. Reagents and conditions: (i) BrCH2CO2tBu, Bu4NBr, THF, NaOH (50% aq.), room
temp., 3 h, 84%; (ii) TBAF·3H2O, THF, room temp., 1 h, 87%; (iii) (COCl)2, DMSO, CH2Cl2, –78 °C, then Et3N, 99 %;
(iv) BnNHCH2C(O)NHBn (11) (3 equiv.), AcOH (3 equiv.), MgSO4, 1 h, then NaBH3CN, room temp., 12 h, 71%; (v) LiAlH4, THF,
room temp., 10 h, 77%; (vi) LiAlH4, THF, reflux, 1.5 h, 73%; (vii) I2, Ph3P, imidazole, toluene, reflux, 4 h, 72%.
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“Unsymmetrical” Sucrose-Based Receptors
transfer conditions) provided product 8 in good yield. Re-
Receptors 16 and 21 were employed in the enantioselec-
moval of the silyl protection on the fructose 6Ј-OH group tive recognition of α-phenylethylammonium chloride [(S)-
with tetrabutylammonium fluoride trihydrate afforded the PEA·HCl and (R)-PEA·HCl].
alcohol 9, which, after Swern oxidation, was converted into
In the complexation of primary ammonium cations by
aldehyde 10. Reductive amination of this compound with aza-crown ethers, polar N+–H···N and N+–H···O hydrogen-
N-benzyl-2-(benzylamino)acetamide (11) provided the bond interactions are the most important. In addition, elec-
amide ester 12 (Scheme 2)
trostatic interactions exist between the cation and the elec-
Reduction of both the ester and amide functions in com- tronegative centers of the ligand and, if the ammonium cat-
pound 12 should provide the amino alcohol 14. Indeed, ion and receptor contain an aromatic moiety, π–π interac-
treatment of 12 with LiAlH4 in THF at reflux provided the tions are possible.
expected compound 14 in good yield. However, it was inter-
The association constants (Ka) of the complexes formed
esting to note that at room temperature only the ester group between the receptors 16 and 21 and the α-phenylethyl-
was reduced (to 13).
ammonium cations were determined by the NMR titration
The reaction of the amino alcohol 14 with the Garegg method[20] in CDCl3. The NMR spectra of solutions con-
reagent (TPP/imidazole/I2[19]) afforded the unstable iodide taining both the host (at a constant concentration) and the
15, which spontaneously cyclized to the desired macrocycle guest (at variable concentrations) were recorded and the
16, bearing the benzylamino group on the fructose moiety, changes in the chemical shifts of the signal(s) sensitive to
in 72% yield (Scheme 2).
the formation of the host–guest complex were measured.
A similar strategy was used to prepare the second “un-
For sucrose-based receptors, the signal of the anomeric
symmetrical” diaza-crown with the benzylamino group on proton (1-H) is the only one that can be monitored in this
the glucose moiety. Thus, alkylation of alcohol 6 with tert- way. Other proton signals of the “aza-crown ring” are su-
butyl bromoacetate provided the appropriate sucrose-based perimposed on each other (see the Exp. Section and Sup-
ester 17 (in 77% yield), which, after desilylation, was con- porting Information) and so they are not diagnostic.
verted into the alcohol 18. Oxidation of 18 under Swern
The difference between the chemical shifts of the 1-H
conditions followed by reductive amination with 11 gave proton in the host–guest mixture and that observed in the
amide ester 19. Reduction of this compound with LiAlH4 host molecule (Δδ) was therefore measured and the experi-
in THF at reflux (as described for the reaction of 12) pro- mental titration curve (the change in chemical shift with
vided the corresponding amino alcohol 20. The ring-closing increasing concentration of guest) was plotted. The associa-
reaction of the “half-crown” 20 with I2/Ph3P/imidazole re- tion constant (Ka) was calculated by fitting the data to the
sulted in the formation of the macrocycle 21 in 72% yield empirical equation described by Fielding by using program
(Scheme 3).
MicroCal Origin®[20]. The Ka values of the receptors 16, 21,
and (previously obtained) 1a,b with (S)-PEA·HCl and (R)-
PEA·HCl are presented in Table 1.
Table 1. Association constants for the complexes of ligands 1a, 1b,
16, and 21 with (S)- and (R)-phenylethylammonium chloride in
CDCl3.
Receptor
Ka(S) [m–1]
Ka(R) [m–1]
[a]
1a
21
16
1b
70Ϯ7
309Ϯ23
522Ϯ33
1244Ϯ192
–
131Ϯ6
–
837Ϯ104
[a] No shift of signal observed in the NMR spectra during the
titration.
In the complexation experiments between (S)-PEA·HCl
and the receptor 16, we observed a change in the chemical
shift of the anomeric proton from δ = 5.49 to 5.42 ppm
(Δδmax ≈ –0.07 ppm); the titration curve is shown in Fig-
ure 2. The association constant was calculated to be 522 m–1
(Table 1, entry 3). We did not observe, however, any signifi-
cant change in the chemical shift in the NMR spectra dur-
ing the titration of the receptor 16 with (R)-PEA·HCl,
which indicates a rather weak interaction between the host
and guest.
Scheme 3. Synthesis of macrocyclic receptor 21. Reagents and con-
ditions: (i) BrCH2CO2tBu, Bu4NBr, THF, NaOH (50% aq.), room
temp., 3 h, 77%; (ii) TBAF·3H2O, THF, room temp., 4 h, 71%;
(iii) 1. (COCl)2, DMSO, CH2Cl2, –78 °C, then Et3N, 99 %;
2. BnNHCH2C(O)NHBn (11) (3 equiv.), AcOH (3 equiv.), MgSO4,
1 h, then NaBH3CN, room temp., 12 h, 74%; (iv) LiAlH4, THF,
On the other hand, diaza-crown ether 21 formed com-
plexes with (S)-PEA·HCl and (R)-PEA·HCl with Ka = 309
reflux, 2 h, 84%; (v) I2, Ph3P, imidazole, toluene, reflux, 4 h, 74%. and 131 m–1, respectively (Δδmax ≈ –0.08 ppm), but the
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M. A. Potopnyk, S. Jarosz
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Figure 2. Titration curve for macrocycle 16 and (S)-phenylethyl-
ammonium chloride.
Figure 4. Titration curve for macrocycle 21 and (R)-phenylethyl-
ammonium chloride.
activity of the receptor, however, the presence of the nitro-
gen atom at the C-6 position reduces the enantioselectivity.
In general, the complexation ability of the sucrose-based
receptors towards the (S)-α-phenylammonium cation is in-
creased with increasing number of nitrogen atoms in the
macrocyclic ring. The selectivity of the complexation of this
cation, however, depends on the positions of the nitrogen
functions in the ring; it is reduced when the “glucose” oxy-
gen atom at the C-6 position is replaced by nitrogen. Recep-
tors 21 and 1b exhibit low selectivity whereas 1a and 16
selectively complex the S cation.
enantioselectivity was rather moderate (Ka(S)/Ka(R) ≈ 2.4).
1
The H NMR titration curves for diaza-crown ether 21 are
shown in Figures 3 and 4.
Conclusions
We have proposed a convenient and efficient route to
“unsymmetrical” macrocyclic receptors with a sucrose scaf-
fold. The enantioselectivity of the complexation of the (S)-
and (R)-phenylethylammonium cations strongly depends on
the position of the nitrogen atom(s) in the macrocyclic ring.
Receptors possessing an oxygen atom at the C-6 position
of the “glucose moiety” selectively complex the S cation.
The enantioselectivity is low when the “glucose” oxygen
atom is replaced by a nitrogen.
Figure 3. Titration curve for macrocycle 21 and (S)-phenyleth-
ylammonium chloride.
We found previously that the monoaza-crown ether 1a
selectively complexes the (S)-α-phenylammonium cation,
but the value of Ka is low (70 m–1).[14b] On the other hand,
the complexation of the (S)-PEA cation by triaza-crown
Experimental Section
General: All reported NMR spectra were recorded with a Varian
ether 1b is much stronger (Ka ≈ 1200), but the enantio- Vnmrs 600 MHz (at 600 and 150 MHz for 1H and 13C NMR,
selectivity is relatively low (Ka(S)/Ka(R) ≈ 1.5).[14a]
respectively) or Varian Mercury 400 MHz spectrometer (at 400 and
100 MHz for 1H and 13C NMR, respectively) for solutions in
Replacement of the oxygen atom by an amino group at
CDCl3 at room temperature. The chemical shifts (δ, ppm) were
the C-6 position (compound 21) increases the association
determined relative to TMS as the internal standard. Most of the
constant for the S cation from 70 to 309 m–1, but it also
resonances were assigned by COSY (1H–1H) and gradient-selected
increases the complexation ability of the R cation. However,
similarly replacing the oxygen atom at the C-6Ј position
(compound 16) also increases Ka for the (S)-PEA·HCl, but
the receptor remains inactive towards (R)-PEA·HCl.
HSQC and HMBC correlations. IR spectra (CHCl3, film) were re-
corded with a Perkin–Elmer FT-IR Spectrum 2000 spectrometer.
Mass spectra were recorded with an ESI/MS Mariner (PerSeptive
Biosystem) mass spectrometer. Elemental analyses were obtained
with a Perkin–Elmer 2400 CHN analyzer. Optical rotations were
These results show that the stepwise replacement of the
oxygen atoms by amino groups increases the complexation measured with a Jasco DIP-360 digital polarimeter for solutions in
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“Unsymmetrical” Sucrose-Based Receptors
CHCl3 or CH2Cl2 at room temperature. Flash and column chroma-
tographic separations were performed on silica gel (Merck, 230–
400 mesh). The progress of reactions was monitored by TLC on
aluminium plates covered with silica gel (60 F254, Merck). Organic
solutions were dried with anhydrous magnesium sulfate.
compound 5 (956 mg, 0.86 mmol) in THF (20 mL) and the mixture
stirred for 6 h at room temp. The solvent was then evaporated in
vacuo and the products were isolated by flash chromatography
(hexane/ethyl acetate, 90:10 to 60:40) to give 6,6Ј-di-O-tert-butyldi-
methylsilyl-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose (5; 211 mg, 22%),
6-O-tert-butyldimethylsilyl-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose (6;
490 g, 57%), and 1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose (3, 130 mg,
17%).
For identification of the sucrose-containing products and interpre-
tation of the NMR spectra, standard numbering of the carbon and
hydrogen atoms in the sucrose molecule is used: the glucose atoms
are numbered 1 through to 6 and the fructose atoms are numbered
1Ј through 6Ј (see compounds 3 and 4 in Scheme 1). The atoms of
groups attached to the glucose or fructose moiety are numbered in
accord with the series of natural numbers.
1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzylsucrose (3): TLC (hexane/AcOEt, 1:1):
Rf = 0.25. Colorless oil. [α]D = +50.2 (c = 1, CHCl3). 1H NMR
(600 MHz): δ = 7.20–7.38 (m, 30 H, Ar-H), 5.49 (d, J1,2 = 3.5 Hz,
1 H, 1-H), 4.87 (d, J = 10.9 Hz, 1 H, benzylic H), 4.86 (d, J =
11.1 Hz, 1 H, benzylic H), 4.76 (d, J = 11.1 Hz, 1 H, benzylic H),
4.71 (d, J = 11.6 Hz, 1 H, benzylic H), 4.69 (d, J = 11.6 Hz, 1 H,
benzylic H), 4.67 (d, J = 12.0 Hz, 1 H, benzylic H), 4.62 (d, J =
11.6 Hz, 1 H, benzylic H), 4.61 (d, J = 11.1 Hz, 1 H, benzylic H),
4.57 (d, J = 11.6 Hz, 1 H, benzylic H), 4.49 (d, J = 11.6 Hz, 1 H,
benzylic H), 4.47 (d, J = 12.1 Hz, 1 H, benzylic H), 4.42 (d, J3Ј,4Ј
= 7.6 Hz, 1 H, 3Ј-H), 4.32 (d, J = 12.0 Hz, 1 H, benzylic H), 4.33
(dd, J4Ј,5Ј = 7.9 Hz, 1 H, 4Ј-H), 4.15 (ddd, J5,6 = 1.9, J5,6 = 5.3, J5,4
= 10.2 Hz, 1 H, 5-H), 3.99 (dd, J3,4 = 9.3, J3,2 = 9.5 Hz, 1 H, 3-
H), 3.96 (dt, J5Ј,6Ј = 2.5 Hz, 1 H, 5Ј-H), 3.83 (dd, J6Ј,6Ј = 11.1 Hz,
1 H, 6Ј-H), 3.81 (dd, J6,6 = 12.3 Hz, 1 H, 6-H), 3.63 (dd, 1 H, 6-
H), 3.59 (dd, 1 H, 6Ј-H), 3.57 (d, J1Ј,1Ј = 11.1 Hz, 1 H, 1Ј-H), 3.50
(dd, 1 H, 2-H), 3.45 (d, 1 H, 1Ј-H), 3.43 (dd, 1 H, 4-H) ppm. 13C
NMR (150 MHz): δ = 138.6, 138.3, 138.13, 138.11, 138.0, 137.7 (6
Preparation of 6,6Ј-Di-O-tert-butyldimethylsilyl-1Ј,2,3,3Ј,4,4Ј-hexa-
O-benzylsucrose (5): Sodium hydride (60% dispersion in mineral
oil, 0.525 mg, 13.1 mmol) was added in portions at 5–10 °C to a
stirred solution of 6,6Ј-bis(O-tert-butyldimethylsilyl)sucrose (4;[16]
1.190 g, 2.08 mmol) in DMF (50 mL) and the mixture was stirred
at room temp. for 30 min. Benzyl bromide (2.32 mL, 13.55 mmol)
was added dropwise during 15 min and the mixture stirred for 24 h
at room temp. The mixture was partitioned between water (50 mL)
and diethyl ether (100 mL), the layers were separated, and the aque-
ous layer extracted with ethyl acetate (3ϫ 100 mL). The combined
organic layers were washed with water (50 mL) and brine (50 mL),
dried, concentrated, and the product was purified by flash
chromatography (hexane/ethyl acetate, 98:2) to afford pure com-
pound 5 (1.926 g, 1.73 mmol, 83%) as a colorless oil. TLC (hexane/
AcOEt, 8:1): Rf = 0.45. [α]D = +34.8 (c = 1, CHCl3). 1H NMR
(600 MHz): δ = 7.26–7.38 (m, 30 H, Ar-H), 5.92 (d, J1,2 = 3.8 Hz,
1 H, 1-H), 4.93 (d, J = 10.8 Hz, 1 H, benzylic H), 4.86 (d, J =
11.1 Hz, 1 H, benzylic H), 4.77 (d, J = 10.8 Hz, 1 H, benzylic H),
4.74 (d, J = 11.2 Hz, 1 H, benzylic H), 4.69 (d, J = 11.5 Hz, 1 H,
benzylic H), 4.68 (d, J = 10.8 Hz, 1 H, benzylic H), 4.64 (d, J =
11.9 Hz, 3 H, benzylic H), 4.54 (d, J = 11.5 Hz, 1 H, benzylic H),
4.52 (d, J = 11.2 Hz, 1 H, benzylic H), 4.48 (d, J3Ј,4Ј = 8.0 Hz, 1
Cquat, Ph), 127.50–128.45 (30 C, C-Ph), 103.9 (C-2Ј), 90.7 (C-1),
83.5 (C-3Ј), 81.7 (C-3), 81.0 (C-5Ј), 79.9 (C-4Ј), 79.5 (C-2), 77.6 (C-
4), 75.6, 75.0, 73.4, 73.3, 73.1, 72.5 (6 O-CH2-Ph), 73.0 (C-5), 71.3
(C-1Ј), 61.9 (C-6), 61.0 (C-6Ј) ppm. HRMS (ESI): calcd. for
C54H58O11Na [M + Na]+ 905.3871; found 905.3853. C54H58O11
(883.06): calcd. C 73.45, H 6.62; found C 73.42, H 6.51.
6-O-tert-Butyldimethylsilyl-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose (6):
TLC (hexane/AcOEt, 4:1): Rf = 0.30. Colorless oil. [α]D = +50.0 (c
= 1, CHCl3). 1H NMR (600 MHz): δ = 7.18–7.38 (m, 30 H, Ar-
H), 5.47 (d, J1,2 = 3.2 Hz, 1 H, 1-H), 4.83 (d, J = 11.4 Hz, 1 H,
benzylic H), 4.68 (d, J = 11.5 Hz, 1 H, benzylic H), 4.67 (d, J =
12.0 Hz, 1 H, benzylic H), 4.66 (d, J = 11.7 Hz, 1 H, benzylic H),
4.59 (d, J = 12.0 Hz, 1 H, benzylic H), 4.57 (d, J = 11.5 Hz, 1 H,
benzylic H), 4.56 (d, J = 12.0 Hz, 1 H, benzylic H), 4.50 (d, J =
11.4 Hz, 1 H, benzylic H), 4.46 (d, J = 11.5 Hz, 1 H, benzylic H),
4.45 (d, J3Ј,4Ј = 8.0 Hz, 1 H, 3Ј-H), 4.38 (d, J = 12.0 Hz, 1 H,
benzylic H), 4.37 (d, J = 12.2 Hz, 1 H, benzylic H), 4.34 (dd, J4Ј,5Ј
= 8.0 Hz, 1 H, 4Ј-H), 4.21 (d, J = 12.0 Hz, 1 H, benzylic H), 4.07–
4.10 (m, 2 H, 3-H, 5-H), 3.98 (m, 1 H, 5Ј-H), 3.83 (m, 1 H, 6Ј-H),
3.72 (dd, J6,6 = 11.0, J6,5 2.8 Hz, 1 H, 6-H), 3.61 (m, 1 H, 6Ј-H),
3.54–3.60 (m, 3 H, 6-H, 1Ј-H, 4-H), 3.40 (d, J1Ј,1Ј = 11.0 Hz, 1 H,
1Ј-H), 3.36 (dd, J2,3 = 9.5 Hz, 1 H, 2-H), 3.26 (dd, JOH,6Ј = 10.7,
JOH,6Ј = 2.4 Hz, 1 H, OH), 0.92 (s, 9 H, tBu), 0.04 (s, 3 H, SiCH3),
0.00 (s, 3 H, SiCH3) ppm. 13C NMR (150 MHz): δ = 138.47,
138.17, 138.09, 138.05, 137.87, 137.80 (6 Cquat, Ph), 127.22–128.30
(30 C, C-Ph), 103.63 (C-2Ј), 91.00 (C-1), 83.52 (C-3Ј), 81.17 (C-5Ј),
79.93 (C-2), 79.38 (C-4Ј), 78.58 (C-4), 74.72, 73.57, 73.56, 73.11,
72.81, 72.41 (6 O-CH2-Ph), 73.47 (C-3), 71.64 (C-1Ј), 71.51 (C-5),
68.13 (C-6), 61.06 (C-6Ј), 26.03 (triple intensity, 3 C, tBu), 18.01
(Cquat, tBu), –4.13, –4.30 (2 CH3Si) ppm. HRMS (ESI): calcd. for
H, 3Ј-H), 4.46 (d, J = 12.5 Hz, 1 H, benzylic H), 4.35 (dd, J4,Ј,5Ј
=
7.0 Hz, 1 H, 4Ј-H), 3.92–3.97 (m, 3 H, 3-H, 5Ј-H, 6Ј-H), 3.85–3.91
(m, 2 H, 5-H, 6Ј-H), 3.73 (d, J1Ј,1Ј = 10.8 Hz, 1 H, 1Ј-H), 3.69 (dd,
J = 9.4, J = 9.8 Hz, 1 H, 4-H), 3.59 (dd, J6,6 = 11.6, J6,5 = 2.7 Hz,
1 H, 6-H), 3.56 (d, 1 H, 1Ј-H), 3.47–3.51 (m, 2 H, 2-H, 6-H), 0.92
(s, 9 H, tBu), 0.88 (s, 9 H, tBu), 0.10 (s, 3 H, SiCH3), 0.08 (s, 3 H,
SiCH3), 0.02 (s, 3 H, SiCH3), 0.01 (s, 3 H, SiCH3) ppm. 13C NMR
(150 MHz): δ = 139.01, 139.00, 138.6, 138.5, 138.1, 138.0 (6 Cquat
,
Ph), 127.35–128.40 (30 C, C-Ph), 104.1 (C-2Ј), 89.2 (C-1), 84.1 (C-
3Ј), 82.1 (C-3), 81.8 (C-4Ј), 80.7 (C-5Ј), 80.5 (C-2), 77.3 (C-4), 75.7,
74.7, 73.4, 73.2, 72.8, 72.0 (6 O-CH2-Ph), 71.7 (C-1Ј), 71.5 (C-5),
63.6 (C-6Ј), 61.6 (C-6), 26.02 (triple intensity, 3 C, C-tBu), 25.98
(triple intensity, 3 C, tBu), 18.4 (Cquat, tBu), 18.3 (Cquat, tBu), –5.1,
–5.2, –5.37, –5.39 (4ϫ SiCH3) ppm. HRMS (ESI): calcd. for
C66H86O11NaSi2 [M
+
Na]+ 1133.5601; found 1133.5654.
C66H86O11Si2 (1111.59): calcd. C 71.32, H 7.80; found C 71.31, H
7.82.
Desilylation of 6,6Ј-Di-O-tert-butyldimethylsilyl-1Ј,2,3,3Ј,4,4Ј-hexa-
O-benzylsucrose (5)
Total Desilylation Procedure: Compound 5 (855 mg, 0.77 mmol)
was dissolved in THF (30 mL) and then tetrabutylammonium
fluoride trihydrate (858 mg, 3.08 mmol) was added and the mixture
stirred at room temperature for 12 h. The solvent was then removed
in vacuo and the product purified by flash chromatography (hex-
ane/ethyl acetate, 85:15 to 60:40) to give the 1Ј,2,3,3Ј,4,4Ј-hexa-O-
benzylsucrose (3; 530 mg, 78%).
C60H72O11NaSi [M
+
Na]+ 1019.4736; found 1019.4741.
C60H72O11Si (997.32): calcd. C 72.26, H 7.28; found C 72.22, H
7.17.
Selective Silylation of 1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzylsucrose (3): A
solution of tert-butyldimethylsilyl chloride (110 g, 0.73 mmol) in
CH2Cl2 (5 mL) was added over 180 min to a solution of diol 3
Selective Monodesilylation Procedure: Tetrabutylammonium
fluoride trihydrate (264 g, 0.95 mmol) was added to a solution of
Eur. J. Org. Chem. 2013, 5117–5126
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5121

M. A. Potopnyk, S. Jarosz
FULL PAPER
(585 mg, 0.66 mmol) in CH2Cl2 (10 mL) containing DMAP (6 mg,
0.05 mmol) and triethylamine (0.37 mL, 2.65 mmol) and the mix-
ture was stirred for 24 h at room temp. The solvent was then evapo-
rated and the mixture separated by flash chromatography (hexane/
ethyl acetate, 9:1 to 7:3) to afford 6,6Ј-di-O-tert-butyldimethylsilyl-
1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose (5; 95 mg, 13%), 6Ј-O-tert-
(dd, J4Ј,5Ј = 6.9 Hz, 1 H, 4Ј-H), 4.01 (dt, J4,5 = 9.9, J5,6 = 2.3 Hz,
1 H, 5-H), 3.87–3.98 (m, 4 H, 6Ј-H, 3-H, 5Ј-H, O-CH2-CO2), 3.81–
3.86 (m, 2 H, O-CH2-CO2, 6Ј-H), 3.76 (d, J1Ј,1Ј = 11.0 Hz, 1 H, 1Ј-
H), 3.64–3.69 (m, 2 H, 4-H, 6-H), 3.53 (d, 1 H, 1Ј-H), 3.51 (dd,
J2,3 = 9.7 Hz, 1 H, 2-H), 3.44 (dd, J6,6 = 11.0 Hz, 1 H, 6-H), 1.43
(s, 9 H, OtBu), 0.89 (s, 9 H, SitBu), 0.07 (s, 3 H, SiCH3), 0.06 (s, 3
butyldimethylsilyl-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose (7; 370 mg, H, SiCH3) ppm. 13C NMR (150 MHz): δ = 169.29 (CO2tBu),
56%) and unreacted alcohol 3 (147 mg, 25%).
139.03, 138.83, 138.44, 138.42, 138.11, 137.95 (6 Cquat, Ph), 127.35–
128.35 (30 C, Ph), 104.47 (C-2Ј), 89.78 (C-1), 84.24 (C-3Ј), 82.75
(C-4Ј), 81.98 (C-3), 81.43 (C-5Ј), 81.18 (Cquat, OtBu), 79.87 (C-2),
77.25 (C-4), 75.51, 74.76, 73.45, 73.13, 72.49, 71.99 (6 O-CH2-Ph),
71.06 (C-1Ј), 70.68 (C-5), 69.72 (C-6), 69.30 (O-CH2-CO2), 64.27
(C-6Ј), 28.09 (triple intensity, 3 C, OtBu), 25.97 (triple intensity, 3
C, SitBu), 18.37 (Cquat, SitBu), –5.28, –5.32 (2 CH3Si) ppm. HRMS
(ESI): calcd. for C66H82O13NaSi [M + Na]+ 1133.5417; found
1133.5456. C66H82O13Si (1111.47): calcd. C 71.32, H 7.44; found C
71.51, H 7.56.
6Ј-O-tert-Butyldimethylsilyl-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose (7):
TLC (hexane/AcOEt, 4:1): Rf = 0.35. Colorless oil. [α]D = +40.3 (c
1
= 1, CH2Cl2). H NMR (600 MHz): δ = 7.23–7.35 (m, 30 H, Ar-
H), 5.96 (d, J1,2 = 3.8 Hz, 1 H, 1-H), 4.93 (d, J = 10.8 Hz, 1 H,
benzylic H), 4.86 (d, J = 11.1 Hz, 1 H, benzylic H), 4.75 (d, J =
10.8 Hz, 1 H, benzylic H), 4.71 (d, J = 11.1 Hz, 1 H, benzylic H),
4.69 (d, J = 11.4 Hz, 1 H, benzylic H), 4.61 (d, J = 11.5 Hz, 1 H,
benzylic H), 4.60 (d, J = 11.7 Hz, 2 H, benzylic H), 4.57 (d, J =
11.5 Hz, 1 H, benzylic H), 4.51 (d, J = 11.4 Hz, 1 H, benzylic H),
4.50 (d, J = 11.0 Hz, 1 H, benzylic H), 4.47 (d, J = 11.0 Hz, 1 H,
1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzyl-6Ј-O-(2-tert-butoxy-2-oxoethyl)-6-O-
tert-butyldimethylsilylsucrose (17): TLC (hexane/AcOEt, 3:1): Rf =
0.55. Colorless oil. [α]D = +40.7 (c = 1, CH2Cl2). 1H NMR
(600 MHz): δ = 7.14–7.34 (m, 30 H, Ar-H), 5.65 (d, J1,2 = 3.5 Hz,
1 H, 1-H), 4.83 (d, J = 11.4 Hz, 1 H, benzylic H), 4.66 (d, J =
11.4 Hz, 1 H, benzylic H), 4.61 (d, J = 11.7 Hz, 1 H, benzylic H),
4.46–4.57 (m, 7 H, benzylic H), 4.42 (d, J3Ј,4Ј = 7.3 Hz, 1 H, 3Ј-H),
benzylic H), 4.45 (d, J3Ј,4Ј = 7.6 Hz, 1 H, 3Ј-H), 4.36 (dd, J4Ј,5Ј
=
7.3 Hz, 1 H, 4Ј-H), 4.02 (m, 1 H, 5-H), 3.88–3.96 (m, 3 H, 3-H, 5Ј-
H, 6Ј-H), 3.81 (dd, J6Ј,6Ј = 10.7, J6Ј,5Ј = 3.6 Hz, 1 H, 6Ј-H), 3.67
(d, J1Ј,1Ј = 10.8 Hz, 1 H, 1Ј-H), 3.63 (m, 1 H, 6-H), 3.53 (d, 1 H,
1Ј-H), 3.50 (dd, J2,3 = 9.6 Hz, 1 H, 2-H), 3.43–3.49 (m, 2 H, 6-H,
4-H), 1.95 (m, 1 H, OH), 0.89 (s, 9 H, tBu), 0.06 (s, 3 H, SiCH3),
0.05 (s, 3 H, SiCH3) ppm. 13C NMR (150 MHz): δ = 138.91, 4.39 (d, J = 12.2 Hz, 1 H, benzylic H), 4.36 (d, J = 12.0 Hz, 1 H,
138.41, 138.37, 138.22, 137.89, 137.78 (6 Cquat, Ph), 127.48–128.38 benzylic H), 4.03–4.15 (m, 4 H, 5Ј-H, 4Ј-H, 3-H, 5-H), 4.02 (d, J
(30 C, Ph), 104.29 (C-2Ј), 88.66 (C-1), 83.61 (C-3Ј), 81.93 (C-3),
80.81 (C-4Ј), 80.67 (C-5Ј), 80.12 (C-2), 77.80 (C-4), 75.61, 74.94,
= 16.3 Hz, 1 H, O-CH2-CO2), 3.94 (d, 1 H, O-CH2-CO2), 3.79 (dd,
J6Ј,6Ј = 10.4, J6Ј,5Ј = 6.8 Hz, 1 H, 6Ј-H), 3.73 (dd, J6Ј,5Ј = 4.1 Hz, 1
73.47, 73.09, 72.64, 71.85 (6 O-CH2-Ph), 72.00 (C-1Ј), 71.23 (C-5), H, 6Ј-H), 3.71 (d, J1Ј,1Ј = 11.1 Hz, 1 H, 1Ј-H), 3.52 (dd, J6,6 = 10.7,
62.96 (C-6Ј), 62.06 (C-6), 25.91 (triple intensity, 3 C, tBu), 18.38 J6,5 = 3.5 Hz, 1 H, 6-H), 3.48 (d, 1 H, 1Ј-H), 3.47 (dd, J4,5 = 10.1,
(Cquat, tBu), –5.37, –5.40 (2 CH3Si) ppm. HRMS (ESI): calcd. for
J4,3 = 8.9 Hz, 1 H, 4-H), 3.38 (dd, J6,5 = 2.0 Hz, 1 H, 6-H), 3.32
(dd, J2,3 = 9.5 Hz, 1 H, 2-H), 1.45 (s, 9 H, OtBu), 0.89 (s, 9 H,
SitBu), 0.012 (s, 3 H, SiCH3), 0.010 (s, 3 H, SiCH3) ppm. 13C NMR
(150 MHz): δ = 169.36 (CO2tBu), 138.68, 138.26, 138.22, 138.21,
137.99, 137.96 (6 Cquat, Ph), 127.17–128.28 (30 C, Ph), 104.57 (C-
2Ј), 90.08 (C-1), 83.84 (C-3Ј), 82.41 (C-4Ј), 81.36 (Cquat, OtBu),
79.85 (C-2), 79.73 (C-5Ј), 79.00 (C-4), 74.56, 73.38, 73.35, 72.88,
72.41, 72.30 (6 O-CH2-Ph), 73.78 (C-3), 72.88 (C-6Ј), 71.33 (C-1Ј),
70.62 (C-5), 69.06 (O-CH2-CO2), 68.76 (C-6), 28.11 (triple inten-
C60H72O11NaSi [M
+
Na]+ 1019.4736; found 1019.4747.
C60H72O11Si (997.32): calcd. C 72.26, H 7.28; found C 72.06, H
7.20.
Preparation of 1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzyl-6-O-(2-tert-butoxy-2-
oxoethyl)-6Ј-O-tert-butyldimethylsilylsucrose (8) and 1Ј,2,3,3Ј,4,4Ј-
Hexa-O-benzyl-6Ј-O-(2-tert-butoxy-2-oxoethyl)-6-O-tert-butyldi-
methylsilylsucrose (17): Tetrabutylammonium bromide (12 mg,
0.036 mmol or 16 mg, 0.048 mmol, respectively) was added to a
solution of the alcohol 7 (359 mg, 0.36 mmol) or 6 (479 mg,
0.48 mmol) in toluene (10 mL), followed by 50% aqueous NaOH
(10 mL). A solution of tert-butyl bromoacetate (0.16 mL,
1.08 mmol or 0.21 mL, 1.44 mmol, respectively) in toluene (1 mL)
was added and the mixture was vigorously stirred at room tempera-
ture for 3 h. The layers were separated and the aqueous layer ex-
tracted with diethyl ether (2ϫ 20 mL). The combined organic solu-
tions were washed with water (10 mL) and brine (10 mL), dried,
concentrated, and the products were isolated by flash chromatog-
sity, 3 C, OtBu), 26.05 (triple intensity, 3 C, SitBu), 18.11 (Cquat
,
SitBu), –3.96, –4.24 (2 CH3Si) ppm. HRMS (ESI): calcd. for
C66H82O13NaSi [M + Na]+ 1133.5417; found 1133.5432.
C66H82O13Si (1111.47): calcd. C 71.32, H 7.44; found C 71.27, H
7.43.
Preparation of 1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzyl-6-O-(2-tert-butoxy-2-
oxoethyl)sucrose (9) and 1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzyl-6Ј-O-(2-tert-
butoxy-2-oxoethyl)sucrose (18): Desilylation of 8 and 17 was per-
formed within 5 h as described previously (see “Total desilylation
raphy (hexane/ethyl acetate, 85:15) to afford pure 8 (335 mg, procedure”), starting from 8 (320 mg, 0.29 mmol) or 17 (394 mg,
0.30 mmol, 84%) or 16 (411 mg, 0.37 mmol, 77%).
0.35 mmol). The crude products were isolated by flash chromatog-
raphy (hexane/ethyl acetate, 75:25) to yield 250 mg (0.25 mmol,
87%) of 9 or 251 mg (0.25 mmol, 71%) of 18.
1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzyl-6-O-(2-tert-butoxy-2-oxoethyl)-6Ј-O-
tert-butyldimethylsilylsucrose (8): TLC (hexane/AcOEt, 3:1): Rf =
0.55. Yellowish oil. [α]D = +27.8 (c = 1, CHCl3). 1H NMR
1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzyl-6-O-(2-tert-butoxy-2-oxoethyl)sucrose
(600 MHz): δ = 7.20–7.33 (m, 30 H, Ar-H), 5.81 (d, J1,2 = 3.6 Hz, (9): TLC (hexane/AcOEt, 3:1): Rf = 0.21. Colorless oil. [α]D
=
1 H, 1-H), 4.92 (d, J = 11.0 Hz, 1 H, benzylic H), 4.85 (d, J =
10.9 Hz, 1 H, benzylic H), 4.75 (d, J = 11.0 Hz, 1 H, benzylic H),
4.73 (d, J = 10.9 Hz, 1 H, benzylic H), 4.66 (d, J = 11.4 Hz, 1 H,
benzylic H), 4.65 (d, J = 11.3 Hz, 1 H, benzylic H), 4.62 (d, J =
11.2 Hz, 1 H, benzylic H), 4.60 (d, J = 11.7 Hz, 1 H, benzylic H),
4.55 (d, J = 11.7 Hz, 1 H, benzylic H), 4.53 (d, J = 11.3 Hz, 1 H,
benzylic H), 4.49 (d, J = 11.4 Hz, 1 H, benzylic H), 4.46 (d, J =
+14.9 (c = 1, CHCl ). IR: ν = 3473, 3063, 3031, 2925, 2869, 1747,
˜
3
1497, 1454, 1393, 1367, 1308, 1229, 1209, 1148, 1088, 1074, 1028,
1002, 952, 912, 845, 736, 698 cm–1. 1H NMR (600 MHz): δ = 7.19–
7.34 (m, 30 H, Ar-H), 5.51 (d, J1,2 = 3.5 Hz, 1 H, 1-H), 4.87 (d, J
= 11.1 Hz, 1 H, benzylic H), 4.86 (d, J = 10.8 Hz, 1 H, benzylic
H), 4.79 (d, J = 11.1 Hz, 1 H, benzylic H), 4.79 (d, J = 10.8 Hz, 1
H, benzylic H), 4.68 (d, J = 11.5 Hz, 2 H, benzylic H), 4.62 (d, J
11.2 Hz, 1 H, benzylic H), 4.44 (d, J3Ј,4Ј = 7.3 Hz, 1 H, 3Ј-H), 4.25 = 11.8 Hz, 1 H, benzylic H), 4.60 (d, J = 11.5 Hz, 1 H, benzylic
5122
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Eur. J. Org. Chem. 2013, 5117–5126

“Unsymmetrical” Sucrose-Based Receptors
H), 4.56 (d, J = 11.8 Hz, 1 H, benzylic H), 4.48 (d, J = 11.5 Hz, 1
H, benzylic H), 4.47 (d, J = 12.2 Hz, 1 H, benzylic H), 4.45 (d,
J3Ј,4Ј = 8.0 Hz, 1 H, 3Ј-H), 4.34 (dd, J4Ј,5Ј = 8.0 Hz, 1 H, 4Ј-H),
127.57 (2 C), 127.33, 127.28, 53.89, 51.85, 42.88 ppm. HRMS
(ESI): calcd. for C16H19N2O [M + H]+ 255.1492; found 255.1501.
C16H18N2O (254.33): calcd. C 75.56, H 7.13, N 11.01; found C
75.68, H 7.37, N 11.19.
4.28 (d, J = 11.8 Hz, 1 H, benzylic H), 4.06 (dt, J4,5 = 9.8, J5,6
=
1.8 Hz, 1 H, 5-H), 3.99 (d, J = 16.0 Hz, 1 H, O-CH2-CO2), 3.96–
4.01 (m, 2 H, 5Ј-H, 3-H), 3.88 (d, 1 H, O-CH2-CO2), 3.82–3.86 (m,
2 H, 6-H, 6Ј-H), 3.76 (dd, J3,4 = 9.4 Hz, 1 H, 4-H), 3.57–3.63 (m,
3 H, 6-H, 1Ј-H, 6Ј-H), 3.55 (dd, J2,3 = 9.8 Hz, 1 H, 2-H), 3.47 (d,
J1Ј,1Ј = 11.4 Hz, 1 H, 1Ј-H), 3.18 (dd, JOH,6Ј = 10.4, JOH,6Ј = 2.6 Hz,
1 H, OH), 1.45 (s, 9 H, OtBu) ppm. 13C NMR (150 MHz): δ =
169.20 (CO2tBu), 138.81, 138.62, 138.29, 138.18, 138.15, 137.80 (6
Preparation of N-(2-Benzylamino-2-oxoethyl)-N-benzyl-6Ј-amino-
6Ј-deoxy-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzyl-6-O-(2-tert-butoxy-2-oxoeth-
yl)sucrose (12) and N-(2-Benzylamino-2-oxoethyl)-N-benzyl-6-
amino-6-deoxy-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzyl-6Ј-O-(2-tert-butoxy-2-
oxoethyl)sucrose (19): A solution of DMSO (170 μL, 2.39 mmol) in
CH2Cl2 (3 mL) was added within 5 min to a cooled (to –78 °C)
solution of oxalyl chloride (75 μL, 0.85 mmol) in CH2Cl2 (10 mL).
After 10 min, alcohol 9 or 18 (242 mg, 0.24 mmol) in CH2Cl2
(3 mL) was added dropwise and the mixture was stirred for 30 min
at –78 °C. Then Et3N (250 μL, 1.78 mmol) was added and the mix-
ture was allowed to warm to room temp. Water (10 mL) was added
and the organic layer was separated, dried, and concentrated in
vacuo. The crude aldehyde was dissolved in CH2Cl2 (20 mL) and
acetic acid (41 μL, 0.72 mmol), amine 11 (184 mg, 0.72 mmol), and
MgSO4 (ca. 100 mg) were added. The mixture was stirred at room
Cquat, Ph), 127.45–128.38 (30 C, Ph), 103.86 (C-2Ј), 91.13 (C-1),
83.60 (C-3Ј), 81.77 (C-3), 81.45 (Cquat, OtBu), 81.22 (C-5Ј), 79.68
(C-4Ј), 79.28 (C-2), 77.08 (C-4), 75.46, 74.92, 73.42, 73.27, 72.91,
72.50 (6 O-CH2-Ph), 71.35 (C-5), 71.16 (C-1Ј), 69.30 (C-6), 69.27
(O-CH2-CO2), 61.24 (C-6Ј), 28.11 (triple intensity, 3 C, tBu) ppm.
HRMS (ESI): calcd. for C60H68O13Na [M + Na]+ 1019.4552; found
1019.4567. C60H68O13 (997.20): calcd. C 72.27, H 6.87; found C
72.10, H 6.80.
1Ј,2,3,3Ј,4,4Ј-Hexa-O-benzyl-6Ј-O-(2-tert-butoxy-2-oxoethyl)sucrose temp. for 1 h. Sodium cyanoborohydride (18 mg, 0.29 mmol) was
(18): TLC (hexane/AcOEt, 3:1): Rf = 0.34. Colorless oil. [α]D
=
then added and the mixture stirred overnight. Water (50 mL), 0.1 m
aq. NH3 (10 mL), and CH2Cl2 (40 mL) were added, the organic
phase was separated, and the aqueous layer extracted with CH2Cl2
(3ϫ 50 mL). The combined organic layers were washed with water
(30 mL) and brine (30 mL), dried, concentrated, and the product
1
+47.7 (c = 1, CH2Cl2). H NMR (600 MHz): δ = 7.17–7.35 (m, 30
H, Ar-H), 5.74 (d, J1,2 = 3.5 Hz, 1 H, 1-H), 4.81 (d, J = 11.3 Hz,
1 H, benzylic H), 4.66 (d, J = 11.7 Hz, 1 H, benzylic H), 4.61 (d,
J = 11.3 Hz, 1 H, benzylic H), 4.56 (d, J = 12.0 Hz, 1 H, benzylic
H), 4.51–4.55 (m, 3 H, benzylic H), 4.50 (d, J = 11.3 Hz, 1 H, was isolated by flash chromatography (hexane/ethyl acetate, 90:10
benzylic H), 4.49 (d, J = 11.3 Hz, 1 H, benzylic H), 4.42 (d, J3Ј,4Ј
= 7.3 Hz, 1 H, 3Ј-H), 4.41 (d, J = 11.7 Hz, 1 H, benzylic H), 4.40
(d, J = 12.4 Hz, 1 H, benzylic H), 4.38 (d, J = 12.5 Hz, 1 H, benz-
ylic H), 4.15 (dd, J4Ј,5Ј = 7.4 Hz, 1 H, 4Ј-H), 4.12 (m, 1 H, 5Ј-H),
4.02–4.07 (m, 2 H, 3-H, 5-H), 4.00 (d, J = 16.3 Hz, 1 H, O-CH2-
CO2), 3.95 (d, 1 H, O-CH2-CO2), 3.73–3.80 (m, 2 H, 2 6Ј-H), 3.72
(d, J1Ј,1Ј = 10.9 Hz, 1 H, 1Ј-H), 3.50–3.56 (m, 2 H, 4-H, 6-H), 3.51
(d, 1 H, 1Ј-H), 3.39 (dd, J6,6 = 10.7, J6,5 = 1.9 Hz, 1 H, 6-H), 3.36
(dd, J2,3 = 9.6 Hz, 1 H, 2-H), 1.45 (s, 9 H, OtBu) ppm. 13C NMR
(150 MHz): δ = 169.33 (CO2tBu), 138.73, 138.24, 138.04, 138.01,
137.98, 137.87 (6 Cquat, Ph), 127.47–128.40 (30 C, Ph), 104.57 (C-
2Ј), 89.35 (C-1), 83.85 (C-3Ј), 82.11 (C-4Ј), 81.43 (Cquat, OtBu),
79.60 (C-5Ј), 78.85 (C-2), 77.47 (C-4), 74.28, 73.46, 73.38, 73.06,
72.51, 71.67 (6 O-CH2-Ph), 73.43 (C-3), 72.57 (C-6Ј), 71.21 (C-1Ј),
70.04 (C-5), 69.02 (O-CH2-CO2), 68.47 (C-6), 28.11 (triple inten-
sity, 3 C, OtBu) ppm. HRMS (ESI): calcd. for C60H68O13Na [M +
Na]+ 1019.4552; found 1019.4524. C60H68O13 (997.20): calcd. C
72.27, H 6.87; found C 72.01, H 6.89.
to 70:30) to afford pure 12 (210 mg, 0.17 mmol, 71 %) or 19
(221 mg, 0.18 mmol, 74%).
N-(2-Benzylamino-2-oxoethyl)-N-benzyl-6Ј-amino-6Ј-deoxy-
1Ј,2,3,3Ј,4,4Ј-hexa-O-benzyl-6-O-(2-tert-butoxy-2-oxoethyl)-sucrose
(12): TLC (hexane/AcOEt, 2:1): Rf = 0.34. Colorless oil. [α]D
=
+38.7 (c = 1, CHCl ). IR: ν = 3357, 3087, 3063, 3030, 3005, 2924,
˜
3
2869, 1952, 1877, 1810, 1747, 1676, 1605, 1585, 1517, 1496, 1453,
1393, 1366, 1307, 1257, 1227, 1208, 1145, 1088, 1074, 1028, 1002,
1
913, 845, 736, 697, 599, 560 cm–1. H NMR (600 MHz): δ = 7.66
(t, J = 6.6 Hz, 1 H, NH), 7.09–7.39 (m, 40 H, Ar-H), 5.44 (d, J1,2
= 3.6 Hz, 1 H, 1-H), 4.87 (d, J = 10.8 Hz, 1 H, benzylic H), 4.85
(d, J = 10.8 Hz, 1 H, benzylic H), 4.75 (d, J = 10.8 Hz, 1 H, benz-
ylic H), 4.70 (d, J = 10.8 Hz, 1 H, benzylic H), 4.64 (d, J = 11.4 Hz,
1 H, benzylic H), 4.59 (d, J = 11.4 Hz, 1 H, benzylic H), 4.58 (d,
J = 11.4 Hz, 1 H, benzylic H), 4.56 (d, J = 11.4 Hz, 1 H, benzylic
H), 4.48 (d, J = 11.4 Hz, 1 H, benzylic H), 4.46 (d, J = 11.4 Hz, 1
H, benzylic H), 4.39 (d, J3Ј,4Ј = 7.8 Hz, 1 H, 3Ј-H), 4.38 (d, J =
12.0 Hz, 1 H, benzylic H), 4.35 (d, J = 12.0 Hz, 1 H, benzylic H),
4.32 [t, J = 6.6 Hz, 2 H, C(O)NH-CH2-Ph], 4.04 (dt, J4Ј,5Ј = 7.8,
J5Ј,6Ј = 2.4 Hz, 1 H, 5Ј-H), 3.99–4.03 (m, 1 H, 5-H), 3.90–3.95 (m,
2 H, 3-H, 4Ј-H), 3.85 (d, J = 16.8 Hz, 1 H, O-CH2-CO2), 3.82 (d,
1 H, O-CH2-CO2), 3.78 (d, J = 13.8 Hz, 1 H, N-CH2-Ph), 3.63 (d,
J1Ј,1Ј = 10.8 Hz, 1 H, 1Ј-H), 3.59–3.63 (m, 3 H, 4-H, 6-H, N-CH2-
N-Benzyl-2-(benzylamino)acetamide (11): Bromoacetyl bromide
(0.50 mL, 5.74 mmol) was added dropwise to a vigorously stirred
solution of benzylamine (3.70 mL, 33.87 mmol) in dry acetonitrile
(30 mL) at 0 °C. The temperature was kept bellow 10 °C during the
addition. The reaction mixture was then warmed to room temp.,
stirred for 12 h, and partitioned between aqueous saturated potas-
sium carbonate (30 mL) and AcOEt (20 mL). The organic phase
was separated and the aqueous layer extracted with AcOEt (3ϫ
40 mL). The combined organic layers were washed with water
(40 mL) and brine (30 mL), dried, concentrated, and the product
isolated by flash chromatography (hexane–ethyl acetate, 50:50 to
0:100) to afford pure 11 (1.38 g, 5.42 mmol, 94%). TLC (AcOEt/
Ph), 3.48 (dd, J2,3 = 9.6 Hz, 1 H, 2-H), 3.44 (dd, J6,6 = 10.8, J5,6
=
1.8 Hz, 1 H, 6-H), 3.41 (d, 1 H, 1Ј-H), 3.36 [d, J = 16.8 Hz, 1 H,
N-CH2-C(O)NH], 3.21 [d, 1 H, N-CH2-C(O)NH], 2.96 (dd, J5Ј,6Ј
= 8.4, J6Ј,6Ј = 13.8 Hz, 1 H, 6Ј-H), 2.79 (dd, J5Ј,6Ј = 2.4 Hz, 1 H,
6Ј-H), 1.43 (s, 9 H, OtBu) ppm. 13C NMR (150 MHz): δ = 171.28
[C(O)NHBn], 169.12 (CO2tBu), 138.82, 138.68, 138.44, 138.18,
138.09, 138.01, 137.96, 137.86 (8 Cquat, Ph), 127.11–129.04 (40 C,
MeOH/H O, 45:5:3): R = 0.47. Yellowish oil. IR: ν = 3316, 3086, Ph), 104.33 (C-2Ј), 90.11 (C-1), 83.27 (C-3Ј), 83.20 (C-4Ј), 81.92
˜
2
f
3063, 3029, 2923, 2836, 1953, 1878, 1810, 1659, 1604, 1585, 1526,
(C-3), 81.27 (Cquat, OtBu), 79.59 (C-2), 78.81 (C-5Ј), 77.35 (C-4),
75.41, 74.75, 73.29, 72.79, 72.63, 72.42 (6 O-CH2-Ph), 71.33 (C-1Ј),
1496, 1454, 1426, 1360, 1331, 1253, 1203, 1124, 1080, 1028, 1002,
1
910, 829, 737, 698, 613 cm–1. H NMR (400 MHz): δ = 7.55 (br. s, 70.68 (C-5), 69.85 (C-6), 68.95 (O-CH2-CO2), 60.09 (N-CH2-Ph),
1 H), 7.17–7.36 (m, 10 H), 4.44 (d, J = 6.0 Hz, 2 H), 3.74 (s, 2 H),
58.66 (C-6Ј), 58.49 [N-CH2-C(O)NH], 42.78 [C(O)NH-CH2-Ph],
3.33 (s, 2 H), 1.82 (br. s, 1 H) ppm. 13C NMR (100 MHz): δ = 28.09 (triple intensity, 3 C, OtBu) ppm. HRMS (ESI): calcd. for
171.31, 139.19, 138.28, 128.59 (2 C), 128.50 (2 C), 128.01 (2 C), C76H84N2O13Na [M + Na]+ 1255.5865; found 1255.5802.
Eur. J. Org. Chem. 2013, 5117–5126
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5123

M. A. Potopnyk, S. Jarosz
FULL PAPER
C78H84N2O13 (1233.52): calcd. C 74.00, H 6.86, N 2.27; found C
74.23, H 6.94, N 2.42.
3.48 (m, 3 H, 2-H, O-CH2-CH2OH), 3.38 (m, 1 H, 6-H), 3.37 (d,
1 H, 1Ј-H), 3.30 [d, J7Ј,7Ј = 17.0 Hz, 1 H, N-CH2-C(O)NH], 3.26
[d, 1 H, N-CH2-C(O)NH], 2.92 (dd, J6Ј,6Ј = 13.8, J6Ј,5Ј = 8.6 Hz, 1
H, 6Ј-H), 2.77 (dd, J6Ј,5Ј = 2.6 Hz, 1 H, 6Ј-H), 2.68 (br. s, 1 H,
OH) ppm. 13C NMR (150 MHz): δ = 171.43 [C(O)NHBn], 138.70,
138.44, 138.34, 138.17, 138.15, 137.96, 137.84, 137.79 (8 Cquat, Ph),
127.17–129.06 (40 C, Ph), 104.43 (C-2Ј), 90.28 (C-1), 83.26 (C-4Ј),
83.17 (C-3Ј), 81.84 (C-3), 79.81 (C-2), 78.28 (C-5Ј), 77.65 (C-4),
75.48, 74.89, 73.29, 73.05, 72.52, 72.33 (6 O-CH2-Ph), 72.90 (O-
CH2-CH2OH), 71.11 (C-1Ј), 70.93 (C-5), 69.68 (C-6), 61.58 (OCH2-
CH2-OH), 59.53 (N-CH2-Ph), 58.67 (C-6Ј), 58.53 [N-CH2-C(O)
NH], 42.92 (NH-CH2-Ph) ppm. HRMS (ESI): calcd. for
C72H78N2O12Na [M + Na]+ 1185.5447; found 1185.5416.
C72H78N2O12 (1163.41): calcd. C 74.33, H 6.76, N 2.41; found C
74.48, H 6.85, N 2.51.
N-(2-Benzylamino-2-oxoethyl)-N-benzyl-6-amino-6-deoxy-
1Ј,2,3,3Ј,4,4Ј-hexa-O-benzyl-6Ј-O-(2-tert-butoxy-2-oxoethyl)sucrose
(19): TLC (hexane/AcOEt, 3:2): Rf = 0.35. Colorless oil. [α]D
+30.5 (c = 1, CH2Cl2). 1H NMR (600 MHz): δ = 7.89 (t, J =
6.0 Hz, 1 H, NH), 7.08–7.33 (m, 40 H, Ar-H), 5.40 (d, J1,2
=
=
3.3 Hz, 1 H, 1-H), 4.85 (d, J = 10.9 Hz, 1 H, benzylic H), 4.80 (d,
J = 11.1 Hz, 1 H, benzylic H), 4.76 (d, J = 11.8 Hz, 1 H, benzylic
H), 4.64 (d, J = 10.9 Hz, 1 H, benzylic H), 4.60 (d, J = 11.5 Hz, 1
H, benzylic H), 4.43–4.54 [m, 5 H, C(O)NH-CH2-Ph, 4 benzylic
H], 4.41 (d, J = 12.4 Hz, 1 H, benzylic H), 4.36 (d, J = 11.1 Hz, 1
H, benzylic H), 4.34 (d, J = 12.0 Hz, 1 H, benzylic H), 4.33 (d,
J3Ј,4Ј = 7.8 Hz, 1 H, 3Ј-H), 4.18–4.24 [m, 2 H, C(O)NH-CH2-Ph,
5-H], 4.06–4.11 (m, 2 H, 4Ј-H, 5Ј-H), 3.97 (dd, J3,4 = 9.1, J3,2
=
9.7 Hz, 1 H, 3-H), 3.89 (d, J = 16.4 Hz, 1 H, O-CH2-CO2), 3.81
(d, 1 H, O-CH2-CO2), 3.75 (d, J1Ј,1Ј = 10.9 Hz, 1 H, 1Ј-H), 3.74 (dd,
J6Ј,6Ј = 10.1, J6Ј,5Ј = 5.0 Hz, 1 H, 6Ј-H), 3.68 (dd, J6Ј,5Ј = 6.1 Hz, 1
H, 6Ј-H), 3.62 (d, J = 13.9 Hz, 1 H, N-CH2-Ph), 3.52 (d, 1 H, N-
CH2-Ph), 3.51 (d, 1 H, 1Ј-H), 3.34 [d, J = 16.7 Hz, 1 H, N-CH2-
C(O)NH], 3.24 (dd, 1 H, 2-H), 3.08 (dd, J4,5 = 9.6 Hz, 1 H, 4-H),
3.07 [d, 1 H, N-CH2-C(O)NH], 2.83 (dd, J6,6 = 13.7, J6,5 = 1.8 Hz,
1 H, 6-H), 2.38 (dd, J6,5 = 8.5 Hz, 1 H, 6-H), 1.42 (s, 9 H,
OtBu) ppm. 13C NMR (150 MHz): δ = 171.12 [C(O)NHBn], 169.27
(CO2tBu), 138.68, 138.62, 138.43, 138.23, 138.16, 138.06, 137.77,
136.87 (8 Cquat, Ph), 127.14–129.42 (40 C, Ph), 105.72 (C-2Ј), 90.41
(C-1), 83.68 (C-3Ј), 83.46 (C-4Ј), 81.35 (Cquat, OtBu), 81.15 (C-3),
80.23 (C-5Ј), 80.08 (C-2), 80.08 (C-4), 75.40, 74.74, 73.36, 72.87,
72.14, 72.04 (6 O-CH2-Ph), 72.45 (C-6Ј), 70.07 (C-1Ј), 69.57 (C-5),
68.81 (O-CH2-CO2), 58.76 [N-CH2-C(O)NH] 58.76 (N-CH2-Ph),
55.39 (C-6), 42.87 [C(O)NH-CH2-Ph], 28.07 (triple intensity, 3 C,
OtBu) ppm. HRMS (ESI): calcd. for C76H85N2O13 [M + H]+
1233.6052; found 1233.6036. C78H84N2O13 (1233.52): calcd. C
74.00, H 6.86, N 2.27; found C 74.16, H 6.99, N 2.31.
Preparation of N-(2-Benzylaminoethyl)-N-benzyl-6Ј-amino-6Ј-de-
oxy-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzyl-6-O-(2-hydroxyethyl)sucrose (14)
and N-(2-Benzylaminoethyl)-N-benzyl-6-amino-6-deoxy-
1Ј,2,3,3Ј,4,4Ј-hexa-O-benzyl-6Ј-O-(2-hydroxyethyl)sucrose (20): This
reaction was conducted under argon. Amido ester 12 (211 mg,
0.17 mmol) or 19 (186 mg, 0.15 mmol) was dissolved in dry THF
(10 mL) and cooled to 0 °C. A 1 m solution of LiAlH4 in THF (1.7
or 1.5 mL, respectively) was added slowly to the vigorously stirred
mixture, which was stirred for 15 min at room temp. and then
heated at reflux for 1.5 h. After cooling to 0 °C, the excess hydride
was carefully decomposed with water (15 mL) and aqueous potas-
sium bisulfate (KHSO4, 10 mL). Ethyl acetate (30 mL) was added,
the layers were separated, and the aqueous layer extracted with
ethyl acetate (3ϫ 30 mL). The combined organic layers were dried,
concentrated, and the product was isolated by flash chromatog-
raphy (dichloromethane/methanol, 88:12) to afford pure 14
(144 mg, 0.125 mmol, 73%) or 20 (145 mg, 0.13 mmol, 84%).
N-(2-Benzylaminoethyl)-N-benzyl-6Ј-amino-6Ј-deoxy-1Ј,2,3,3Ј,4,4Ј-
hexa-O-benzyl-6-O-(2-hydroxyethyl)sucrose (14): TLC (AcOEt/
MeOH/H2O, 45:5:3): Rf = 0.43. Colorless oil. [α]D = +40.4 (c = 1,
CH2Cl2). 1H NMR (600 MHz): δ = 7.13–7.35 (m, 40 H, Ar-H),
5.47 (d, J1,2 = 3.5 Hz, 1 H, 1-H), 4.87 (d, J = 11.0 Hz, 1 H, benzylic
H), 4.86 (d, J = 11.1 Hz, 1 H, benzylic H), 4.73 (d, J = 11.0 Hz, 1
H, benzylic H), 4.68 (d, J = 11.4 Hz, 1 H, benzylic H), 4.55–4.62
(m, 4 H, benzylic H), 4.51 (d, J = 12.1 Hz, 1 H, benzylic H), 4.49
(d, J = 11.4 Hz, 1 H, benzylic H), 4.45 (d, J = 11.7 Hz, 1 H, benz-
ylic H), 4.40 (d, J3Ј,4Ј = 7.3 Hz, 1 H, 3Ј-H), 4.39 (d, J = 12.1 Hz, 1
H, benzylic H), 4.16 (ddd, J5Ј,4Ј = 7.7, J5Ј,6Ј = 7.7, J5Ј,6Ј = 3.6 Hz,
1 H, 5Ј-H), 4.06 (m, 1 H, 5-H), 3.97 (dd, J3,2 = 9.2, J3,4 = 9.4 Hz,
1 H, 3-H), 3.92 (dd, 1 H, 4Ј-H), 3.70 (d, J = 13.8 Hz, 1 H, N-CH2-
Ph), 3.66 (d, J1Ј,1Ј = 11.1 Hz, 1 H, 1Ј-H), 3.51–3.63 (m, 7 H, 4-H,
6-H, OCH2-CH2-OH, N-CH2-Ph, NH-CH2-Ph), 3.41–3.49 (m, 5
H, 2-H, O-CH2-CH2OH, 1Ј-H, 6-H), 2.94 (dd, J6Ј,6Ј = 14.0 Hz, 1
H, 6Ј-H), 2.82 (dd, 1 H, 6Ј-H), 2.62–2.73 (m, 4 H, N-CH2-CH2-
NH) ppm. 13C NMR (150 MHz): δ = 140.26 (Cquat, Ph-CH2NH),
139.42 (Cquat, Ph-CH2N), 138.80, 138.54, 138.33, 138.22, 138.18,
138.00 (6 Cquat, Ph), 126.72–128.96 (40 C, Ph), 104.57 (C-2Ј), 90.01
(C-1), 83.89 (C-4Ј), 83.46 (C-3Ј), 81.88 (C-3), 79.93 (C-2), 78.34 (C-
5Ј), 77.75 (C-4), 75.47, 74.81, 72.98, 72.82, 72.57, 72.26 (6 O-CH2-
Ph), 73.30 (O-CH2-CH2OH), 71.31 (C-1Ј), 70.74 (C-5), 69.71 (C-
6), 61.48 (OCH2-CH2-OH), 58.65 (N-CH2-Ph), 57.56 (C-6Ј), 53.79
(N-CH2-CH2NH), 53.36 (NH-CH2-Ph), 46.57 (NCH2-CH2-
NH) ppm. HRMS (ESI): calcd. for C72H81N2O11 [M + H]+
1149.5835; found 1149.5842. C72H80N2O11 (1149.45): calcd. C
75.24, H 7.02, N 2.44; found C 75.47, H 7.05, N 2.53.
Preparation of N-(2-Benzylamino-2-oxoethyl)-N-benzyl-6Ј-amino-
6Ј-deoxy-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzyl-6-O-(2-hydroxyethyl)sucrose
(13): This reaction was conducted under argon. LiAlH4 (38 mg,
1.00 mmol) was slowly added to a solution of amido ester 12
(125 mg, 0.10 mmol) in dry THF (5 mL) at –78 °C. After 15 min,
the mixture was allowed to warm to room temperature and then
stirred for 10 h. Excess of the hydride was carefully decomposed
with water (10 mL) and aqueous potassium bisulfate (KHSO4,
5 mL). Ethyl acetate (20 mL) was added, the layers were separated,
and the aqueous layer extracted with ethyl acetate (3ϫ 20 mL).
The combined organic layers were dried, concentrated, and the
product was isolated by flash chromatography (hexane/ethyl acet-
ate, 35:65) to afford pure 13 (91 mg, 0.08 mmol, 77%). TLC (hex-
ane/AcOEt, 1:2): Rf = 0.55. Colorless oil. [α]D = +41.1 (c = 1,
1
CHCl3). H NMR (600 MHz): δ = 7.70 (t, J = 5.9 Hz, 1 H, NH),
7.12–7.34 (m, 40 H, Ar-H), 5.36 (d, J1,2 = 3.5 Hz, 1 H, 1-H), 4.86
(d, J = 11.0 Hz, 1 H, benzylic H), 4.85 (d, J = 11.0 Hz, 1 H, benz-
ylic H), 4.75 (d, J = 11.0 Hz, 1 H, benzylic H), 4.65 (d, J = 11.4 Hz,
1 H, benzylic H), 4.62 (d, J = 11.5 Hz, 1 H, benzylic H), 4.60 (d,
J = 13.0 Hz, 1 H, benzylic H), 4.59 (d, J = 11.0 Hz, 1 H, benzylic
H), 4.55 (d, J = 11.5 Hz, 1 H, benzylic H), 4.46 (d, J = 11.4 Hz, 1
H, benzylic H), 4.45 (d, J = 12.0 Hz, 1 H, benzylic H), 4.37–4.42
(m, 3 H, 3Ј-H, NH-CH2-Ph, benzylic H), 4.32 (d, J = 12.0 Hz, 1
H, benzylic H), 4.28 (dd, J = 15.1, J = 5.3 Hz, 1 H, NH-CH2-Ph),
4.08 (ddd, J4Ј5Ј = 7.8, J5Ј6Ј = 8.6, J5Ј,6Ј = 2.6 Hz, 1 H, 5Ј-H), 3.99
(m, 1 H, 5-H), 3.95 (dd, J3,2 = 9.3, J3,4 = 9.4 Hz, 1 H, 3-H), 3.88
(dd, J4Ј,3Ј = 7.8 Hz, 1 H, 4Ј-H), 3.68 (d, J = 13.5 Hz, 1 H, N-CH2-
Ph), 3.65 (d, 1 H, N-CH2-Ph), 3.62 (m, 2 H, OCH2-CH2-OH), 3.61
(d, J1Ј,1Ј = 11.0 Hz, 1 H, 1Ј-H), 3.54–3.58 (m, 2 H, 4-H, 6-H), 3.41–
N-(2-Benzylaminoethyl)-N-benzyl-6-amino-6-deoxy-1Ј,2,3,3Ј,4,4Ј-
hexa-O-benzyl-6Ј-O-(2-hydroxyethyl)sucrose (20): TLC (AcOEt/
5124
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5117–5126

“Unsymmetrical” Sucrose-Based Receptors
MeOH/H2O, 45:5:3): Rf = 0.45. Colorless oil. [α]D = +38.6 (c = 1, J4,5 = 9.8 Hz, 1 H, 4-H), 2.97 (dd, J6Ј,6Ј = 13.6, J6Ј,5Ј = 5.7 Hz, 1
CH2Cl2). 1H NMR (600 MHz): δ = 7.15–7.31 (m, 40 H, Ar-H), H, 6Ј-H), 2.65–2.82 (m, 7 H, 6Ј-H, N-CH2-CH2-N, OCH2-CH2-
5.74 (d, J1,2 = 3.3 Hz, 1 H, 1-H), 4.90 (d, J = 10.9 Hz, 1 H, benzylic
H), 4.87 (d, J = 11.2 Hz, 1 H, benzylic H), 4.72 (d, J = 11.5 Hz, 1
H, benzylic H), 4.69 (d, J = 10.9 Hz, 1 H, benzylic H), 4.63 (d, J
= 11.4 Hz, 1 H, benzylic H), 4.60 (d, J = 11.8 Hz, 1 H, benzylic
N) ppm. 13C NMR (150 MHz): δ = 139.77 (Cquat, Ph-CH2N),
139.66 (Cquat, Ph-CH2N), 138.71, 138.66, 138.34, 138.29, 138.26,
138.22 (6 Cquat, Ph), 128.99–126.56 (40 C, Ph), 105.28 (C-2Ј), 90.57
(C-1), 84.66 (C-3Ј), 84.48 (C-4Ј), 81.76 (C-3), 79.97 (C-2), 79.57 (C-
H), 4.52 (d, J = 10.6 Hz, 1 H, benzylic H), 4.51 (d, J = 11.4 Hz, 1 4), 77.64 (C-5Ј), 75.43, 74.79, 73.37, 73.26, 72.24, 71.56 (6 O-CH2-
H, benzylic H), 4.50 (d, J = 10.9 Hz, 2 H, benzylic H), 4.42 (d, J
= 11.5 Hz, 1 H, benzylic H), 4.41 (d, J3Ј,4Ј = 6.8 Hz, 1 H, 3Ј-H),
4.38 (d, J = 11.8 Hz, 1 H, benzylic H), 4.23 (dd, J4Ј,5Ј = 7.1 Hz, 1
Ph), 72.20 (C-6), 71.27 (C-1Ј), 70.87 (C-5), 70.87 (O-CH2-CH2N),
60.74 (N-CH2-Ph), 59.99 (N-CH2-Ph), 53.61 (C-6Ј), 52.89 (OCH2-
CH2-N), 52.47 (NCH2-CH2-N), 50.78 (N-CH2-CH2N) ppm.
HRMS (ESI): calcd. for C72H79N2O10 [M + H]+ 1131.5735; found
H, 4Ј-H), 4.19 (m, 1 H, 5-H), 4.02 (m, 1 H, 5Ј-H), 4.00 (dd, J3,2
=
9.7, J3,4 = 8.8 Hz, 1 H, 3-H), 3.76 (dd, J6Ј,6Ј = 10.8, J6Ј,5Ј = 6.1 Hz, 1131.5724. C72H78N2O10 (1131.43): calcd. C 76.43, H 6.95, N 2.48;
1 H, 6Ј-H), 3.74 (d, J1Ј,1Ј = 11.1 Hz, 1 H, 1Ј-H), 3.54–3.65 (m, 6 found C 76.58, H 6.89, N 2.41.
H, 6Ј-H, 1Ј-H, NH-CH2-Ph, N-CH2-Ph), 3.48–3.53 (m, 3 H, N-
6,6Ј-(1,4-Dibenzyl-1,4-hexane-1,6-diyl)-6-deoxy-1Ј,2,3,3Ј,4,4Ј-hexa-
CH2-CH2-NH), 3.44 (m, 1 H, O-CH2-CH2OH), 3.42 (dd, 1 H, 2-
O-benzylsucrose (21): TLC (AcOEt/MeOH/H2O, 45:5:3): Rf = 0.48.
H), 3.34 (dd, J4,5 = 9.7 Hz, 1 H, 4-H), 2.73 (m, 1 H, N-CH2-
1
Colorless oil. [α]D = +31.3 (c = 1, CH2Cl2). H NMR (600 MHz):
CH2NH), 2.63 (m, 1 H, 6-H), 2.54–2.58 (m, 2 H, OCH2-CH2-OH),
δ = 7.08–7.33 (m, 40 H, Ar-H), 5.71 (d, J1,2 = 3.5 Hz, 1 H, 1-H),
2.46–2.53 (m, 2 H, 6-H, O-CH2-CH2OH) ppm. 13C NMR
4.92 (d, J = 10.8 Hz, 1 H, benzylic H), 4.85 (d, J = 11.5 Hz, 1 H,
(150 MHz): δ = 140.28 (Cquat, Ph-CH2NH), 139.18 (Cquat, Ph-
benzylic H), 4.74 (d, J = 12.0 Hz, 1 H, benzylic H), 4.73 (d, J =
CH2N), 138.83, 138.62, 138.48, 138.33, 138.16, 137.89 (6 Cquat, Ph),
10.8 Hz, 1 H, benzylic H), 4.72 (d, J = 12.0 Hz, 1 H, benzylic H),
4.66 (s, 2 H, benzylic H), 4.63 (d, J = 11.8 Hz, 1 H, benzylic H),
129.40–126.81 (40 C, Ph), 104.73 (C-2Ј), 89.59 (C-1), 83.71 (C-3Ј),
81.83 (C-4Ј), 81.68 (C-3), 80.21 (C-2), 79.64 (C-5Ј), 79.61 (C-4),
4.53 (d, J = 12.0 Hz, 1 H, benzylic H), 4.51 (d, J = 11.5 Hz, 1 H,
75.25, 74.43, 73.37, 72.84, 72.36, 72.21 (6 O-CH2-Ph), 73.17 (O-
benzylic H), 4.43–4.48 (m, 3 H, 3Ј-H, 4Ј-H, benzylic H), 4.35 (d, J
CH2-CH2OH), 71.50 (C-6Ј), 71.39 (C-1Ј), 70.62 (C-5), 61.25
= 12.0 Hz, 1 H, benzylic H), 4.24 (m, 1 H, 5-H), 4.05 (m, 1 H, 5Ј-
(OCH2-CH2-OH), 59.39 (N-CH2-Ph), 54.24 (C-6), 53.36 (N-CH2-
H), 4.01 (dd, J3,2 = 9.3, J3,4 = 9.3 Hz, 1 H, 3-H), 3.86 (dd, J6Ј,6Ј
=
CH2NH), 53.22 (NH-CH2-Ph), 46.08 (NCH2-CH2-NH) ppm.
HRMS (ESI): calcd. for C72H81N2O11 [M + H]+ 1149.5835; found
1149.5847. C72H80N2O11 (1149.45): calcd. C 75.24, H 7.02, N 2.44;
found C 75.29, H 7.14, N 2.32.
11.1, J6Ј,5Ј = 5.7 Hz, 1 H, 6Ј-H), 3.81 (dd, J6Ј,5Ј = 2.5 Hz, 1 H, 6Ј-
H), 3.68 (d, J1Ј,1Ј = 10.9 Hz, 1 H, 1Ј-H), 3.46–3.58 (m, 6 H, 1Ј-H,
2-H, O-CH2-CH2N, N-CH2-Ph), 3.39–3.44 (m, 3 H, 4-H, N-CH2-
Ph), 2.52–2.77 (m, 8 H, 26-H, N-CH2-CH2-N, OCH2-CH2-N) ppm.
13C NMR (150 MHz): δ = 139.82 (Cquat, Ph-CH2N), 139.03 (Cquat
Ph-CH2N), 138.85, 138.80, 138.46, 138.44, 138.19, 138.03 (6 Cquat
,
,
Preparation of 6,6Ј-(3,5-Dibenzyl-3,5-diazahexane-1,6-diyl)-6Ј-de-
oxy-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose (16) and 6,6Ј-(1,4-Dibenzyl-
1,4-hexane-1,6-diyl)-6-deoxy-1Ј,2,3,3Ј,4,4Ј-hexa-O-benzylsucrose
(21): Compound 14 (115 mg, 0.10 mmol) or 20 (127 mg,
0.11 mmol) in toluene (50 mL) was heated at reflux with PPh3
(31 mg, 0.12 mmol or 35 mg, 0.13 mmol, respectively) for 10 min
and cooled to 80 °C. Imidazole (34 mg, 0.50 mmol or 37 mg,
0.55 mmol, respectively) was added followed by the slow addition
(during 10 min) of a solution of iodine (33 g, 0.13 mmol or 36 mg,
0.14 mmol, respectively) in toluene (5 mL) and the mixture was
heated at reflux for 4 h. It was then concentrated and the residue
taken up in ethyl acetate (30 mL). The organic phase was washed
with saturated aqueous Na2S2O3 and water, dried, concentrated,
and the product was isolated by column chromatography (dichloro-
methane/methanol, 100:0 to 90:10) to afford the macrocycle 16
(82 mg, 0.72 mmol, 72%) or 21 (93 mg, 0.82 mmol, 74%).
Ph), 129.12–126.56 (40 C, Ph), 103.98 (C-2Ј), 88.74 (C-1), 83.49 (C-
3Ј), 82.07 (C-3), 81.54 (C-4Ј), 79.74 (C-5Ј), 79.73 (C-2), 79.59 (C-
4), 75.46, 74.55, 73.24, 72.64, 72.54, 72.50 (6 O-CH2-Ph), 72.28 (C-
1Ј), 71.25 (C-6Ј), 70.92 (C-5), 70.70 (O-CH2-CH2N), 60.24 (N-CH2-
Ph), 59.99 (N-CH2-Ph), 54.58 (C-6), 53.88, 52.12, 51.09 (N-CH2-
CH2-N, OCH2-CH2-N) ppm. HRMS (ESI): calcd. for
C72H79N2O10 [M + H]+ 1131.5735; found 1131.5748. C72H78N2O10
(1131.43): calcd. C 76.43, H 6.95, N 2.48; found C 76.44, H 6.81,
N 2.35.
General Procedure for the Titration Experiments: A solution of the
respective macrocycle in CDCl3 (0.5 mL) was prepared (concentra-
1
tion given separately for each experiment) and the H NMR spec-
trum was recorded. Subsequently, small portions of the guest [(R)-
or (S)-phenylethylammonium chloride] were added to the solution.
1
6,6Ј-(3,5-Dibenzyl-3,5-diazahexane-1,6-diyl)-6Ј-deoxy-1Ј,2,3,3Ј,4,4Ј-
hexa-O-benzylsucrose (16): TLC (AcOEt/MeOH/H2O, 45:5:3): Rf =
0.60. Yellowish oil. [α]D = +11.1 (c = 1, CH2Cl2). 1H NMR
(600 MHz): δ = 7.12–7.35 (m, 40 H, Ar-H), 5.49 (d, J1,2 = 3.3 Hz,
1 H, 1-H), 4.87 (d, J = 10.6 Hz, 1 H, benzylic H), 4.86 (d, J =
10.6 Hz, 1 H, benzylic H), 4.79 (d, J = 11.8 Hz, 1 H, benzylic H),
4.71 (m, 1 H, 5Ј-H), 4.70 (d, J = 11.0 Hz, 1 H, benzylic H), 4.68
(d, J = 11.8 Hz, 1 H, benzylic H), 4.66 (d, J = 11.8 Hz, 1 H, benz-
ylic H), 4.53 (d, J = 11.0 Hz, 1 H, benzylic H), 4.47 (d, J = 11.9 Hz,
1 H, benzylic H), 4.46 (d, J = 12.0 Hz, 1 H, benzylic H), 4.44 (d,
J = 11.9 Hz, 1 H, benzylic H), 4.39 (d, J = 12.0 Hz, 1 H, benzylic
H), 4.37 (d, J = 11.8 Hz, 1 H, benzylic H), 4.27 (m, 1 H, 5-H), 4.26
(d, J3Ј,4Ј = 2.8 Hz, 1 H, 3Ј-H), 4.13 (dd, J4Ј,5Ј = 5.2 Hz, 1 H, 4Ј-H),
4.10 (dd, J3,2 = 9.3, J3,4 = 9.2 Hz, 1 H, 3-H), 3.71 (dd, J6,6 = 9.9,
J6,5 = 1.7 Hz, 1 H, 6-H), 3.67 (d, J1Ј,1Ј = 11.2 Hz, 1 H, 1Ј-H), 3.65
(d, J = 13.8 Hz, 1 H, N-CH2-Ph), 3.59 (d, J = 13.8 Hz, 1 H, N-
CH2-Ph), 3.50–3.54 (m, 4 H, 2-H, 1Ј-H, N-CH2-Ph), 3.43–3.47 (m,
2 H, O-CH2-CH2N), 3.36 (dd, J6,5 = 8.7 Hz, 1 H, 6-H), 3.19 (dd,
After each addition of the ammonium salt, a H NMR spectrum
was recorded. The change in the shift of the signal of the anomeric
proton of sucrose (δ ≈ 5.5 ppm) was followed. Further additions of
the guest were made until a constant value of the chemical shift of
1-H (anomeric) was observed. The shift in the signal was then plot-
ted against the concentration of the guest in solution. A curve was
fitted to the plot by using the empirical Equation (1), in which δ is
an experimentally measured chemical shift, Δδ is the measured
change in chemical shift (upon addition of guest species) referenced
to that of the uncomplexed host, and CH and CG are the total
concentrations of the host and guest, respectively, in the program
MicroCal Origin®[20]. Based on this plot, Ka (association constant)
(1)
Eur. J. Org. Chem. 2013, 5117–5126
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5125

M. A. Potopnyk, S. Jarosz
FULL PAPER
[10] a) S. P. Upadhyay, R. R. S. Pissurlenkar, E. C. Coutinho, A. V.
Karnik, J. Org. Chem. 2007, 72, 5709–5714; b) M. E. Amato,
F. P. Ballistreri, S. Gentile, A. Pappalardo, G. A. Tomaselli,
R. M. Toscano, J. Org. Chem. 2010, 75, 1437–1443.
[11] W.-L. Wong, K.-H. Huang, P.-F. Teng, C.-S. Lee, H.-L. Kwong,
Chem. Commun. 2004, 384–385.
and Δδmax (the difference in the chemical shift of the host–guest
complex and the host molecule) were calculated.
This methodology can be used for 1:1 complexes. If the method is
applied successfully (the error in the Ka determination is not very
high, 10%), the stoichiometry of the complex does not have to be
additionally proven by preparation of a Job plot.
[12] a) J. Xie, Eur. J. Org. Chem. 2002, 3411–3418; b) Yu. E.
Alexeev, I. S. Vasilchenko, B. I. Kharisov, L. M. Blanco, A. D.
Garnovskii, Yu. A. Zhdanov, J. Coord. Chem. 2004, 57, 1447–
1517; c) S. Striegler, M. Dittel, Inorg. Chem. 2005, 44, 2728–
2733; d) M. Ménand, J.-C. Blais, J.-M. Valéry, J. Xie, J. Org.
Chem. 2006, 71, 3295–3298; e) S. Jarosz, A. Listkowski, Curr.
Org. Chem. 2006, 10, 643–662; f) S. Porwanski, A. Marsura,
Eur. J. Org. Chem. 2009, 2047–2050; g) S. Muthana, H. Yu, H.
Cao, J. Cheng, X. Chen, J. Org. Chem. 2009, 74, 2928–2936; h)
Y.-C. Hsieh, J.-L. Chir, W. Zou, H.-H. Wu, A.-T. Wu, Car-
bohydr. Res. 2009, 344, 1020–1023; i) Y.-C. Hsieh, J.-L. Chir,
S.-T. Yang, S.-J. Chen, C.-H. Hu, A.-T. Wu, Carbohydr. Res.
2011, 346, 978–981; j) S.-T. Yang, D.-J. Liao, S.-J. Chen, C.-H.
Hu, A.-T. Wu, Analyst 2012, 137, 1553–1555; k) P. Bakó, G.
Keglevich, Z. Rapi, L. To˝ke, Curr. Org. Chem. 2012, 16, 297–
304.
Supporting Information (see footnote on the first page of this arti-
cle): Data for NMR titrations of macrocycles 16 and 21 with phen-
ylethylammonium chloride in CDCl3, 1H and 13C NMR spectra
for all new compounds.
Acknowledgments
This work was financially supported in part by the European
Union (EU) within the European Regional Development Fund
(grant number POIG.01.01.02-14-102/09).
[13] a) S. Jarosz, M. Mach, Eur. J. Org. Chem. 2002, 769–780; b) Y.
Queneau, S. Jarosz, B. Lewandowski, J. Fitremann, Adv. Car-
bohydr. Chem. Biochem. 2007, 61, 217–292; c) S. Jarosz, B. Le-
wandowski, Carbohydr. Res. 2008, 343, 965–969.
[14] a) B. Lewandowski, S. Jarosz, Chem. Commun. 2008, 6399–
6401; b) M. A. Potopnyk, B. Lewandowski, S. Jarosz, Tetrahe-
dron: Asymmetry 2012, 23, 1474–1479.
[1] a) J. W. Steed, J. L. Atwood, Supramolecular Chemistry, 2nd
ed., Wiley, Chichester, UK, 2009; b) F. Davis, S. Higson,
Macrocycles: Construction, Chemistry, and Nanotechnology Ap-
plication, Wiley, Chichester, 2011.
[2] Z. Rapi, P. Bakó, G. Keglevich, Á. Szo˝llösy, L. Drahos, A.
Botyánszki, T. Holczbauer, Tetrahedron: Asymmetry 2012, 23,
489–496.
[15] a) M. Mach, S. Jarosz, A. Listkowski, J. Carbohydr. Chem.
2001, 20, 485–493; b) B. Lewandowski, A. Listkowski, K. Pe-
trova, S. Jarosz, Carbohydrate Chemistry: Proven Synthetic
Methods, vol. 1 (Ed.: P. Kovácˇ), Taylor & Francis, Boca Raton,
London, New York, 2012, p. 413–430.
[3] J. R. Pfeifer, P. Reiß, U. Koert, Angew. Chem. 2006, 118, 515;
Angew. Chem. Int. Ed. 2006, 45, 501–504.
[4] Z. Li, W. Liu, J. Wu, S. H. Liu, J. Yin, J. Org. Chem. 2012, 77,
7129–7135.
[5] P. T. Glink, A. I. Oliva, J. F. Stoddart, A. J. P. White, D. J. Wil-
liams, Angew. Chem. 2001, 113, 1922; Angew. Chem. Int. Ed.
2001, 40, 1870–1875.
[16] M. A. Potopnyk, P. Cmoch, S. Jarosz, Org. Lett. 2012, 14,
4258–4261.
[17] S. Jarosz, M. Mach, J. Frelek, J. Carbohydr. Chem. 2000, 19,
693–705.
[6] a) T. Bakó, P. Bakó, G. Keglevich, N. Báthori, M. Czugler, J.
Tatai, T. Novák, G. Parlagh, L. To˝ke, Tetrahedron: Asymmetry
2003, 14, 1917–1923; b) P. Bakó, T. Bakó, A. Mészáros, G.
Keglevich, Á. Szo˝llösy, S. Bodor, A. Makó, L. To˝ke, Synlett
2004, 643–646; c) P. Bakó, Z. Rapi, G. Keglevich, T. Szabó,
P. L. Sóti, T. Vígh, A. Grun, T. Holczbauer, Tetrahedron Lett.
2011, 52, 1473–1476; d) Z. Rapi, T. Szabó, G. Keglevich, Á.
Szo˝llösy, L. Drahos, P. Bakó, Tetrahedron: Asymmetry 2011,
22, 1189–1196.
[18] a) M. T. Barros, K. T. Petrova, A. M. Ramos, J. Org. Chem.
2004, 69, 7772–7775; b) M. T. Barros, K. T. Petrova, A. M.
Ramos, Eur. J. Org. Chem. 2007, 1357–1363; c) M. T. Barros,
K. T. Petrova, P. Correia-da-Silva, T. M. Potewar, Green Chem.
2011, 13, 1897–1906; d) M. Mach, A. Zawisza, B. Lewandow-
ski, S. Jarosz, Carbohydrate Chemistry: Proven Synthetic Meth-
ods, vol. 1 (Ed.: P. Kovácˇ), Taylor & Francis, Boca Raton, Lon-
don, New York, 2012, p. 387–411.
[7] K. Hirose, Y. Yachi, Y. Tobe, Chem. Commun. 2011, 47, 6617.
[8] T. Ema, J. Inclusion Phenom. Macrocycl. Chem. 2012, 74, 41–
55.
[9] a) P. Deniz, Y. Turgut, M. Togrul, H. Hosgoren, Tetrahedron
2011, 67, 6227–6232; b) H. N. Demirtas, S. Bozkurt, M. Dur-
maz, M. Yilmaz, A. Sirit, Tetrahedron 2009, 65, 3014–3018.
[19] P. J. Garegg, B. Samuelsson, J. Chem. Soc. Perkin Trans. 1
1980, 2866–2869.
[20] a) L. Fielding, Tetrahedron 2000, 56, 6151–6170; b) L. Fielding,
Prog. Nucl. Magn. Reson. Spectrosc. 2007, 51, 219–242.
Received: March 22, 2013
Published Online: July 4, 2013
5126
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Eur. J. Org. Chem. 2013, 5117–5126