Synthesis of N-glycosyl conjugates through a multicomponent domino process

Article abstract of DOI:10.1002/ejoc.201301887

The development of efficient methods for the combinatorial synthesis of N-glycosyl conjugates is vital for many fields of modern synthetic organic chemistry. Herein, we report a multicomponent domino process for the regioselective synthesis of a large array N-glycosyl-Asp-urea conjugates, which could be further functionalized in a chemoselective way, starting from easily accessible reactants such as N-glycosylamines, fumaric acid monoesters, azides, and isocyanates. The process occurs under very mild conditions, does not require the use of strong bases/acids or high temperature, and is highly versatile, working efficiently with a range of protecting groups and substituents.

Full text of DOI:10.1002/ejoc.201301887

FULL PAPER
DOI: 10.1002/ejoc.201301887
Synthesis of N-Glycosyl Conjugates through a Multicomponent Domino
Process
Maria Cristina Bellucci[a] and Alessandro Volonterio*[b]
Dedicated to Professor Stefano Servi on the occasion of his retirement
Keywords: Multicomponent reactions / Domino reactions / Glycoconjugates / Regioselectivity
The development of efficient methods for the combinatorial
synthesis of N-glycosyl conjugates is vital for many fields of
modern synthetic organic chemistry. Herein, we report a
multicomponent domino process for the regioselective syn-
thesis of a large array N-glycosyl-Asp-urea conjugates,
which could be further functionalized in a chemoselective
way, starting from easily accessible reactants such as N-glyc-
osylamines, fumaric acid monoesters, azides, and isocyan-
ates. The process occurs under very mild conditions, does not
require the use of strong bases/acids or high temperature,
and is highly versatile, working efficiently with a range of
protecting groups and substituents.
synthesized in which the N-glycosyl linkage is replaced by
non-native bonds such as urea,[4] retroamide,[5] triazole,[6]
and others.[7] Another strategy used for the synthesis of
novel building blocks for N-linked glycoconjugates involves
the use of N-glycosylamines and suitably protected and ac-
tivated amino acids as starting materials.[8] However, all the
above strategies are stepwise synthetic procedures, which
are not ideal for the combinatorial and diversity-oriented
synthesis of N-linked glycoconjugates in general, due to
economic and environmental concerns. In this context,
multicomponent (MC)[9] and domino[10] reactions have at-
tracted much interest in recent years. Indeed, the possibility
of building even elaborate scaffolds in a single step starting
from three or more simple reactants is very attractive for
combinatorial and diversity oriented synthetic programs,
thus this approach is playing an increasingly central role
in the development of modern synthetic methodology for
pharmaceutical and drug discovery research. However, al-
though many MC reactions have been developed in the past
decade, only a few can be applied to the synthesis of glyco-
peptide mimetics.[11] Thus, despite these advances, there re-
mains a need to discover new carbohydrate-based MC reac-
tions to broaden the possible scaffold diversity.
Introduction
The synthesis of carbohydrates linked to a peptide back-
bone has become a principal focus for synthetic bioorganic
and medicinal chemists. Indeed, there is a growing interest
in understanding the role of glycopeptides and glycoconju-
gates in a range of biochemical processes, such as cellular
recognition, adhesion, and signalling, as well as in the syn-
thesis of potential drug candidates. In many of these appli-
cations, the sugar moiety is able to induce specific interac-
tions with the bioreceptor, generating new properties in
terms of activity, selectivity, tissue permeability and pharm-
acodynamic effects.[1] For these reasons, the development
of combinatorial approaches to obtain diverse sugar-based
scaffolds in a rapid manner has attracted the attention of
organic chemists. Much effort has focused on the synthesis
and assembly of native N- and O-linked glycopeptides, as
well as C- and S-linked glycopeptides,[2] because protein
glycosylation is not under direct genetic control.[3] In natu-
ral N-linked glycoproteins, the sugar moiety is often teth-
ered to an asparagine residue through a β-N-glycosylic link-
age. However, several N-glycopeptide mimetics have been
[a] Department of Food, Environmental and Nutritional Sciences,
Università degli Studi di Milano,
Recently, within the framework of developing novel dom-
ino process for the synthesis of heterocycles starting from
suitable carboxylic acids such as fumaric acid monoesters 2
and carbodiimides 3 (Scheme 1, path a),[12] we have discov-
ered a novel three-component regioselective domino process
for the synthesis of urea-peptide (Scheme 1, R1 and R2 =
alkyl or aryl) and glyco-peptide (R1 = sugar) conjugates
Via Celoria 2, 20133 Milano, Italy
[b] Department of Chemistry, Materials, and Chemical Engineer
“G. Natta”, Politecnico di Milano,
Via Mancinelli 7, 20131 Milano, Italy
E-mail: alessandro.volonterio@polimi.it
http://www.chem.polimi.it/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301887.
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Multicomponent Synthesis of N-Glycosyl Conjugates
Scheme 1. Proposed mechanism for the synthesis of compounds 4.
that takes place when the reaction is carried out in the pres-
ence of N-nucleophiles 1 such as amines, α-amino esters,
and peptides (Scheme 1, path b).[13]
Results and Discussion
The reaction with 2,3,4,6-tetra-O-acetyl-β-d-glucopyr-
Herein, we report on the synthesis of a novel class of N- anosylamine (1a), fumaric acid monoethyl ester (2a) and
glycosyl conjugates, i.e., N-glycosyl-Asp-urea conjugates, by commercially available diisopropylcarbodiimide (DIC; 3a)
exploiting the same MC domino process with N-glyc- was conducted under the same optimised conditions used
osylamines as nucleophiles. The reaction conditions have in the previous work for the synthesis of glyco-peptide con-
been optimised to minimise the formation of hydantoin by- jugates, namely stoichiometric TMP (2,4,6-trimethylpyr-
product 7 (Scheme 1, path a), which occurs due to the lower idine), CH3CN as solvent at 0 °C (Table 1, entry 1).[13]
nucleophilicity of glycosylamines compared with amines or However, in this case, we obtained the desired product 4a
α-amino esters. The process is highly regioselective when N- in only 40% yield and in ca. 2:1 diastereoisomeric ratio (dr),
primary alkyl, NЈ-tertiary alkyl asymmetric carbodi- along with the corresponding hydantoin byproduct 7a in
imides[12] are used and the synthesis could be accomplished almost the same molar quantity (43% yield). To increase
through a four-component sequential domino process when the yield of the desired product, the reaction conditions
the carbodiimide reactant is generated in situ by the Stau- were reoptimised in terms of solvent and temperature. We
dinger reaction.
hypothesised that the modest yields obtained in the first
Table 1. Process optimization.
Entry
Solvent
Cosolvent
Temp. [°C]
Yield of 4a [%][a]
Yield of 7a [%][a]
1
2
3
4
5
6
7
CH3CN
CH3CN
CH3CN
CH3CN
DMF
CH3CN
CH3CN
–
0
0
0
0
0
–30
25
40[b]
43
–
39
21
33
–
[c]
MeOH
tBuOH
DMF
–
DMF
DMF
–
43[b]
65[b]
56[d]
n.r.[e]
15[b]
70
[a] Isolated yield. [b] Formed as a mixture of diastereoisomers (ca. 2:1). [c] Nucleophilic addition of MeOH to intermediate of type 6
occurred. [d] Equimolecular mixture of diastereoisomers. [e] No reaction occurred.
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attempt were probably due to two factors: (1) poor nucleo- mers (see the Supporting Information).[15] Moreover, vari-
philicity of the glycosylamine, which renders the OǞN acyl able-temperature 1H NMR spectroscopic analysis con-
migration mechanism very competitive, and (2) relatively ducted with 4a in [D6]dimethyl sulfoxide (DMSO) over a
low solubility of the nucleophile in CH3CN. In an attempt range of 25–65 °C did not show any coalescence of the sig-
to improve the yield, the concentration of the solution was nals, indicating the absence of restricted rotation and thus
adjusted, but no improvement in yield was achieved under the absence of rotamers (see the Supporting Information).
either more dilute conditions (favouring the solubility of the Our surprise at obtaining a certain diastereoselection in this
nucleophile) or with more concentrated solutions (favour- process arose from considering that, according to the pro-
ing the intermolecular process vs. the intramolecular re- posed mechanism (Scheme 1), the new stereocenter is al-
arrangement; data not shown). The use of polar solvents as ready formed before the chiral N-glycosylamine is involved
co-solvent was also investigated with the aim of increasing in the reaction.[16] It may be that during the intramolecular
both the nucleophilicity and the solubility of the glycos- aza-Michael reaction, the sugar interacts with intermediate
amine reagent. However, by using a 4:1 (v/v) mixture of 5 through hydrogen bonds and acts as an organocatalyst.[17]
CH3CN/MeOH (Table 1, entry 2) under the same reaction Such a complex is likely disrupted in the presence of a large
conditions, the formation of 4a was not observed; instead, amount of polar solvents because when the reaction was
the product arising from nucleophilic attack of methanol to
the intermediate 6 was recovered in very good yield (87%;
see Scheme 1). To avoid the nucleophilic attack of the co-
solvent, the more bulky additive tBuOH was employed
(Table 1, entry 3) and, indeed, the N-glycosyl-Asp-urea con-
jugate 4a was obtained, again in a 2:1 dr, albeit in modest
yields (43%). To our delight, by using a more polar but
non-nucleophilic cosolvent, such as N,N-dimethylform-
amide (DMF) (Table 1, entry 4), the desired compound 4a
was produced in acceptable yield (ca. 2:1 dr; 65% yield)
along with hydantoin 7a as a minor byproduct (21%). This
result confirms that the presence of a polar solvent in the
reaction leads to an increase in the rate of nucleophilic at-
tack to the intermediate 6. However, when the reaction was
carried out in DMF as solvent (Table 1, entry 5) the desired
product 4a was formed in slightly lower yields (56%) and
as an equimolecular mixture of two diastereoisomers, dem-
onstrating that the polar solvent also accelerates the OǞN
acyl migration mechanism.
Table 2. Synthesis of N-glycosyl-Asp-urea conjugates with DIC.
Having optimised the reaction conditions in terms of sol-
vents, we investigated the influence of the temperature on
the process. By lowering the temperature to –30 °C, the for-
mation of intermediate 5 did not occur and the starting
materials were recovered (Table 1, entry 6), whereas when
the reaction was performed at room temperature an acceler-
ation of the OǞN acyl migration mechanism was observed
with the consequent formation of hydantoin 7a in 70%
yield along with the desired product 4a in only 15% yield
(Table 1, entry 7). Thus, as observed in previous work,[13]
the process works most efficiently when conducted at 0 °C.
We were very surprised to find that when the reaction
was carried out in CH3CN as solvent, with or without a
cosolvent, a ca. 2:1 mixture of two isomeric products was
always formed. These products were identified as two dia-
stereoisomers that differed at the newly formed stereocenter,
i.e., the α-carbon of the aspartic acid unit.[14] These isomers
could have been, instead, either diastereoisomers at the an-
1
omeric carbon or rotamers, however, the H NMR spec-
trum of 4a displayed a triplet at δ = 5.18 ppm (J = 9.2 Hz),
arising from the anomeric protons of the two isomers, with
the same chemical shift and the same coupling constant
with the NH and the vicinal anti-axial proton, thus con-
[a] Formed as a mixture of diastereoisomers (ca. 2:1). [b] Isolated
yield. [c] The corresponding hydantoins were formed in ca. 20%
yield. [d] The corresponding hydantoin was recovered as the only
firming that the two isomers are not anomeric diastereoiso- product in high yields.
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Multicomponent Synthesis of N-Glycosyl Conjugates
carried out in DMF no diastereoselectivity was observed of N-glycosylamines. Accordingly, the reaction between 2-
(Table 1, entry 5).[18]
N-phthaloyl-3,4,6-tri-O-acetyl-β-d-glucopyranosylamine
With these results in hand, we studied in more depth the (1d) and acid 2a in the presence of 3a led to the formation
reactivity of fumaric acid monoesters with a range of glyc- of conjugate 4d in acceptable yields (Table 2, entry 5),
osylamines to establish the versatility of the process whereas disaccharides 1e and 1f produced N-glycosylconju-
(Table 2). Because N-glycosyl-Asp-urea conjugates of type gated products 4e and 4f, respectively, with fumaric acid
4 are very intriguing synthons since they could be further monobenzyl ester 2b in good yields (Table 2, entries 6 and
functionalized at the ester moiety after simple hydrolysis 7). It is worth noting that all the above reactions generate
(see below), we explored the reactivity of other derivatives a mixture of two diastereoisomers with a 2:1 dr along with
with different ester protecting groups, such as benzyl and the formation of the corresponding hydantoin byproduct in
tert-butyl esters, to allow chemoselective hydrolysis of the ca. 20% yield.
ester function with respect to the protecting groups of the
Having established that the process works efficiently with
sugar moiety. As expected, fumaric acid monobenzyl ester a range of fumaric acid monoesters and N-glycosyl nucleo-
(2b) reacted with nucleophile 1a and DIC 3a under the op- philes, we investigated the use of symmetric and asymmetric
timised conditions [DMF/CH3CN (20% v/v), 0 °C], afford- carbodiimides (Scheme 2). Commercially available symmet-
ing conjugate 4b in similar yield (68%) and with almost the ric N,N-dicyclohexylcarbodiimide (DCC; 3b) reacted nicely
same dr (Table 2, entry 1). Unfortunately, the same result with acid 2b and sugar 1e, affording the desired conjugate
was not obtained with acid 2c, having a bulky tert-butyl 4g in good yields, again as a ca. 2:1 mixture of diastereoiso-
ester group, probably because this substrate was too steri- mers, along with the corresponding hydantoin (19%), dem-
cally hindered (Table 2, entry 2). For the same reason ex- onstrating that the process works efficiently with symmetric
plained above, we also investigated the compatibility of dif- N,NЈ-dialkyl carbodiimides in general [Scheme 2, Equa-
ferent protecting groups on the sugar moiety. Again, tion (1)].
2,3,4,6-tetra-O-pivaloyl-β-d-glucopyranosylamine (1b) did
Surprisingly, asymmetric carbodiimides reacted dif-
not react in the presence of DIC 3a and acid 2a, presumably ferently in this process depending on the nature of the car-
for steric reasons (Table 2, entry 3), whereas 2,3,4,6-tetra-O- bodiimide substituents. Indeed, the use of carbodiimides
benzyl-β-d-glucopyranosylamine (1c) produced, under the having the two N-substituents very different in terms of ste-
same conditions, conjugate 4c in excellent yields, again as a ric hindrance, such as N-p-methoxybenzyl NЈ-tert-butyl car-
ca. 2:1 mixture of diastereoisomers (Table 2, entry 4). The bodiimide (3c), in the presence of acid 2b and nucleophile
process is highly versatile and worked nicely with a range 1a, as expected, gave rise to a completely regioselective pro-
Scheme 2. Reaction with symmetric and asymmetric carbodiimides.
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cess producing N-glycosyl-Asp-urea conjugate 4h as the glycosyl-Asp-urea conjugates 4, we explored the reaction of
only regioisomer, again as a ca. 2:1 mixture of diastereoiso- acids 2a and 2b and a range of N-glycosyl nucleophiles with
mers [Scheme 2, Equation (2)].[19] This result was in com- asymmetric N,NЈ-dialkyl carbodiimides, with the latter be-
plete agreement with those obtained in previous work when ing generated in situ through the Staudinger reaction
fumaric acid monoesters were found to react with N-pri- (Table 3).
mary alkyl, NЈ-tertiary alkyl asymmetric carbodiimides in
Accordingly, benzyl azide 8a was treated with tert-butyl
the absence[12] or presence of N-nucleophiles.[13] Accord- isocyanate 9a in CH3CN as solvent in the presence of
ingly, the condensation between the two starting reagents 1 equiv. Ph3P, affording carbodiimide 3e along with Ph3PO
produced a mixture of O-acylisoureas 5-A and 5-B in equi- byproduct (reaction monitored by TLC). Thus the solution
librium (Figure 1). Subsequent intramolecular nucleophilic was diluted with DMF (20% in volume) and TMP, cooled
attack of the less congested nitrogen bearing the primary to 0 °C and nucleophile 1a followed by acid 2b were added,
alkyl substituent to the activated carbon–carbon double producing a 2:1 diastereoisomeric mixture of the desired
bond is exclusive, resulting in the formation, after nucleo- conjugate 4k in good yields and as the only regioisomer
philic addition of the N-glycosylamine, of the only re- (Table 3, entry 1). Analogously, starting from p-meth-
gioisomeric conjugate 4h.
oxybenzyl azide 8b, conjugate 4j was obtained with almost
the same dr, regiospecificity, and yield (Table 3, entry 2).
Propargyl azide 8c also reacted smoothly with isocyanate
9a, giving carbodiimide 3f, which reacted in situ with acid
2a in the presence of N-glycosyl monosaccharide and disac-
charide 1a/e producing good yields of the very interesting
clickable N-glycosyl-Asp-urea conjugates 4i/l, respectively
(Table 3, entries 3 and 4).
The behaviour of carbodiimides bearing N-secondary
alkyl and NЈ-tertiary alkyl substituents was then investi-
gated to check whether a totally regioselective process could
also be achieved in this case. To our delight, N-cyclohexyl
NЈ-tert-butyl carbodiimide (3g), obtained by reaction of the
corresponding azide 8d and isocyanate 9a, reacted with acid
2b and nucleophiles 1a and 1e to afford conjugates 4m and
4n, respectively, as mixtures of diastereoisomers (ca. 2:1 dr)
but as single regioisomers (Table 3, entries 5 and 6). Finally,
we investigated the possibility of synthesising even more in-
triguing conjugates, such as N-glycosyl-peptide mimetics
and disaccharide mimetics, by incorporating an α-amino
acid or a sugar moiety, respectively, in the carbodiimide
framework. Accordingly, starting from azidoglycine benzyl
ester 8e and tert-butyl isocyanate 9a, we were able to pro-
duce regiospecifically N-glycopeptide 4o (Table 3, entry 7),
which could be further elongated by selective hydro-
genolysis of the benzyl ester functionality. In this case, the
Figure 1. Reaction mechanism with asymmetric carbodiimides.
Unfortunately, asymmetric carbodiimides having N-alkyl yield was lower (53%), although still acceptable, likely due
and NЈ-aryl substituents, such as N-benzyl NЈ-phenyl car- to the less nucleophilic nature of α-amino esters than
bodiimide (3d), did not afford the desired product but gave amines in both the Staudinger reaction and in the intramo-
the corresponding hydantoin 7b in excellent yields lecular aza-Michael process. On the other hand, glycoazide
[Scheme 2, Equation (3)].
8f reacted under the same conditions with isocyanate 9a,
The above result was unexpected because, in previous acid 2b and N-glycosylamine 1a, producing, in good yields
works, similar reactions between N-alkyl, NЈ-aryl asym- and total regiocontrol, a diastereoisomeric mixture (ca. 2:1
metric carbodiimides, fumaric acid monoesters and dr) of novel disaccharide mimetic 4p, in which two sugar
stronger N-nucleophiles produced the corresponding conju- moieties are tethered through an Asp-urea linkage (Table 3,
gates in a regiospecific way in high yields.[17] In this case, entry 8).
the reaction between poorly nucleophilic N-glycosylamines
The N-glycosyl-Asp-urea conjugates 4 described above
and intermediates of type 5-C, which is more stable and are interesting synthons because their structure could be
therefore less reactive due to conjugation between the C=N further modified by simple chemoselective transformations.
double bond and the aromatic ring, is likely very slow, and Accordingly, by choosing the appropriate starting alkyl az-
the faster OǞN acyl migration mechanism becomes exclus- ide reactant 8 we were able to obtain products that could
ive, resulting in the formation of hydantoin 7b (Figure 1).
be selectively deprotected, affording conjugates having a
Finally, to investigate whether the process could be used free urea framework, which is known to be of special inter-
effectively for the combinatorial synthesis of interesting N- est because of its promising features in drug discovery and
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Multicomponent Synthesis of N-Glycosyl Conjugates
Table 3. Four-component synthesis of N-glycosyl-Asp-urea conjugates 4.
[a] Formed as a mixture of diastereoisomers (ca. 2:1). [b] The corresponding hydantoins were formed in ca. 20% yield. [c] Isolated yield.
interesting hydrogen-bonding properties.[20] For instance, be envisaged in which selective deprotection could be
starting from azide 8b, derivatives having an N-p-meth- achieved. For example, derivative 4b was selectively hydro-
oxybenzyl urea moiety, such as 4j, were obtained, which lysed at the benzyl ester function by hydrogenolysis. Subse-
could be easily removed by oxidative cleavage with ce- quent coupling with an α-amino ester, such as H-Leu-OMe,
rium(IV) ammonium nitrate (CAN) [Scheme 3, Equation mediated by 1-hydroxybenzotriazole (HOBt) / N-ethyl-NЈ-
(1)].[21] Moreover, because the MC domino process works (3-dimethylaminopropyl)carbodiimide (EDC), afforded N-
well with sugars 1 and fumaric acid monesters 2 having dif- glycosylpeptide 11 in good overall yields [Scheme 3, Equa-
ferent protecting groups, a synthetic plan can almost always tion (2)].
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Scheme 3. Chemoselective functionalization of synthons 4.
0.17 mmol, 60.0 mg) followed by TMP (1 equiv., 0.17 mmol, 23 μL)
and a solution of acid 2a (1 equiv., 0.17 mmol, 24.5 mg) in a mini-
mum amount of CH3CN were added at 0 °C. The resulting solution
was stirred until the reaction was complete (TLC monitoring, ca.
3 h.). A 1 n HCl aqueous solution was added and the mixture was
extracted three times with EtOAc. The combined organic layers
were dried with anhydrous Na2SO4, filtered, concentrated under
vacuum, and the crude material was purified by flash chromatog-
raphy (FC) to obtain an approximate 2:1 mixture of diastereoiso-
mers 4a (68.2 mg, 65%).
Conclusions
We have developed a MC sequential domino process for
the synthesis of a novel class of N-glycosyl conjugates, i.e.,
N-glycosyl-Asp-urea conjugates, starting from readily ac-
cessible reactants, such as azides, isocyanates, fumaric acid
monoesters, and N-glycosylamines. Because the latter com-
pounds are poor nucleophiles, fine-tuning of the reaction
conditions in terms of solvent and temperature was re-
quired to achieve the target compounds in good yields. The
reaction works nicely with either symmetric or asymmetric
N,NЈ-dialkyl carbodiimides, giving rise in the latter case to
completely regioselective reactions. By applying this pro-
cess, we obtained a small library of multifunctional com-
pounds that could be used to increase the diversity of sugar
frameworks and may find application as synthons in the
synthesis of potential glycomimetics and/or glycopeptido-
mimetics. Moreover, starting from suitable azides, such as
α-azido esters or azido sugars, it is possible to synthesise,
respectively, novel N-glycosyl-urea-peptides or disaccharide
mimetics in which two sugar moieties are tethered by an
Asp-urea linkage. The operational simplicity and the mild
conditions combined with favourable atom economy and
environmental aspects render this strategy attractive and
promising for the preparation of novel classes of glycocon-
jugates; it is particularly suitable for solid-phase/combinato-
rial chemistry. Investigations into these latter issues are in
progress in our laboratories.
Four-Component Synthesis of 4j; Typical Procedure: To a stirred
solution of benzyl azide 8a (1.1 equiv., 0.19 mmol, 25.3 mg) and
tert-butyl isocyanate 9a (1.1 equiv., 0.19 mmol, 21.7 μL) in CH3CN
(2.0 mL), Ph3P (1.1 equiv., 0.19 mmol, 49.0 mg) was added at room
temp. and the solution stirred overnight. The solution was diluted
with DMF (500 μL), the temperature was lowered to 0 °C, and
glycosylamine 1a (1 equiv., 0.17 mmol, 60.0 mg) followed by TMP
(1 equiv., 0.17 mmol, 23 μL) and a solution of acid 2b (1 equiv.,
0.17 mmol, 35.0 mg) in a minimum amount of CH3CN were added.
The resulting solution was stirred until the reaction was complete
(TLC monitoring, ca. 3 h.). A 1N HCl aqueous solution was added
and the mixture was extracted three times with EtOAc. The com-
bined organic layers were dried with anhydrous Na2SO4, filtered,
concentrated under vacuum, and the crude material was purified
by flash chromatography (FC) to give an approximate 2:1 mixture
of diastereoisomers 4j (85.9 mg, 61%).
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-[2-(1,3-diisopropylureido)-
4-ethoxy-4-oxobutanamido]tetrahydro-2H-pyran-3,4,5-triyl Triace-
tate (4a): Obtained as a mixture of two diastereoisomers; Rf = 0.25
(hexane/EtOAc, 50:50). FTIR (neat): ν = 3360, 1743, 1721 cm–1.
˜
1H NMR (400 MHz, CDCl3): δ [major diastereoisomer (S)] = 7.25
(d, J = 9.2 Hz, 1 H, amidic NH), 5.25 (dd, J = 9.2, 9.2 Hz, 1 H, 3-
H), 5.18 (dd, J = 9.2, 9.2 Hz, 1 H, 1-H), 5.04 (dd, J = 9.2, 9.2 Hz,
1 H, 4-H), 4.92 (dd, J = 9.2, 9.2 Hz, 1 H, 2-H), 4.47 (d, J = 7.2 Hz,
1 H, ureido NH), 4.39 (m, 1 H, Asp Cα-H), 4.27 (dd, J = 12.4,
4.4 Hz, 1 H, 6-H), 4.14 (q, J = 7.2 Hz, 2 H, COCH2CH3), 4.06 (dd,
J = 12.4, 2.4 Hz,1 H, HЈ-6), 3.92 [m, 2 H, -NCH(CH3)2], 3.78 (m,
1 H, 5-H), 3.36 (dd, J = 16.8, 7.6 Hz, 1 H, Asp Cβ-H), 2.45 (dd, J
= 16.8, 4.8 Hz, 1 H, Asp Cβ-HЈ), 2.06 (s, 3 H), 2.02 (s, 3 H), 2.00
(s, 3 H), 1.98 (s, 3 H), 1–30–1.11 (m, 15 H) ppm; δ [minor dia-
stereoisomer (R)] = 7.43 (d, J = 9.2 Hz, 1 H, amidic NH), 5.26 (dd,
J = 9.2, 9.2 Hz, 1 H, 3-H), 5.18 (dd, J = 9.2, 9.2 Hz, 1 H, 1-H),
5.04 (dd, J = 9.2, 9.2 Hz, 1 H, 4-H), 4.94 (dd, J = 9.2, 9.2 Hz, 1
H, 2-H), 4.47 (d, J = 7.2 Hz, 1 H, ureido NH), 4.39 (m, 1 H, Asp
Cα-H), 4.21 (dd, J = 12.4, 4.4 Hz, 1 H, 6-H), 4.13 (q, J = 7.2 Hz,
Experimental Section
General Methods: Commercially available reagent-grade solvents
were employed without purification. TLC were run on silica gel 60
F254 Merck. Flash chromatography (FC) was performed with silica
1
gel 60 (60–200 μm, Merck). H NMR spectra were recorded with
400 MHz spectrometers. Chemical shifts are expressed in ppm (δ),
using tetramethylsilane (TMS) as internal standard for 1H and 13
C
nuclei (δH and δC = 0.00 ppm). Glycosylamines 1a–f were prepared
by catalytic hydrogenation of the corresponding azides obtained as
reported in ref.[22]
Three-Component Synthesis of 4a; Typical Procedure: To a stirred
solution of carbodiimide 3a (1 equiv., 0.17 mmol, 26 μL) in a mix-
ture of CH3CN/DMF (4:1, 2.5 mL) glycosylamine 1a (1 equiv., 2 H, COCH2CH3), 4.06 (m, 1 H, HЈ-6), 3.92 [m, 2 H, -NCH-
2392
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2386–2397

Multicomponent Synthesis of N-Glycosyl Conjugates
(CH3)2], 3.78 (m, 1 H, 5-H), 3.22 (dd, J = 16.8, 8.4 Hz, 1 H, Asp
Cβ-H), 2.55 (dd, J = 16.8, 4.8 Hz, 1 H, Asp Cβ-HЈ), 2.04 (s, 3 H),
2.03 (s, 3 H), 2.00 (s, 3 H), 1.99 (s, 3 H), 1.30–1.11 (m, 15 H) ppm;
= 3361, 1745, 1726 cm–1. 1H NMR (400 MHz, CDCl3): δ [major
diastereoisomer (S)] = 7.82 (m, 2 H), 7.71 (m, 2 H), 7.46 (d, J =
9.6 Hz, 1 H), 6.03 (dd, J = 9.6, 9.6 Hz, 1 H), 5.89 (dd, J = 9.6,
13C NMR (100.6 MHz, CDCl3): δ = 172.5, 171.6, 171.2, 170.7, 9.6 Hz, 1 H), 5.14 (dd, J = 9.6, 9.6 Hz, 1 H), 5.34 (dd, J = 9.6,
170.5, 170.4, 170.3, 169.8, 169.4, 169.3, 157.0, 156.5, 78.5, 78.3,
73.5, 73.4, 73.1, 72.9, 70.4, 70.1, 68.3, 61.7, 60.8, 60.7, 53.7, 47.8,
9.6 Hz, 1 H), 4.12 (m, 1 H), 4.31 (m, 2 H), 4.06 (q, J = 7.2 Hz, 2
H), 3.96 (m, 1 H), 3.94 (m, 1 H), 3.69 (m, 1 H), 3.59 (m, 1 H), 3.00
47.4, 42.8, 42.6, 42.1, 35.9, 35.4, 23.45, 23.42, 23.2, 23.1, 23.0, 21.4, (dd, J = 16.4, 7.2 Hz, 1 H), 2.46 (dd, J = 16.4, 6.0 Hz, 1 H), 2.08
21.3, 21.1, 20.9, 20.6, 20.5, 20.4, 14.1 ppm. ESI: m/z (%) = 656.6 (2) (s, 3 H), 2.01 (s, 3 H), 1.82 (s, 3 H), 1.20–0.95 (m, 15 H) ppm; δ
[M+ + K], 640.6 (100) [M+ + Na], 618.4 (1) [M+ + 1]. C27H43N3O13
(617.65): calcd. C 52.50, H 7.02, N 6.80; found C 52.52, H 7.05, N
6.81.
[minor diastereoisomer (R)] = 7.82 (m, 2 H), 7.71 (m, 3 H), 5.99
(dd, J = 9.6, 9.6 Hz, 1 H), 5.89 (dd, J = 9.6, 9.6 Hz, 1 H), 5.14 (dd,
J = 9.6, 9.6 Hz, 1 H), 5.39 (m, 1 H), 4.31 (m, 2 H), 4.12 (m, 1 H),
4.06 (q, J = 7.2 Hz, 2 H), 3.96 (m, 1 H), 3.94 (m, 1 H), 3.69 (m, 1
H), 3.59 (m, 1 H), 3.00 (dd, J = 16.4, 7.2 Hz, 1 H), 2.58 (dd, J =
16.4, 6.0 Hz, 1 H), 2.06 (s, 3 H), 2.01 (s, 3 H), 1.83 (s, 3 H), 1.20–
0.95 (m, 15 H) ppm; 13C NMR (100.6 MHz, CDCl3), δ = 172.3,
171.1, 170.9, 170.6, 170.5, 169.8, 169.4, 167.3, 162.5, 157.3, 156.9,
134.2, 131.5, 123.7, 76.1, 76.0, 73.5, 71.0, 70.9, 68.9, 68.8, 61.9,
60.7, 60.6, 54.2, 54.1, 54.0, 53.8, 47.5, 42.8, 42.5, 36.4, 35.4, 23.3,
23.1, 23.0, 21.2, 20.8, 20.6, 20.5, 20.3, 20.2, 14.0, 13.9 ppm. ESI:
m/z (%) = 743.6 (9) [M+ + K], 727.6 (100) [M+ + Na], 705.5 (6)
[M+ + 1] ppm. C33H44N4O13 (704.73): calcd. C 56.24, H 6.29, N
7.95; found C 56.21, H 6.33, N 7.97.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-[4-(benzyloxy)-2-(1,3-di-
isopropylureido)-4-oxobutanamido]tetrahydro-2H-pyran-3,4,5-triyl
Triacetate (4b): Obtained as a mixture of two diastereoisomers; Rf
= 0.32 (hexane/EtOAc, 50:50). FTIR (neat): ν = 3344, 1763,
˜
1
1720 cm–1. H NMR (400 MHz, CDCl3): δ [major diastereoisomer
(S)] = 7.33 (m, 6 H), 5.25 (dd, J = 9.2, 9.2 Hz, 1 H), 5.18 (m, 1 H),
5.14 (d, J = 12.4 Hz, 1 H), 5.08 (d, J = 12.4 Hz, 1 H), 5.03 (dd, J
= 10.0, 10.0 Hz, 1 H), 4.92 (dd, J = 9.6, 9.6 Hz, 1 H), 4.47 (m, 1
H), 4.38 (m, 1 H), 4.26 (dd, J = 12.4, 4.4 Hz, 1 H), 4.03 (d, J =
12.4 Hz, 1 H), 3.91 (m, 1 H), 3.83 (m, 1 H), 3.76 (m, 1 H), 3.42
(dd, J = 16.8, 7.2 Hz, 1 H), 2.53 (dd, J = 16.8, 5.2 Hz, 1 H), 2.04
(s, 3 H), 1.99 (s, 6 H), 1.97 (s, 3 H), 1.27 (d, J = 6.8 Hz, 3 H), 1.16–
1.01 (m, 9 H) ppm: δ [minor diastereoisomer (R)] = 7.43 (d, J =
9.6 Hz, 1 H), 7.32 (m, 5 H), 5.26 (dd, J = 9.6, 9.6 Hz, 1 H), 5.18
(m, 1 H), 5.13 (d, J = 12.4 Hz, 1 H), 5.06 (d, J = 12.4 Hz, 1 H),
5.03 (dd, J = 10.0, 10.0 Hz, 1 H), 4.93 (dd, J = 9.2, 9.2 Hz, 1 H),
4.47 (m, 1 H), 4.38 (m, 1 H), 4.20 (dd, J = 12.4, 4.4 Hz, 1 H), 4.03
(d, J = 12.4 Hz, 1 H), 3.91 (m, 1 H), 3.83 (m, 1 H), 3.76 (m, 1 H),
3.28 (dd, J = 16.8, 8.4 Hz, 1 H), 2.63 (dd, J = 16.8, 5.2 Hz, 1 H),
2.02 (s, 3 H), 1.99 (s, 6 H), 1.98 (s, 3 H), 1.21 (d, J = 6.8 Hz, 3 H),
1.16–1.01 (m, 9 H) ppm; 13C NMR (100.6 MHz, CDCl3): δ =
172.4, 171.4, 171.1, 170.6, 170.4, 170.3, 169.8, 169.4, 169.3, 157.1,
156.5, 135.7, 128.5, 128.4, 128.2, 128.15, 128.11, 78.5, 78.3, 73.6,
73.5, 73.1, 73.0, 70.4, 70.2, 68.4, 66.6, 53.9, 47.9, 47.5, 42.8, 42.6,
42.1, 35.9, 35.4, 23.4, 23.3, 23.2, 23.0, 22.9, 21.5, 21.3, 21.1, 20.8,
20.6, 20.5, 20.4 ppm. ESI: m/z (%) = 718.7 (11) [M+ + K], 702.7
(100) [M+ + Na]. C32H45N3O13 (679.72): calcd. C 56.54, H 6.67, N
6.18; found C 56.58, H 6.63, N 6.19.
(3S,4S,5S,6S)-2-(Acetoxymethyl)-6-{(3R,4S,5S,6R)-4,5-diacetoxy-
2-(acetoxymethyl)-6-[4-(benzyloxy)-2-(1,3-diisopropylureido)-4-oxo-
butanamido]tetrahydro-2H-pyran-3-yloxy}tetrahydro-2H-pyran-
3,4,5-triyl Triacetate (4e): Obtained as a mixture of two diastereo-
isomers; R = 0.26 (hexane/EtOAc, 40:60). FTIR (neat): ν = 3345,
˜
f
1744, 1721 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
stereoisomer (S)] = 7.30 (m, 6 H), 5.33 (d, J = 2.8 Hz, 1 H), 5.22
(dd, J = 9.2, 9.2 Hz, 1 H), 5.12–5.03 (m, 4 H), 4.93 (d, J = 2.8 Hz,
1 H), 4.83 (dd, J = 9.2, 9.2 Hz, 1 H), 4.46–4.35 (m, 4 H), 4.07 (m,
3 H), 4.85 (m, 3 H), 3.75 (dd, J = 9.6, 9.6 Hz, 1 H), 3.69 (m, 1 H),
3.35 (dd, J = 16.8, 7.2 Hz, 1 H), 2.58 (dd, J = 16.8, 5.6 Hz, 1 H),
2.11 (s, 3 H), 2.07 (s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H), 2.00 (s, 6
H), 1.92 (s, 3 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.14–1.08 (m, 9 H) ppm;
δ [minor diastereoisomer (R)] = 7.47 (d, J = 9.6 Hz, 1 H), 7.30 (m,
5 H), 5.33 (d, J = 2.8 Hz, 1 H), 5.23 (dd, J = 9.2, 9.2 Hz, 1 H),
5.12–5.03 (m, 4 H), 4.93 (d, J = 2.8 Hz, 1 H), 4.84 (dd, J = 9.2,
9.2 Hz, 1 H), 4.46–4.35 (m, 4 H), 4.07 (m, 3 H), 4.85 (m, 3 H), 3.75
(dd, J = 9.6, 9.6 Hz, 1 H), 3.69 (m, 1 H), 3.21 (dd, J = 16.8, 7.2 Hz,
1 H), 2.64 (dd, J = 16.8, 5.6 Hz, 1 H), 2.11 (s, 3 H), 2.04 (s, 3 H),
2.03 (s, 3 H), 2.02 (s, 3 H), 2.00 (s, 6 H), 1.92 (s, 3 H), 1.22 (d, J =
6.8 Hz, 3 H), 1.14–1.08 (m, 9 H) ppm; 13C NMR (100.6 MHz,
CDCl3): δ = 172.4, 172.3, 171.3, 170.9, 170.7, 170.2, 170.1, 170.0,
169.9, 169.3, 168.8, 157.2, 156.7, 135.7, 135.6, 128.5, 128.4, 128.2,
128.1, 100.8, 78.3, 78.2, 76.0, 75.9, 74.4, 74.3, 72.8, 72.7, 70.8, 70.6,
69.1, 66.8, 66.5, 61.0, 54.0, 47.8, 47.4, 42.8, 42.6, 42.4, 36.3, 35.7,
35.2, 31.3, 23.3, 23.2, 23.1, 23.0, 22.9, 21.2, 20.8, 20.7, 20.6, 20.5,
20.3 ppm. ESI: m/z (%) = 990.7 (1000) [M+ + Na]. C44H61N3O21
(967.97): calcd. C 54.60, H 6.35, N 4.34; found C 54.57, H 6.33, N
4.36.
Ethyl 3-(1,3-Diisopropylureido)-4-oxo-4-[(2R,3S,4S,5R)-3,4,5-tris-
(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-ylamino]-
butanoate (4c): Obtained as a mixture of two diastereoisomers; Rf
= 0.35 (hexane/EtOAc, 60:40). FTIR (neat): ν = 3340, 1747,
˜
1
1714 cm–1. HNMR (400 MHz, CDCl3): δ [major diastereoisomer
(S)] = 7.30 (m, 21 H), 5.12 (dd, J = 9.2, 9.2 Hz, 1 H), 4.85 (m, 4
H), 4.54 (m, 6 H), 4.14 (m, 2 H), 3.91 (m, 2 H), 3.74 (m, 4 H), 3.49
(m, 2 H), 3.18–2.88 (m, 2 H), 1.27–1.11 (m, 15 H) ppm: δ [minor
diastereoisomer (R)] = 7.30 (m, 21 H), 5.16 (dd, J = 9.2, 9.2 Hz, 1
H), 4.85 (m, 4 H), 4.54 (m, 6 H), 4.14 (m, 2 H), 3.91 (m, 2 H), 3.74
(m, 4 H), 3.49 (m, 2 H), 3.18–2.88 (m, 2 H), 1.27–1.11 (m, 15
H) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 172.9, 172.3, 171.1,
171.0, 157.8, 138.2, 138.1, 138.0, 128.3, 128.2, 128.1, 127.9, 127.8,
127.78, 127.70, 127.6, 127.59, 127.53, 127.4, 85.8, 85.7, 81.6, 81.1,
79.6, 79.4, 75.5, 75.4, 74.9, 74.8, 74.6, 73.5, 68.6, 68.5, 60.8, 55.2,
54.7, 54.4, 48.1, 47.6, 44.9, 42.9, 42.7, 35.5, 35.2, 35.2, 23.3, 23.1,
21.5, 21.4, 21.2, 21.1 ppm. ESI: m/z (%) = 832.7 (100) [M+ + Na],
810.7 (1) [M+ + 1]. C47H59N3O9 (810.00): calcd. C 69.69, H 7.34,
N 5.19; found C 69.70, H 7.37, N 5.21.
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-{(3R,4S,5S,6R)-4,5-diacetoxy-
2-(acetoxymethyl)-6-[4-(benzyloxy)-2-(1,3-diisopropylureido)-4-oxo-
butanamido]tetrahydro-2H-pyran-3-yloxy}tetrahydro-2H-pyran-
3,4,5-triyl Triacetate (4f): Obtained as a mixture of two diastereo-
isomers; R = 0.21 (hexane/EtOAc, 40:60). FTIR (neat): ν = 3355,
˜
f
1749, 1722 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
stereoisomer (S)] = 7.34 (m, 6 H), 5.38–5.30 (m, 3 H), 5.22 (dd, J
= 8.8, 8.8 Hz, 1 H), 5.17 (d, J = 12.4 Hz, 1 H), 5.11 (d, J = 12.4 Hz,
1 H), 5.05 (dd, J = 9.2, 9.2 Hz, 1 H), 4.86 (dd, J = 10.8, 4.0 Hz, 1
H), 4.80 (dd, J = 9.2, 9.2 Hz, 1 H), 4.45 (m, 1 H), 4.40 (d, J =
12.4 Hz, 1 H), 4.24 (d, J = 2.4 Hz, 1 H), 4.21 (d, J = 2.4 Hz, 1 H),
4.05 (dd, J = 12.4, 2.4 Hz, 1 H), 3.94 (m, 3 H), 3.84 (m, 1 H), 3.77
(2R,3S,4R,5R,6R)-2-(Acetoxymethyl)-6-[2-(1,3-diisopropylureido)-
4-ethoxy-4-oxobutanamido]-5-(1,3-dioxoisoindolin-2-yl)tetrahydro-
2H-pyran-3,4-diyl Diacetate (4d): Obtained as a mixture of two dia-
stereoisomers; R = 0.22 (hexane/EtOAc, 30:70). FTIR (neat): ν
˜
f
Eur. J. Org. Chem. 2014, 2386–2397
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2393

M. C. Bellucci, A. Volonterio
FULL PAPER
(m, 1 H), 3.36 (dd, J = 16.8, 7.2 Hz, 1 H), 2.61 (dd, J = 16.8,
(s, 3 H), 2.01 (s, 3 H), 2.00 (s, 3 H), 1.97 (s, 3 H), 1.20 (s, 9 H),
5.6 Hz, 1 H), 2.12 (s, 3 H), 2.09 (s, 3 H), 2.06 (s, 3 H), 2.02 (s, 3 1.86 (m, 3 H) ppm; δ [minor diastereoisomer (R)] = 7.40 (d, J =
H), 2.00 (s, 3 H), 1.99 (s, 3 H), 1.98 (s, 3 H), 1.26–1.11 (m, 12 9.6 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H),
H) ppm; δ [minor diastereoisomer (R)] = 7.50 (d, J = 9.6 Hz, 1 H),
7.34 (m, 5 H), 5.38–5.30 (m, 3 H), 5.25 (dd, J = 8.8, 8.8 Hz, 1 H),
5.14 (d, J = 12.4 Hz, 1 H), 5.07 (d, J = 12.4 Hz, 1 H), 5.05 (dd, J
5.25 (dd, J = 9.6, 9.6 Hz, 1 H),5.24 (dd, J = 9.6, 9.6 Hz, 1 H), 5.15
(dd, J = 9.8, 6.8 Hz, 1 H), 5.02 (dd, J = 10.0, 10.0 Hz, 1 H), 4.93
(dd, J = 6.4, 6.4 Hz, 1 H), 4.48 (s, 1 H), 4.21 (m, 2 H), 4.08 (m, 4
= 9.2, 9.2 Hz, 1 H), 4.86 (dd, J = 10.8, 4.0 Hz, 1 H), 4.81 (dd, J = H), 3.77 (s, 3 H), 3.75 (m, 1 H), 3.00 (dd, J = 16.4, 9.2 Hz, 1 H),
9.2, 9.2 Hz, 1 H), 4.45 (m, 1 H), 4.39 (d, J = 12.4 Hz, 1 H), 4.24 2.50 (dd, J = 16.4, 5.2 Hz, 1 H), 2.04 (s, 3 H), 2.02 (s, 3 H), 2.00
(d, J = 2.4 Hz, 1 H), 4.21 (d, J = 2.4 Hz, 1 H), 4.05 (dd, J = 12.4, (s, 3 H), 1.98 (s, 3 H), 1.86 (m, 3 H), 1.16 (s, 9 H) ppm; 13C NMR
2.4 Hz, 1 H), 3.94 (m, 3 H), 3.84 (m, 1 H), 3.77 (m, 1 H), 3.24 (dd,
J = 16.8, 8.0 Hz, 1 H), 2.68 (dd, J = 16.8, 5.2 Hz, 1 H), 2.12 (s, 3 170.2, 169.9, 169.6, 169.4, 159.3, 158.0, 129.1, 129.0, 127.9, 127.6,
H), 2.09 (s, 3 H), 2.06 (s, 3 H), 2.02 (s, 3 H), 2.00 (s, 3 H), 1.99 (s, 3 114.6, 114.5, 78.2, 78.1, 73.6, 73.3, 73.1, 70.7, 70.4, 68.4, 68.2, 61.9,
H), 1.98 (s, 3 H), 1.26–1.11 (m, 12 H) ppm; 13C NMR (100.6 MHz, 61.8, 60.8, 60.6, 55.7, 55.3, 54.6, 51.2, 51.1, 48.9, 48.5, 34.3, 33.8,
(100.6 MHz, CDCl3): δ = 171.7, 171.5, 170.7, 170.6, 170.5, 170.4,
CDCl3): δ = 172.3, 171.3, 170.6, 170.5, 170.4, 170.3, 169.7, 169.6,
169.3, 162.5, 156.7, 135.7, 128.5, 128.4, 128.2, 128.1, 95.6, 78.0,
77.9, 75.4, 75.2, 74.0, 73.9, 73.0, 72.9, 71.2, 71.0, 70.0, 69.4, 68.6,
68.2, 66.6, 62.9, 62.8, 61.6, 54.1, 47.9, 47.5, 42.9, 42.7, 36.4, 35.7,
35.1, 31.4, 23.3, 23.2, 23.1, 23.0, 21.6, 21.2, 21.1, 20.8, 20.6, 20.57,
20.52, 20.48, 20.41 ppm. ESI: m/z (%) = 990.7 (100) [M+ + Na].
C44H61N3O21 (967.97): calcd. C 54.60, H 6.35, N 4.34; found C
54.55, H 6.36, N 4.33.
29.1, 29.0, 20.6, 20.4, 14.0, 13.9 ppm. ESI: m/z (%) = 732.7 (100)
[M+ + Na]. C33H47N3O14 (709.75): calcd. C 55.84, H 6.67, N 5.92;
found C 55.82, H 6.67, N 5.93.
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-[2-(1-benzyl-3-tert-butyl-
ureido)-4-(benzyloxy)-4-oxobutanamido]tetrahydro-2H-pyran-3,4,5-
triyl Triacetate (4k): Obtained as a mixture of two diastereoiso-
mers; R = 0.23 (hexane/EtOAc, 50:50). FTIR (neat): ν = 3342,
˜
f
1748, 1724 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
(3S,4S,5S,6S)-2-(Acetoxymethyl)-6-{(3R,4S,5S,6R)-4,5-diacetoxy-
2-(acetoxymethyl)-6-[4-(benzyloxy)-2-(1,3-dicyclohexylureido)-4-
oxobutanamido]tetrahydro-2H-pyran-3-yloxy}tetrahydro-2H-pyran-
3,4,5-triyl Triacetate (4g): Obtained as a mixture of two diastereo-
stereoisomer (S)] = 7.33 (m, 10 H, ArH), 7.18 (d, J = 7.2 Hz, 1 H,
amidic NH), 5.31 (dd, J = 9.2, 9.2 Hz, 1 H, 3-H), 5.28 (dd, J =
9.2, 9.2 Hz, 1 H, 1-H), 5.24 (dd, J = 9.2, 9.2 Hz, 1 H, 4-H), 5.11
(d, J = 12.4 Hz, 1 H, -OCHHPh), 5.10 (m, 1 H, Asp Cα-H), 5.08
(d, J = 12.4 Hz, 1 H, -OCHHPh), 4.94 (d, J = 9.6, 9.6 Hz, 1 H, 2-
H), 4.46 (s, 1 H, ureido NH), 4.32 (d, J = 17.6 Hz, CHHPh), 4.28
(dd, J = 12.4, 4.4 Hz, 1 H, 6-H), 4.17 (d, J = 17.6 Hz, CHHPh),
4.08 (dd, J = 12.4, 2.0 Hz, 1 H, 6Ј-H), 3.79 (m, 1 H, 5-H), 3.06
(dd, J = 16.8, 7.6 Hz, 1 H, Asp Cβ-H), 2.67 (dd, J = 16.8, 6.8 Hz,
1 H, Asp Cβ-HЈ), 2.08 (s, 3 H), 2.04 (s, 3 H), 2.03 (s, 3 H), 2.01 (s,
3 H), 1.22 (s, 9 H) ppm: δ [minor diastereoisomer (R)] = 7.33 (m,
10 H), 7.22 (d, J = 7.2 Hz, 1 H), 5.28 (dd, J = 9.2, 9.2 Hz, 1 H),
5.24 (m, 2 H), 5.09 (m, 3 H), 4.97 (d, J = 9.6 Hz, 1 H), 4.93 (d, J
= 9.6 Hz, 1 H), 4.47–4.14 (m, 3 H), 4.08 (dd, J = 12.0, 2.0 Hz, 1
isomers; R = 0.26 (hexane/EtOAc, 40:60). FTIR (neat): ν = 3368,
˜
f
1741, 1724 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
stereoisomer (S)] = 7.33 (m, 5 H), 7.22 (d, J = 8.8 Hz, 1 H), 5.33
(d, J = 2.8 Hz, 1 H), 5.24 (dd, J = 9.2, 9.2 Hz, 1 H), 5.15–5.05 (m,
4 H), 4.93 (dd, J = 10.4, 3.6 Hz, 1 H), 4.83 (dd, J = 9.6, 9.6 Hz, 1
H), 4.46–4.36 (m, 4 H), 4.10 (m, 3 H), 3.85 (dd, J = 6.8, 6.8 Hz, 1
H), 3.75 (d, J = 8.8 Hz, 1 H), 3.67 (m, 1 H), 3.58 (m, 1 H), 3.43
(m, 1 H), 3.38 (dd, J = 16.4, 7.6 Hz, 1 H), 2.53 (dd, J = 16.4,
5.2 Hz, 1 H), 2.13 (s, 3 H), 2.09 (s, 3 H), 2.05 (s, 3 H),2.01 (s, 6 H),
1.99 (s, 3 H), 1.94 (s, 3 H), 1.92–1.08 (m, 20 H) ppm; δ [minor
diastereoisomer (R)] = 7.48 (d, J = 8.8 Hz, 1 H), 7.33 (m, 5 H), H), 3.79 (m, 1 H), 3.11 (dd, J = 16.8, 9.2 Hz, 1 H), 2.62 (dd, J =
5.33 (d, J = 2.8 Hz, 1 H), 5.24 (dd, J = 9.2, 9.2 Hz, 1 H), 5.15–5.05
(m, 4 H), 4.93 (dd, J = 10.4, 3.6 Hz, 1 H), 4.85 (dd, J = 9.6, 9.6 Hz,
1 H), 4.46–4.36 (m, 4 H), 4.10 (m, 3 H), 3.85 (dd, J = 6.8, 6.8 Hz,
16.8, 5.2 Hz, 1 H), 2.09 (s, 3 H), 2.06 (s, 3 H), 2.04 (s, 3 H), 2.02 (s,
3 H), 1.18 (s, 9 H) ppm; 13C NMR (100.6 MHz, CDCl3): δ [major
diastereoisomer (S)] = 171.6, 170.5, 169.9, 169.6, 169.4, 158.1,
1 H), 3.77 (dd, J = 10.0, 5.6 Hz, 1 H), 3.67 (m, 1 H), 3.58 (m, 1 137.1, 135.6, 129.2, 128.5, 128.3, 128.2, 127.9, 126.3, 78.1, 73.7,
H), 3.38 (m, 1 H), 3.25 (dd, J = 16.8, 8.0 Hz, 1 H), 2.68 (dd, J = 73.3, 70.8, 68.2, 66.7, 61.8, 55.9, 51.3, 49.6, 34.2, 29.1, 20.7,
16.8, 5.2 Hz, 1 H), 2.13 (s, 3 H), 2.08 (s, 3 H), 2.05 (s, 3 H),2.01 (s, 20.5 ppm. ESI: m/z (%) = 780.6 (21) [M+ + K], 764.7 (100) [M+
+
6 H), 1.99 (s, 3 H), 1.94 (s, 3 H), 1.92–1.08 (m, 20 H) ppm; 13C Na]. C37H47N3O13 (741.79): calcd. C 59.91, H 6.39, N 5.66; found
NMR (100.6 MHz, CDCl3): δ = 172.5, 172.4, 171.4, 170.9, 170.7, C 59.95, H 6.41, N 5.65.
170.3, 170.2, 170.1, 170.0, 169.9, 169.3, 169.2, 168.9, 157.1, 156.5,
135.8, 135.6, 128.5, 128.4, 128.2, 128.1, 100.8, 78.4, 78.1, 77.2, 76.7,
76.0, 75.8, 74.4, 74.3, 72.8, 72.7, 71.0, 70.8, 70.6, 69.1, 66.7, 66.6,
66.5, 62.1, 61.0, 60.3, 58.7, 56.7, 54.5, 54.4, 49.6, 49.5, 49.1, 35.8,
35.4, 33.9, 33.8, 33.5, 33.4, 33.3, 31.8, 31.7, 31.5, 26.1, 26.0, 25.6,
25.2, 25.1, 25.0, 24.9, 24.8, 20.7, 20.6, 20.5, 20.4 ppm. ESI: m/z (%)
= 1070.9 (100) [M+ + Na]. C50H69N3O21 (1048.10): calcd. C 57.30,
H 6.64, N 4.01; found C 57.32, H 6.62, N 4.04.
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-{4-(Benzyloxy)-2-[3-tert-butyl-
1-(4-methoxybenzyl)ureido]-4-oxobutanamido}tetrahydro-2H-pyran-
3,4,5-triyl Triacetate (4j): Obtained as a mixture of two diastereo-
isomers; R = 0.39 (hexane/EtOAc, 50:50). FTIR (neat): ν = 3360,
˜
f
1751, 1729 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
stereoisomer (S)] = 7.32 (m, 6 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.84
(d, J = 8.8 Hz, 2 H), 5.27 (dd, J = 9.6, 9.6 Hz, 1 H), 5.26 (dd, J =
9.6, 9.6 Hz, 1 H), 5.19 (m, 1 H), 5.09 (m, 3 H), 4.96 (d, J = 9.6 Hz,
1 H), 4.91 (d, J = 9.6 Hz, 1 H), 4.50 (s, 1 H), 4.26 (m, 2 H), 4.10
(m, 2 H), 3.78 (s, 3 H), 3.07 (dd, J = 16.8, 7.2 Hz, 1 H), 2.66 (dd,
J = 16.8, 7.2 Hz, 1 H), 2.07 (s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H),
1.99 (s, 3 H), 1.22 (s, 9 H) ppm; δ [minor diastereoisomer (R)] =
7.42 (d, J = 9.6 Hz, 1 H),7.32 (m, 5 H), 7.13 (d, J = 8.8 Hz, 2 H),
6.84 (d, J = 8.8 Hz, 2 H), 5.28 (dd, J = 9.6, 9.6 Hz, 1 H), 5.25 (dd,
J = 9.6, 9.6 Hz, 1 H), 5.19 (m, 1 H), 5.09 (m, 3 H), 4.96 (d, J =
9.6 Hz, 1 H), 4.91 (d, J = 9.6 Hz, 1 H), 4.47 (s, 1 H), 4.26 (m, 2
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-{2-[3-tert-butyl-1-(4-methoxy-
benzyl)ureido]-4-ethoxy-4-oxobutanamido}tetrahydro-2H-pyran-
3,4,5-triyl Triacetate (4h): Obtained as a mixture of two diastereo-
isomers; R = 0.15 (hexane/EtOAc, 50:50). FTIR (neat): ν = 3289,
˜
f
1741, 1715 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
stereoisomer (S)] = 7.33 (d, J = 9.6 Hz, 1 H), 7.10 (d, J = 8.4 Hz,
2 H), 6.87 (d, J = 8.4 Hz, 2 H), 5.25 (dd, J = 9.6, 9.6 Hz, 1 H),5.24
(dd, J = 9.6, 9.6 Hz, 1 H), 5.15 (dd, J = 6.8, 6.8 Hz, 1 H), 5.02 (dd,
J = 10.0, 10.0 Hz, 1 H), 4.91 (dd, J = 9.6, 9.6 Hz, 1 H), 4.53 (s, 1 H), 4.10 (m, 2 H), 3.78 (s, 3 H), 3.11 (dd, J = 16.8, 8.8 Hz, 1 H),
H), 4.21 (m, 2 H), 4.08 (m, 4 H), 3.78 (s, 3 H), 3.75 (m, 1 H), 2.97
(dd, J = 16.8, 8.0 Hz, 1 H), 2.56 (dd, J = 16.8, 6.8 Hz, 1 H), 2.06
2.66 (dd, J = 16.8, 5.6 Hz, 1 H), 2.07 (s, 3 H), 2.05 (s, 3 H), 2.02
(s, 3 H), 2.00 (s, 3 H), 1.18 (s, 9 H) ppm; 13C NMR (100.6 MHz,
2394
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2386–2397

Multicomponent Synthesis of N-Glycosyl Conjugates
CDCl3): δ = 171.6, 171.4, 170.6, 170.5, 170.4, 170.3, 169.9, 169.6,
169.4, 159.3, 158.0, 135.6, 135.5, 129.0, 128.9, 128.5, 128.4, 128.3,
128.2, 127.8, 127.6, 114.6, 114.5, 78.2, 78.1, 73.6, 73.5, 73.3, 73.1,
70.8, 70.4, 68.4, 68.2, 66.7, 66.5, 61.9, 61.8, 55.8, 55.3, 54.6, 51.2,
51.1, 49.1, 48.5, 34.2, 33.7, 29.1, 29.0, 20.65, 20.62, 20.5, 20.4 ppm.
triyl Triacetate (4m): Obtained as a mixture of two diastereoiso-
mers; R = 0.41 (hexane/EtOAc, 50:50). FTIR (neat): ν = 3335,
˜
f
1731, 1722 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
stereoisomer (S)] = 7.49 (d, J = 8.8 Hz, 1 H), 7.32 (m, 5 H), 5.26–
5.03 (m, 5 H), 4.93 (dd, J = 9.2, 9.2 Hz, 1 H), 4.67 (s, 1 H), 4.40
ESI: m/z (%) = 794.7 (100) [M+ + Na]. C38H49N3O14 (771.82): (m, 1 H), 4.26 (dd, J = 12.4, 4.4 Hz, 1 H), 4.04 (d, J = 12.4 Hz, 1
calcd. C 59.13, H 6.40, N 5.44; found C 59.16, H 6.41, N 5.46.
H), 3.76 (m, 1 H), 3.37 (m, 1 H), 3.29 (dd, J = 16.8, 7.6 Hz, 1 H),
2.60 (dd, J = 16.8, 5.6 Hz, 1 H), 2.04 (s, 3 H), 1.99 (s, 3 H), 1.98
(s, 3 H), 1.97 (s, 3 H), 1.83–1.44 (m, 8 H), 1.30 (s, 9 H), 1.07 (m, 2
H) ppm; δ [minor diastereoisomer (R)] = 7.32 (m, 6 H), 5.26–5.03
(m, 5 H), 4.91 (dd, J = 9.2, 9.2 Hz, 1 H), 4.67 (s, 1 H), 4.40 (m, 1
H), 4.18 (dd, J = 12.4, 4.4 Hz, 1 H), 4.05 (d, J = 12.4 Hz, 1 H),
3.76 (m, 1 H), 3.55 (m, 1 H), 3.29 (dd, J = 16.8, 7.6 Hz, 1 H), 2.56
(dd, J = 16.8, 4.4 Hz, 1 H), 2.02 (s, 3 H), 2.01 (s, 3 H), 1.98 (s, 3
H), 1.97 (s, 3 H), 1.83–1.44 (m, 8 H), 1.30 (s, 9 H), 1.07 (m, 2
H) ppm; 13C NMR (100.6 MHz, CDCl3): δ = 173.0, 172.6, 171.1,
170.5, 170.46, 170.41, 170.2, 169.8, 169.7, 169.4, 156.9, 135.7,
128.5, 128.25, 128.22, 128.1, 78.5, 78.3, 73.5, 73.4, 73.3, 73.0, 70.4,
70.3, 68.3, 68.2, 66.7, 61.8, 57.0, 56.3, 54.7, 54.0, 51.2, 51.1, 35.8,
35.7, 32.0, 31.8, 31.7, 29.3, 29.2, 26.2, 26.0, 25.2, 20.6, 20.5, 20.4,
14.1 ppm. ESI: m/z (%) = 756.7 (100) [M+ + Na]. C36H51N3O13
(733.81): calcd. C 58.92, H 7.01, N 5.73; found C 58.90, H 7.00, N
5.77.
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-{2-[3-tert-butyl-1-(prop-2-
ynyl)ureido]-4-ethoxy-4-oxobutanamido}tetrahydro-2H-pyran-
3,4,5-triyl Triacetate (4i): Obtained as a mixture of two diastereo-
isomers; R = 0.46 (hexane/EtOAc, 40:60). FTIR (neat): ν = 3371,
˜
f
1767, 1741 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
stereoisomer (S)] = 7.22 (d, J = 9.2 Hz, 1 H), 5.28–5.20 (m, 2 H),
5.08–5.02 (m, 2 H), 4.97–4.88 (m, 2 H), 4.26 (dd, J = 12.4, 4.4 Hz,
1 H), 4.14 (q, J = 7.2 Hz, 2 H), 4.08 (d, J = 12.8 Hz, 1 H), 3.96
(dd, J = 18.8, 2.4 Hz, 1 H), 2.87 (dd, J = 18.8, 2.4 Hz, 1 H), 3.77
(m, 1 H), 3.07 (dd, J = 16.8, 7.6 Hz, 1 H), 2.75 (dd, J = 16.8,
7.2 Hz, 1 H), 2.39 (t, J = 2.4 Hz, 1 H), 2.08 (s, 3 H), 2.01 (s, 3 H),
2.00 (s, 3 H), 1.99 (s, 3 H), 1.37 (s, 9 H), 1.24 (t, J = 7.2 Hz, 3
H) ppm: δ [minor diastereoisomer (R)] = 7.20 (d, J = 9.2 Hz, 1 H),
5.28–5.20 (m, 2 H), 5.08–5.02 (m, 2 H), 4.97–4.88 (m, 2 H), 4.21
(dd, J = 12.4, 4.4 Hz, 1 H), 4.14 (q, J = 7.2 Hz, 2 H), 4.08 (d, J =
12.8 Hz, 1 H), 4.02 (dd, J = 18.8, 2.4 Hz, 1 H), 3.77 (m, 2 H), 3.12
(dd, J = 16.8, 8.0 Hz, 1 H), 2.68 (dd, J = 16.8, 6.0 Hz, 1 H), 2.43
(t, J = 2.4 Hz, 1 H), 2.05 (s, 3 H), 2.03 (s, 3 H), 2.01 (s, 3 H), 1.99
(s, 3 H), 1.35 (s, 9 H), 1.25 (t, J = 7.2 Hz, 3 H) ppm; 13C NMR
(100.6 MHz, CDCl3): δ = 171.3, 171.2, 170.6, 170.5, 170.4, 170.3,
169.8, 169.4, 156.8, 156.6, 79.2, 78.3, 78.2, 73.9, 73.8, 73.7, 73.2,
73.0, 70.7, 70.4, 68.4, 68.2, 61.8, 61.7, 60.8, 60.7, 55.5, 55.1, 51.5,
35.2, 35.1, 33.8, 33.6, 29.4, 29.2, 29.1, 20.6, 20.5, 14.0 ppm. ESI:
m/z (%) = 666.6 (2) [M+ + K], 650.6 (100) [M+ + Na]. C28H41N3O13
(627.64): calcd. C 53.58, H 6.58, N 6.69; found C 53.60, H 6.57, N
6.71.
(3S,4S,5S,6S)-2-(Acetoxymethyl)-6-{(3R,4S,5S,6R)-4,5-diacetoxy-
2-(acetoxymethyl)-6-[4-(benzyloxy)-2-(3-tert-butyl-1-cyclohexyl-
ureido)-4-oxobutanamido]tetrahydro-2H-pyran-3-yloxy}tetrahydro-
2H-pyran-3,4,5-triyl Triacetate (4n): Obtained as a mixture of two
diastereoisomers; R = 0.27 (hexane/EtOAc, 40:60). FTIR (neat): ν
˜
f
= 3326, 1728, 1725 cm–1. 1H NMR (400 MHz, CDCl3): δ [major
diastereoisomer (S)] = 7.51 (d, J = 8.8 Hz, 1 H, amidic NH), 7.35
(m, 5 H, ArH), 5.35 (dd, J = 3.6, 1.2 Hz, 1 H, Gal 4-H), 5.25 (dd,
J = 9.2, 9.2 Hz, 1 H, Glu 3-H), 5.16 (dd, J = 9.2, 9.2 Hz, Glu 1-
H), 5.15 (d, J = 12.4 Hz, 1 H, OCHHPh), 5.11 (d, J = 12.4 Hz, 1
H, OCHHPh), 5.10 (dd, J = 10.4, 8.0 Hz, 1 H, Gal 2-H), 4.96 (dd,
J = 10.4, 3.6 Hz, 1 H, Gal 3-H), 4.88 (dd, J = 9.2, 9.2 Hz, 1 H,
Glu 2-H), 4.66 (s, 1 H, ureido NH), 4.48 (d, J = 8.0 Hz, 1 H, Gal
1-H), 4.39 (m, 1 H, Asp Cα-H), 4.40 (dd, J = 12.0, 2.0 Hz, 1 H,
Glu 6-H), 4.13 (m, 1 H, Glu 6Ј-H), 4.12 (m, 1 H, Gal 6-H), 4.11
(dd, J = 6.8, 6.8 Hz, 1 H, Gal 6Ј-H), 3.88 (dd, J = 6.8, 1.2 Hz, 1
H, Gal 5-H), 3.80 (dd, J = 9.2, 9.2 Hz, 1 H, Glu 4-H), 3.71 (m, 1
H, Glu 5-H), 3.37 (m, 1 H, NCH), 3.26 (dd, J = 16.4, 7.2 Hz, 1 H,
Asp Cβ-H), 2.65 (dd, J = 16.4, 6.0 Hz, 1 H, Asp Cβ-HЈ), 2.15 (s,
3 H), 2.10 (s, 3 H), 2.07 (s, 3 H), 2.044 (s, 3 H), 2.041 (s, 3 H), 2.00
(s, 3 H), 1.96 (s, 3 H), 1.85–1.50 (m, 8 H), 1.31 (s, 9 H), 1.12 (m, 2
H) ppm: δ [minor diastereoisomer (R)] = 7.35 (m, 6 H), 5.35 (d, J
= 3.2 Hz, 1 H), 5.27 (dd, J = 9.2, 9.2 Hz, 1 H), 5.18–5.08 (m, 4 H),
4.95 (dd, J = 10.4, 3.6 Hz, 1 H), 4.83 (dd, J = 9.6, 9.6 Hz, 1 H),
4.66 (s, 1 H), 4.49–4.39 (m, 3 H), 4.15–4.06 (m, 3 H), 3.86 (dd, J
= 6.8, 6.8 Hz, 1 H), 3.79 (dd, J = 9.6, 9.6 Hz, 1 H), 3.68 (m, 1 H),
3.60 (m, 1 H), 3.26 (dd, J = 16.8, 7.2 Hz, 1 H), 2.59 (dd, J = 16.8,
4.8 Hz, 1 H), 2.15 (s, 3 H), 2.10 (s, 3 H), 2.07 (s, 3 H), 2.044 (s, 3
H), 2.041 (s, 3 H), 2.00 (s, 3 H), 1.96 (s, 3 H), 1.85–1.50 (m, 8 H),
1.30 (s, 9 H), 1.12 (m, 2 H) ppm; 13C NMR (100.6 MHz, CDCl3):
δ [major diastereoisomer (S)] = 172.9, 171.1, 170.3, 170.2, 170.0,
169.9, 168.9, 157.1, 135.7, 128.6, 128.5, 128.3, 128.2, 100.9, 78.3,
76.0, 74.4, 73.0, 71.0, 70.8, 70.7, 70.6, 69.1, 66.7, 66.6, 62.0, 60.9,
56.9, 54.7, 51.1, 35.6, 31.9, 31.7, 29.3, 26.2, 26.1, 25.3, 20.8, 20.7,
20.6, 20.5, 20.4 ppm. ESI: m/z (%) = 1060.8 (34) [M+ + K], 1044.8
(100) [M+ + Na]. C48H67N3O21 (1022.06): calcd. C 56.41, H 6.61,
N 4.11; found C 56.38, H 6.60, N 4.15.
(3S,4S,5S,6S)-2-(Acetoxymethyl)-6-((3R,4S,5S,6R)-4,5-diacetoxy-
2-(acetoxymethyl)-6-{2-[3-tert-butyl-1-(prop-2-ynyl)ureido]-4-
ethoxy-4-oxobutanamido}tetrahydro-2H-pyran-3-yloxy)tetrahydro-
2H-pyran-3,4,5-triyl Triacetate (4l): Obtained as a mixture of two
diastereoisomers; R = 0.12 (hexane/EtOAc, 60:40). FTIR (neat): ν
˜
f
= 3358, 1734, 17216 cm–1. H NMR (400 MHz, CDCl3): δ [major
1
diastereoisomer (S)] = 7.18 (d, J = 8.8 Hz, 1 H), 5.34 (d, J = 3.2 Hz,
1 H), 5.24 (dd, J = 9.2, 9.2 Hz, 1 H), 5.17 (dd, J = 9.2, 9.2 Hz, 1
H), 5.07 (dd, J = 7.6 Hz, 1 H), 4.98–4.91 (m, 2 H), 4.82 (dd, J =
9.2, 9.2 Hz, 1 H), 4.49–4.39 (m, 2 H), 4.12 (m, 6 H),3.87–3.76 (m,
4 H), 3.69 (m, 1 H), 3.05 (dd, J = 16.8, 7.2 Hz, 1 H), 2.73 (dd, J =
16.8, 7.2 Hz, 1 H), 2.38 (t, J = 2.4 Hz, 1 H), 2.14 (s, 3 H), 2.12 (s,
3 H), 2.06 (s, 3 H), 2.04 (s, 6 H), 1.99 (s, 3 H), 1.95 (s, 3 H), 1.37
(s, 9 H), 1.24 (t, J = 7.2 Hz, 3 H) ppm: δ [minor diastereoisomer
(R)] = 7.16 (d, J = 8.8 Hz, 1 H), 5.34 (d, J = 3.2 Hz, 1 H), 5.25
(dd, J = 9.2, 9.2 Hz, 1 H), 5.17 (dd, J = 9.2, 9.2 Hz, 1 H), 5.07 (dd,
J = 7.6 Hz, 1 H), 4.98–4.91 (m, 2 H), 4.85 (dd, J = 9.2, 9.2 Hz, 1
H), 4.49–4.39 (m, 2 H), 4.12 (m, 6 H),3.87–3.76 (m, 4 H), 3.69 (m,
1 H), 3.09 (dd, J = 16.8, 8.4 Hz, 1 H), 2.66 (dd, J = 16.8, 6.0 Hz,
1 H), 2.41 (t, J = 2.4 Hz, 1 H), 2.14 (s, 3 H), 2.12 (s, 3 H), 2.08 (s,
3 H), 2.05 (s, 3 H), 2.04 (s, 3 H), 1.99 (s, 3 H), 1.95 (s, 3 H), 1.34
(s, 9 H), 1.24 (t, J = 7.2 Hz, 3 H) ppm; 13C NMR (100.6 MHz,
CDCl3): δ = 171.1, 171.0, 170.6, 170.4, 170.2, 170.0, 169.9, 169.4,
168.9, 156.9, 156.7, 100.9, 79.1, 78.1, 78.0, 74.5, 73.8, 72.8, 71.0,
70.8, 69.1, 66.7, 62.0, 61.8, 60.9, 60.8, 55.2, 54.9, 51.5, 35.0, 34.9,
33.7, 33.6, 29.2, 29.1, 20.7, 20.67, 20.61, 20.5, 20.4, 14.0 ppm. ESI:
m/z (%) = 938.7 (100) [M+ + Na]. C40H57N3O21 (915.90): calcd. C
52.45, H 6.27, N 6.69; found C 52.46, H 6.29, N 4.57.
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-(2-{1-[2-(benzyloxy)-2-oxo-
ethyl]-3-tert-butylureido}-4-ethoxy-4-oxobutanamido)tetrahydro-
2H-pyran-3,4,5-triyl Triacetate (4o): Obtained as a mixture of two
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-[4-(benzyloxy)-2-(3-tert-butyl-
1-cyclohexylureido)-4-oxobutanamido]tetrahydro-2H-pyran-3,4,5-
Eur. J. Org. Chem. 2014, 2386–2397
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2395

M. C. Bellucci, A. Volonterio
FULL PAPER
diastereoisomers; R = 0.28 (hexane/EtOAc, 50:50). FTIR (neat): ν
(s, 3 H), 1.36 (s, 9 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
˜
f
= 3321, 1731, 1726 cm–1. 1H NMR (400 MHz, CDCl3): δ [major 172.6, 172.1, 171.7, 170.5, 169.7, 169.4, 155.9, 135.4, 128.6, 128.3,
diastereoisomer (S)] = 8.45 (d, J = 8.8 Hz, 1 H), 7.37 (m, 5 H),
5.28–5.17 (m, 4 H), 5.09 (dd, J = 9.6, 9.6 Hz, 1 H), 4.97 (dd, J =
9.6, 9.6 Hz, 1 H), 4.66 (dd, J = 8.4, 5.6 Hz, 1 H), 4.46 (m, 1 H),
4.24 (dd, J = 12.0, 4.4 Hz, 1 H), 4.17–4.08 (m, 4 H), 3.84–3.78 (m,
2 H), 3.06 (dd, J = 16.8, 5.6 Hz, 1 H), 2.69 (dd, J = 16.8, 8.4 Hz,
1 H), 2.07 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3 H), 1.96 (s, 3 H), 1.29
(s, 9 H), 1.23 (t, J = 7.2 Hz, 3 H) ppm; δ [minor diastereoisomer
(R)] = 8.70 (br. s, 1 H), 7.37 (m, 5 H), 5.28–5.17 (m, 4 H), 5.07 (dd,
J = 9.6, 9.6 Hz, 1 H), 4.98 (dd, J = 9.6, 9.6 Hz, 1 H), 4.62 (m, 1
H), 4.46 (m, 1 H), 4.17–4.08 (m, 5 H), 3.84–3.78 (m, 2 H), 3.06
(dd, J = 16.8, 5.6 Hz, 1 H), 2.67 (dd, J = 16.8, 7.6 Hz, 1 H), 2.03
(s, 3 H), 2.02 (s, 3 H), 2.00 (s, 3 H), 1.99 (s, 3 H), 1.27 (s, 9 H),
1.24 (t, J = 7.2 Hz, 3 H) ppm; 13C NMR (100.6 MHz, CDCl3): δ
= 172.1, 171.9, 171.2, 171.0, 170.9, 170.5, 170.4, 169.94, 169.91,
169.7, 169.6, 169.3, 156.4, 155.7, 134.94, 134.91, 128.8, 128.7,
128.6, 128.59, 128.51, 128.4, 78.5, 78.4, 73.6, 73.5, 73.4, 70.6, 70.5,
70.4, 68.6, 68.3, 68.2, 68.1, 67.7, 67.6, 62.0, 61.9, 61.8, 61.0, 60.3,
58.2, 57.8, 51.5, 51.3, 49.7, 48.9, 34.2, 34.0, 29.1, 29.0, 28.9, 20.6,
20.5, 20.4, 14.1, 14.0 ppm. ESI: m/z (%) = 776.6 (1) [M+ + K],
760.6 (100) [M+ + Na]. C34H47N3O15 (737.76): calcd. C 55.35, H
6.42, N 5.70; found C 55.37, H 6.43, N 5.72.
127.9, 78.3, 73.7, 72.7, 71.0, 68.3, 66.6, 50.8, 49.8, 35.4, 29.4,
20.6 ppm. ESI: m/z (%) = 674.6 (100) [M+ + Na]. C30H41N3O13
(651.67): calcd. C 55.29, H 6.34, N 6.45; found C 55.30, H 6.36, N
6.44.
(3R,4S,5S,6R)-2-(acetoxymethyl)-6-{2-(1,3-diisopropylureido)-4-
[(S)-1-methoxy-4-methyl-1-oxopentan-2-ylamino]-4-oxobutan-
amido}tetrahydro-2H-pyran-3,4,5-triyl triacetate (11): Obtained as a
mixture of two diastereoisomers; Rf = 0.25 (hexane/EtOAc, 30:70).
FTIR (neat): ν = 3312, 1722, 1721 cm–1 1H NMR (400 MHz,
.
˜
CDCl3): δ [major diastereoisomer (S)] = 7.27 (d, J = 8.8 Hz, 1 H),
6.49 (d, J = 8.0 Hz, 1 H), 5.25 (dd, J = 9.6, 9.6 Hz, 1 H), 5.20 (dd,
J = 9.6, 9.6 Hz, 1 H), 5.03 (dd, J = 9.6, 9.6 Hz, 1 H), 4.91 (dd, J
= 9.6, 9.6 Hz, 1 H), 4.56 (m, 2 H), 4.24 (m, 2 H), 4.04 (dd, J =
12.8, 2.4 Hz, 1 H), 3.92–3.76 (m, 3 H), 3.70 (s, 3 H), 3.23 (dd, J =
14.8, 6.8 Hz, 1 H), 2.46 (dd, J = 14.8, 4.8 Hz, 1 H), 2.04 (s, 3 H),
2.02 (s, 3 H), 1.99 (s, 3 H), 1.97 (s, 3 H), 1.62 (m, 2 H), 1.52 (m, 1
H), 1.28–1.11 (m, 12 H), 0.91 (m, 6 H) ppm; δ [minor diastereoiso-
mer] = 7.78 (d, J = 9.2 Hz, 1 H), 6.09 (d, J = 8.0 Hz, 1 H), 5.22
(dd, J = 9.6, 9.6 Hz, 1 H), 5.19 (dd, J = 9.6, 9.6 Hz, 1 H), 5.04 (dd,
J = 9.6, 9.6 Hz, 1 H), 4.92 (dd, J = 9.6, 9.6 Hz, 1 H), 4.56 (m, 2
H), 4.24 (m, 2 H), 4.04 (dd, J = 12.8, 2.4 Hz, 1 H), 3.92–3.76 (m,
3 H), 3.67 (s, 3 H), 3.02 (dd, J = 14.8, 6.8 Hz, 1 H), 2.46 (dd, J =
14.8, 6.4 Hz, 1 H), 2.04 (s, 3 H), 2.02 (s, 3 H), 1.99 (s, 3 H), 1.97
(s, 3 H), 1.62 (m, 2 H), 1.52 (m, 1 H), 1.28–1.11 (m, 12 H), 0.91
(m, 6 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 173.1, 173.0,
170.8, 170.6, 170.5, 170.1, 170.0, 169.8, 169.7, 169.4, 169.3, 78.5,
78.3, 73.5, 73.1, 70.5, 70.2, 68.4, 68.3, 61.8, 61.7, 54.6, 54.2, 52.1,
52.0, 50.9, 48.5, 48.3, 42.8, 42.6, 42.1, 41.3, 41.2, 38.7, 37.8, 23.5,
23.4, 23.2, 23.1, 22.9, 22.7, 21.9, 21.8, 21.3, 21.0, 20.8, 20.7, 20.6,
20.5, 20.4 ppm. ESI: m/z (%) = 739.7 (100) [M+ + Na].
C32H52N4O14 (716.78): calcd. C 53.62, H 7.31, N 7.82; found C
53.61, H 7.33, N 7.80.
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-[4-(benzyloxy)-2-(3-tert-butyl-
1-{[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-
d][1,3]dioxol-4-yl]methyl}ureido)-4-oxobutanamido]tetrahydro-2H-
pyran-3,4,5-triyl Triacetate (4p): Obtained as a mixture of two dia-
stereoisomers; R = 0.21 (hexane/EtOAc, 50:50). FTIR (neat): ν
˜
f
= 3333, 1727, 1718 cm–1. 1H NMR (400 MHz, CDCl3): δ [major
diastereoisomer (S)] = 7.50 (d, J = 9.6 Hz, 1 H), 7.30 (m, 5 H),
5.25 (dd, J = 9.2, 9.2 Hz, 1 H), 5.22 (dd, J = 9.2, 9.2 Hz, 1 H), 5.08
(d, J = 2.4 Hz, 2 H), 5.04–4.88 (m, 3 H), 4.77 (m, 1 H), 4.62 (dd,
J = 6.0, 1.2 Hz, 1 H), 4.54 (d, J = 6.4 Hz, 1 H), 4.45 (dd, J = 6.0,
2.0 Hz, 1 H), 4.23–4.16 (m, 2 H), 4.01 (dd, J = 12.4, 2.4 Hz, 1 H),
3.75 (m, 1 H), 3.34 (s, 3 H), 3.28 (dd, J = 10.4, 6.8 Hz, 1 H), 3.19
(m, 2 H), 2.77 (dd, J = 16.8, 7.2 Hz, 1 H), 2.02 (s, 3 H), 2.00 (s, 3
H), 1.98 (s, 3 H), 1.95 (s, 3 H), 1.43 (s, 3 H), 1.42 (s, 3 H), 1.29 (s,
9 H) ppm; δ [minor diastereoisomer (R)] = 7.30 (m, 6 H), 5.27 (dd,
J = 9.2, 9.2 Hz, 1 H), 5.23 (dd, J = 9.2, 9.2 Hz, 1 H), 5.07 (d, J =
2.4 Hz, 2 H), 5.04–4.88 (m, 3 H), 4.77 (m, 1 H), 4.62 (dd, J = 6.0,
1.2 Hz, 1 H), 4.56 (d, J = 6.4 Hz, 1 H), 4.49 (dd, J = 6.0, 2.0 Hz,
1 H), 4.23–4.16 (m, 2 H), 4.01 (dd, J = 12.4, 2.4 Hz, 1 H), 3.75 (m,
1 H), 3.32 (s, 3 H), 3.28 (dd, J = 10.4, 6.8 Hz, 1 H), 3.19 (m, 1 H),
3.00 (dd, J = 16.8, 8.8 Hz, 1 H), 2.66 (dd, J = 16.8, 6.0 Hz, 1 H),
2.01 (s, 3 H), 2.00 (s, 3 H), 1.97 (s, 3 H), 1.96 (s, 3 H), 1.47 (s, 3 H),
1.43 (s, 3 H), 1.26 (s, 9 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ
= 171.9, 171.6, 170.9, 170.8, 170.5, 170.4, 169.8, 169.5, 169.4, 157.5,
157.4, 135.7, 135.6, 128.5, 128.4, 128.2, 128.1, 113.4, 112.8, 112.2,
110.4, 110.2, 109.9, 87.2, 86.7, 86.5, 85.4, 84.3, 84.2, 82.1, 82.0,
81.6, 78.2, 78.1, 73.6, 73.5, 73.4, 73.3, 70.6, 70.5, 68.2, 66.6, 61.8,
56.1, 55.8, 55.0, 51.2, 51.1, 50.3, 43.0, 34.3, 33.6, 29.5, 29.2, 29.0,
26.6, 26.5, 26.4, 25.1, 24.9, 24.8, 20.5, 20.4 ppm. ESI: m/z (%) =
860.7 (100) [M+ + Na], 838.7 (1) [M+ + H]. C39H55N3O17 (837.87):
calcd. C 55.91, H 6.62, N 5.02; found C 55.88, H 6.60, N 5.03.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H NMR, 13C NMR, and ESI-MS spectra of all
new compounds. Copies of 1H-1H COSY spectra of 4a and (S)-4n.
1
Variable-temperature H NMR spectra of 4a in [D6]DMSO.
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˜
f
1730, 1720 cm–1 1H NMR (400 MHz, CDCl3): δ [major dia-
.
stereoisomer (S)] = 7.35 (m, 7 H), 5.32 (dd, J = 9.6, 9.6 Hz, 1 H),
5.20 (dd, J = 9.2 Hz, 1 H), 5.10 (m, 3 H), 4.94 (dd, J = 9.6, 9.6 Hz,
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= 12.4, 2.4 Hz, 1 H), 3.25 (dd, J = 17.6, 4.0 Hz, 1 H), 2.63 (dd, J
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 2386–2397

Multicomponent Synthesis of N-Glycosyl Conjugates
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[18] To investigate whether N-glycosylamine 1a acts as a base to
produce the thermodynamic mixture of diastereoisomers, we
treated the equimolar mixture of 4a obtained in the reaction
carried out in DMF (entry 5, Table 1) with 1a under the reac-
tion conditions (0 °C, CH3CN/DMF). After 3 h, the mixture of
diastereoisomers was recovered with the same equimolar ratio.
Moreover, in a separate experiment, when a ca. 2:1 diastereo-
isomeric mixture of 4a was treated with secondary and tertiary
amines, under the same reaction condition, we did not observe
any change in the diastereoisomeric ratio. Only by treating a
ca. 2:1 diastereoisomeric mixture of 4a with stronger bases,
such as aqueous NaOH, was epimerisation detected. These re-
sults suggest that the process is irreversible, leading to the for-
mation of the kinetic mixture of diastereoisomers.
[19] In this reaction we also detected the regioselective formation
of the corresponding hydantoin derivative.
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with glycosylamine 1a, affording conjugate (S)-13, which, after
Boc-deprotection, was treated with tert-butyl isocyanate 10a to
produce (S)-10, which corresponds to the major diastereoiso-
mer obtained with our MC process.
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[14] The stereochemistry of the major diastereoisomer was assessed
by chemical correlation.
[15] The exact assignment of the 1H NMR signals of both dia-
stereoisomers 4a was achieved on the basis of 1H-1H COSY
spectra (see the Supporting Information).
[16] Indeed, with chiral α-amino esters or peptides as nucleophiles
we never obtained any diastereoselection (see ref.[13]).
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Received: December 19, 2013
Published Online: February 11, 2014
Eur. J. Org. Chem. 2014, 2386–2397
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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