Three-component, one-pot sequential synthesis of glyco-hydantoin conjugates

Article abstract of DOI:10.1039/c1ob06312j

The development of new methods for linking sugars to heterocycles and peptides is an attractive area of research because glyco-conjugates play important roles in biology and medicine and are indispensable tools for probing several processes. Herein we report a one-pot, three-component sequential procedure for the synthesis of a novel class of glyco-conjugates, i.e. glyco-hydantoin conjugates, in high yields and very mild conditions, using readily accessible starting materials. We also demonstrated that some of the glyco-hydantoin conjugates obtained are synthons for the preparation of a novel class of glyco-pseudopeptides in which the amino acid is tethered to the sugar through the hydantoin ring. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06312j

Organic &
Biomolecular
Chemistry
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Volume 9 | Number 24 | 21 December 2011 | Pages 8205–8512
ISSN 1477-0520
FULL PAPER
Alessandro Volonterio et al.
Three-component, one-pot
sequential synthesis of
glyco-hydantoin conjugates
1477-0520(2011)9:24;1-R

Organic &
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PAPER
Three-component, one-pot sequential synthesis of glyco-hydantoin conjugates†
Maria Cristina Bellucci,a Alessandra Ghilardib and Alessandro Volonterio*b
Received 2nd August 2011, Accepted 14th September 2011
DOI: 10.1039/c1ob06312j
The development of new methods for linking sugars to heterocycles and peptides is an attractive area of
research because glyco-conjugates play important roles in biology and medicine and are indispensable
tools for probing several processes. Herein we report a one-pot, three-component sequential procedure
for the synthesis of a novel class of glyco-conjugates, i.e. glyco-hydantoin conjugates, in high yields and
very mild conditions, using readily accessible starting materials. We also demonstrated that some of the
glyco-hydantoin conjugates obtained are synthons for the preparation of a novel class of
glyco-pseudopeptides in which the amino acid is tethered to the sugar through the hydantoin ring.
and/or selectivity, may appear due to specific interactions between
Introduction
glycoside residues and bioreceptors.6
The development of new multicomponent (MC) coupling pro-
Among different heterocycles, hydantoins have been widely
used in biological screenings resulting in numerous pharma-
allow the efficient construction of elaborate molecules from simple
ceutical applications. In fact, many derivatives have been iden-
cesses has attracted intense interest in recent years.1 Such processes
tified as anti-convulsants7 and antimuscarinics,8 antiulcer and
antiarrythmics,9 antiviral, antidiabetics,10 serotonin and fibrino-
gen receptor antagonists,11 inhibitors of the glycine binding site of
the NMDA receptor,12 and antagonists of leukocyte cell adhesion
acting as allosteric inhibitors of the protein–protein interaction.13
Moreover, substituted hydantoins are important building blocks
for the synthesis of non-natural amino acids both in racemic
form by alkaline degradation14 and in an enantioselective way
by enzymatic resolution.15 The observed activities usually do not
arise from the heterocycle itself but from the different ligands that
have been attached to it. For this reason, there is a lot of interest
in developing new strategies for a straightforward synthesis of
selectively substituted hydantoins both in solution and in solid
phase.16 However, quite surprisingly, the synthesis of hydantoin
glycoconjugates is an issue that has been almost ignored so far,
except for spirohydantoins incorporated at the anomeric position
of the carbohydrates.17
Within the frame of a project aimed at developing new domino
processes for the synthesis of small heterocycles, we recently
demonstrated that carbodiimides, when treated with suitable
carboxylic acids such as activated a,b-unsaturated and a-bromo
carboxylic acids, are useful reagents for the synthesis, in very
mild conditions, of diversely substituted hydantoins through
a regiospecific domino condensation–aza-Michael–N→O acyl
migration one-pot process (Scheme 1).18
precursors in a minimum number of steps, and many are ideally
suited for the generation of structurally diverse libraries of small
molecules. In particular, “one-pot” MC sequential syntheses, in
which a number (≥2) of synthetic steps involving three or more
reactants are carried out in the same flask without isolation
of any intermediate, feature a high degree of reaction mass
efficiency and are especially suitable in combinatorial chemistry
and diversity-oriented synthesis programs, thus playing a central
role in the development of modern synthetic methodology for
pharmaceutical and drug discovery research.2 In this context,
since carbohydrates have secured their place in pharmaceutical
chemistry, in biopharmaceuticals as well as in small molecule
chemistry, development of new methods for linking sugars to
heterocycles, peptides or proteins is an active area of research.3
However, despite the advances made recently in discovering
new MC reactions for the construction of different arrays of
heterocyclic compounds,4 there is a need to broaden the scope of
carbohydrate-based one-pot MC processes for the construction
of novel carbohydrate conjugates. In fact, the resulting sugar-
heterocycle conjugates are expected to be important structural
scaffolds in drug discovery because, apart from their different
pharmacodynamic effects, these hybrid molecules often exhibit
unusual pharmacokinetic properties, such as tissue permeability.5
In addition, new biological properties, both in terms of activity
Herein we wish to report on the extension of this chemistry
to the synthesis of a large array of interesting glyco-hydantoin
conjugates, some of them have been further functionalized for
the synthesis of novel glyco-hydantoin-pseudopeptide conjugates.
We envisioned that the transformation of easily accessible sugar-
azides and isocyanates to glyco-hydantoin conjugates could be
accomplished in a one-pot, MC sequential fashion by forming
aDipartimento di Chimica Agroalimentare, Universita` degli Studi di Milano,
via Celoria 2, 20133 Milano, Italy
bDepartment of Chemistry, Materials and Chemical Engineering “Giulio
Natta”, Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy.
E-mail: alessandro.volonterio@polimi.it; Fax: +39 0223993080; Tel: +39
0223993136
† Electronic supplementary information (ESI) available: Copies of 1H and
13C NMR spectra of all new compounds. See DOI: 10.1039/c1ob06312j
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Since carbodiimides could be easily synthesized in high yield
by Staudinger reaction, we decided to exploit such reaction in
order to perform our synthesis in a MC sequential fashion. The
first attempts were made by using 4,4,4-trifluoro-3-trifluoromethyl
(Tfm)-crotonic acid 3a since it was already known that this
acid readily reacts with glyco-carbodiimides giving rise to the
formation, in the presence of a nucleophile, of peptide-sugar
conjugates incorporating hexafluorovaline.22 Accordingly, when
azido-galactose 1a was reacted with tert-butyl isocyanate 2a
in CH3CN and in the presence of triphenylphosphine, car-
bodiimide and triphenylphosphine oxide were cleanly formed
(TLC monitoring).23 By adding to the resulting solution 2,4,6-
trimethylpyridine (sym-collidine, TMP) followed by acid 3a we
were able to obtain in high yield the desired diastereoisomeric
conjugates 4a in a 3.5 to 1.0 diastereoisomeric ratio (d.r.) (entry 1,
Table 1).24 As expected, the reaction was completely regioselective,
with only compounds 4a formed by the nucleophilic attack
of the less sterically hindered primary alkyl carbodiimide N-
substituent, i.e. the glycosyl substituent, during the intramolecular
aza-Michael step.
Scheme 1 One-pot domino process for the synthesis of substituted
hydantoins.
Starting with another primary glycosyl azide, namely methyl 5-
azido-5-deoxy-2,3-O-isopropylidene-b-ribofuranoside 1b, the re-
action worked nicely as well, producing only the regioisomeric
glyco-hydantoin conjugates 4b in high yield and in an almost
equimolecular d.r. (entry 2, Table 1).
in situ the reactant carbodiimide through the Staudinger (aza-
Wittig) reaction19 (Scheme 2).
We then tried the reaction with in situ generated “strongly
asymmetric” carbodiimides. Accordingly, by treating glyco-azide
1a with phenyl isocyanate 2b in the presence of triphenylphosphine
we detected the clean formation of the corresponding carbodi-
imide after 3 h in CH3CN at rt. After the addition of TMP
followed by acid 3a we obtained the formation, in high yields and
with complete control of the regioselection, of the corresponding
diastereoisomeric glyco-hydantoins 4c (d.r. 3.2 to 1.0) arising from
the nucleophilic attack of the N-alkyl carbodiimide substituent in
the aza-Michael step (entry 3, Table 1). The reaction with strongly
asymmetric carbodiimides was shown to be highly versatile since
it worked well with either electron-rich N-aryl carbodiimides, such
as N-p-methoxyphenyl, N¢-galactosyl carbodiimide (entry 4, Table
1), and with electron-poor N-aryl carbodiimides, such as N-p-
trifluoromethylphenyl, N¢-galactosyl carbodiimide (entry 5, Table
1) giving rise to the formation of adducts 4d,e respectively, with
almost the same d.r. obtained with the unsubstituted N-phenyl
carbodiimide. However, while the reaction with electron poor
N-p-trifluoromethylphenyl carbodiimide derivative was totally
regioselective, in the reaction with the carbodiimide bearing the
more nucleophilic N-p-methoxyphenyl group a small amount (less
than 15%) of the regioisomer arising from the nucleophilic attack
of the aniline moiety was observed.
In order to expand the scope of this methodology, we de-
cided to explore the reaction with other acids, starting with
differently substituted a-bromo acetic acids. In this context, a-
bromo phenylacetic acid 3b and a-bromo-4-fluorophenylacetic
acid 3c were already known to be very reactive in the presence
of carbodiimides even in low polarity solvents such as DCM.18c
Thus, azides 1a and 1b were reacted with t-butyl isocyanate 2a and
Ph3P in CH2Cl2 as a solvent, giving rise to the formation of the
corresponding carbodiimides as well. The resulting solutions were
treated with TMP followed by acids 3b,c, respectively, affording
an equimolar diastereoisomeric mixture of only the regioisomeric
Scheme 2 Retrosynthetic analysis.
Results and discussion
In a previous work, we have defined “strongly asymmetric” those
carbodiimides that have two N-substituents very different in
terms of electronic features, such as an aromatic and an alkyl
substituent, and “weakly asymmetric” those carbodiimides that
have two alkyl substituents at the nitrogen atoms very different
in terms of steric bulkiness.18b We have demonstrated that both
strongly and weakly asymmetric carbodiimides react with suitable
carboxylic acids giving rise to the formation of hydantoins with
total regioselectivity in most cases. Thus, we decided to exploit
such reactivity for the synthesis of glyco-hydantoin conjugates
in a highly regioselective manner starting from carbodiimides
having a N-primary glyco-substituent, such as 6-aminohexoses
and 5-aminopentoses, and a N¢-tertiary or -aryl substituent.20
Apart from regiochemical concern, the choice to use N-primary
glyco-substituents is very intriguing because linking heterocycles
or peptides at the primary positions of 6-aminohexoses and
5-aminopentoses provides conjugates with enzymatically stable
artificial linkages, also considering the fact that the –CHNH2
moiety present in these sugars might mimic some elements of
the glycine structure.21
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Table 1 Three-component sequential synthesis of glyco-hydantoin conjugates
Entry
1
Azide
Isocyanate
Acid
Solvent
CH3CN
Method
Product
d.r.
Yield(%)a
89
A
3.5 : 1.0
2
3
CH3CN
CH3CN
A
A
1.5 : 1.0
3.2 : 1.0
83
65
4
5
CH3CN
A
A
3.2 : 1.0
69b
CH3CN
3.2 : 1.0
64
6
7
CH2Cl2
A
A
1.0 : 1.0
1.0 : 1.0
78
64
CH2Cl2
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Table 1 (Contd.)
Entry
8
Azide
Isocyanate
Acid
Solvent
CH2Cl2
Method
Product
d.r.
Yield(%)a
73b
A
1.0 : 1.0
9
DMF
A
/
89
10
11
DMF
DMF
B
B
/
/
69
71
12
13
CH3CN
CH3CN
A
A
2.5 : 1.0
1.0 : 1.0
87
82
14
CH3CN
A
1.2 : 1.0
76b
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Table 1 (Contd.)
Entry Azide
15
Isocyanate
Acid
Solvent
CH3CN
Method
Product
d.r.
Yield(%)a
81
A
2.5 : 1.0
16
17
18
CH3CN
CH3CN
CH3CN
A
B
B
/
95
69
72
1.0 : 1.0
1.0 : 1.0
a Overall yields. b A small amount of the other regioisomers was detected by 1H NMR.
glyco-hydantoin conjugates 4f,g, respectively, which arose from
the nucleophilic attack of the primary glycosyl amine moiety.
Also with these acids, the reaction with “strongly asymmetric”
carbodiimides resulted to be regioselective. In fact, in situ formed
N-galactosyl, N¢-p-methoxyphenyl carbodiimide reacted with acid
3b in the same conditions described above, i.e. in DCM at rt,
producing the regioisomers 4h in an equimolar ratio and almost
quantitative yields (entry 8, Table 2).25
a-Bromo dimethylacetic acid 3d, considering the inductive
electron donating effect of the two methyl groups, was expected
to be much less reactive than the corresponding arylacetic acids
3b,c in the intramolecular aza-Michael step. Indeed, when reacted
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Table 2 Three-component sequential synthesis of glycosyl-hydantoin conjugates
Entry Azide
1
Isocyanate Acid
Solvent Producta
CH3CN
Yield (%)b
75
2
CH3CN
71
3
4
CH3CN
CH3CN
78
68
5
6
CH3CN
CH3CN
72
69
7
DMF
65
a Equimolecular mixture of diastereoisomers. b Overall yields.
with the carbodiimide arising from Staudinger reaction between
galactose-azide 1a and isocyanate 2a, we obtained the formation
of only the regioisomeric N-acylurea derivative 5i in high yields
even when the reaction was performed in highly polar solvent
such as DMF (entry 9, Table 1). Evidently, in this case the
O→N acyl migration process is favorable compared to the slow
intramolecular aza-Michael step (see the mechanism depicted in
Scheme 1). However, treatment of compound 5i with a base,
such as NaOH, triggered the formation of the corresponding
hydantoin 4i in almost quantitative yields (data not shown).
Moreover, the cyclization step could be performed in situ by adding
the base solution to the reaction mixture once the formation
of the N-acylurea intermediate has occurred. Indeed, through a
three component sequential procedure consisting of the formation
of the carbodiimide starting from azide 1a and isocyanate 2a,
reaction with acid 3d, and cyclization of the resulting N-acylurea
intermediate 5i triggered by the addition of a 2 N aqueous solution
of NaOH, we obtained the direct formation of the regioisomeric
glyco-hydantoin 4i, as the only product, in high yield (entry 10,
Table 1). To our surprise, when the latter methodology was used
starting with azide 1b, we obtained, at the end of the process,
an equimolar mixture of the two regioisomeric glyco-hydantoin
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conjugates 4j,k (entry 11, Table 1). Probably, the sterically and
electronic features of the ribose moiety and the t-butyl substituent
are not different enough to render the O→N acyl migration step
regioselective, on the contrary to what happens in the aza-Michael
step (see for instance entries 2 and 7, Table 1).
of 6-aminohexoses and 5-aminopentoses, we could not prepare
glycosyl-hydantoin conjugates at the anomeric carbon since the
corresponding carbodiimides were not reactive at all. Thus, we
decided to synthesize glycosyl-azides 1c,d in which the anomeric
carbons of the sugars are tethered to a simple linker bearing a
primary azido group (Scheme 3).
Finally, we decided to explore the reactivity of fumaric acid
monoesters. As expected, fumaric acid ethyl ester 3e reacted
smoothly with carbodiimides arising from Staudinger reaction
between primary glyco-azides 1a,b and t-butyl isocyanate 2a,
giving rise to the formation of glyco-conjugates 4l,m, respectively,
as the only regioisomers and in high yields by performing the
reaction in CH3CN as solvent (entries 12 and 13, Table 1). These
reactions were slightly less diastereoselective (2.5 to 1.0 and 1.0
to 1.0 d.r. respectively) compared to the corresponding reactions
with acid 3a, probably because the activating ester moiety is
less sterically hindered that the two trifluoromethyl groups.26
Similarly, “strongly asymmetric” carbodiimide in situ generated
from azide 1a and p-methoxyisocyanate 2c produced an equimolar
mixture of two diastereoisomeric glyco-hydantoins 4n as the major
regioisomers27 (entry 14, Table 1).
Scheme 3 Synthesis of glyco-azides 1c,d.
Accordingly, acetylation of glucose 7 and lactose 8 followed
by selective bromination of the anomeric carbons and hydrolysis,
led us to prepare derivatives 9,10, respectively, which were
submitted to O-glycosylation, via trichloroacetimidate, with 3-Br-
propanol and finally transformed to the targets glycosyl-azides
1c,d by nucleophilic displacement of the bromine atom. By the
use of the 3-azido-propanol linker, we were able to synthesize
glycosyl-hydantoin conjugates 6 in a very efficient way (Table
2). Accordingly, glucosyl-azide 1c and lactosyl-azide 1d reacted
smoothly with t-butyl isocyanate 2a in the presence of Ph3P leading
to the clean formation of the corresponding carbodiimide (TLC
monitoring) along with Ph3PO. After addition of TMP followed
by acid 3a, two pairs of diastereoisomers 6a and 6b, respectively,
were obtained in high yields (entries 1 and 2, Table 2). Also
in this case, the reactions were completely regioselective giving
rise to the formation of only the regioisomers arising from the
nucleophilic attack of the nitrogens bearing the primary N-alkyl
substituents, i.e. the glycosyl substituents. On the contrary, the
process was completely non stereoselective (d.r. 1.0 : 1.0 in both
cases). However, this was not surprising since the chiral sugar
moieties in these reactions are quite far from the incipient new
stereogenic center forming during the intramolecular aza-Michael
step. Gratifyingly, the process worked very well also with fumaric
acid monoesters 3e,f producing only the regioisomeric glycosyl-
hydantoin conjugates 6c–f in high yields (entries 3–6, Table 2).
Finally, 1-bromo-dimethylacetic acid 3d also reacted efficiently
with weakly asymmetric carbodiimide produced from azide 1c and
isocyanate 2a, giving rise to the formation of the only regioisomeric
glycosyl-hydantoin conjugate 6g (entry 8, Table 2). It is worth
noting that in this case we did not observe the intermediate
formation of the corresponding N-acyl urea derivative, so it was
not necessary to treat the solution with a base to trigger the
cyclization of the latter, as happened when azido-galactose 1a
was used (entry 18, Table 1). Probably, the distance between the
bulky glyco moiety and the reactive site allows the intramolecular
aza-Michael reaction to occur even if the electrophilic carbon on
the acid is not so reactive.
Since glyco-hydantoin conjugates arising from the reaction of
fumaric acid monoesters are very intriguing synthons because they
could be further functionalized at the ester moiety after simple
hydrolysis (see below), we decided to explore the reactivity of
other derivatives having different ester protecting groups, such
as benzyl and t-butyl esters. In such a way, it is possible to
design glyco-hydantoin conjugates having orthogonal protecting
groups at the glyco and ester moieties. Accordingly, fumaric acid
monobenzyl ester 3f reacted efficiently with carbodiimide derived
from the reaction between azide 1a and isocyanate 2a producing
in the same condition, i.e. CH3CN as solvent, regioisomeric
hydantoins 4o in very good yields (entry 15, Table 1). To our
surprise, fumaric acid mono-t-butyl ester 3f reacted with the same
kind of carbodiimides leading to the formation of an equimolar
mixture of the two regioisomeric N-acylurea derivatives 5p,q
in almost quantitative yield (entry 16, Table 1). Probably, the
sterically hindered t-butyl ester hampers the nucleophilic aza-
Michael addition, rendering the O→N acyl migration the only
operative mechanism. Moreover, as occurred with acid 3d, the
O→N acyl migration mechanism involving N-ribofuranosyl, N¢-
t-butyl carbodiimide was not regioselective. Also in this case,
by treating the solution mixture at 0 ◦C with a 2 N aqueous
solution of NaOH, we obtained the direct formation of the
regioisomeric glyco-hydantoins 4p,q in quantitative yields and as
an equimolecular mixture of two diastereoisomers28 (entry 17,
Table 1). The same three component sequential procedure could
be used for the synthesis of N-glyco, N¢-aryl hydantoins such as
4r in high yield and with total control of the regioselectivity (entry
18, Table 1).
The preparation of compounds in which a glycosyl residue
is linked to another sugar or nonsugar moiety, such as amino
acids and heterocyles, through the anomeric carbon is very
important since the resulting compounds have application in
medicinal chemistry as leads for new drug discovery and for
improvement of known drugs acting as inhibitors of carbohydrate
processing enzymes, and in glycobiology for studying the role
of carbohydrates in biological process.5,6 Although through this
procedure we can have access to a large array of glyco-hydantoin
derivatives in which the conjugation arises at the primary positions
Some of the derivatives described above, namely the glyco-
hydantoin conjugates derived from the reaction of fumaric acid
monoesters 3e–g, could be further modified to synthesize a novel
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class of pseudopeptide-sugar conjugates where the glyco moiety
is tethered to the peptidic chain through the hydantoin ring.
This could be accomplished by hydrolyzing the ester function
and coupling the resulting acid with amino acids or peptides.
Accordingly, glyco-hydantoin conjugate 4l was treated with a
1 N aqueous solution of NaOH and the resulting acid coupled
with alanine benzyl ester to obtain the sugar-pseudopeptide
conjugate 11, while benzyl ester derivatives 6e,f were hydrolyzed by
catalytic hydrogenation and coupled with leucine and isoleucine
benzyl esters, respectively, giving rise to the formation of glycosyl-
pseudopeptides conjugates 12 and 13, in all cases with very good
overall yields (Scheme 4). It is worth noting that since the MC
sequential process works efficiently with fumaric acid monoethyl,
monobenzyl, and mono-t-butyl esters, one can always have the
possibility to hydrolyze chemoselectively the ester function while
maintaining the protecting groups on the glyco moiety, or vice
versa, by choosing suitable starting materials. While for the
synthesis of the pseudoglycopeptides described above this is
not necessary, the possibility to accomplish a chemoselective
deprotection on our glyco-conjugates is a surplus value of our
strategy because selective and efficient protection and deprotection
often plays a central role in the completion of multistep syntheses
of organic molecules.
The operational simplicity, the very good chemical yields and the
mild conditions combined with favorable atom economy aspects
and a small number of synthetic steps, render this strategy attrac-
tive and promising for the preparation of a novel class of glyco-
conjugates and particularly suitable for solid phase/combinatorial
chemistry. Also investigation of these latter issues are currently in
progress.
Experimental section
General methods
Commercially available reagent-grade solvents were employed
without purification. Primary glyco-azides 1a,b30 and fumaric acid
monoesters 3e–g31 were prepared following reported procedures.
1H NMR spectra were run on spectrometers 250, 400 or 500 MHz.
Chemical shifts are expressed in ppm (d), using tetramethylsilane
1
(TMS) as internal standard for H and 13C nuclei (dH and dC
=
0.00). High-resolution MS spectra were recorded with a FT-
ICR (Fourier Transform Ion Ciclotorn Resonance) instrument,
equipped with an ESI source, or a standard MS instrument,
equipped with an EI source.
General procedure for the three-component sequential synthesis of
glyco-hydantoin conjugates, METHOD A
To a stirred solution of glycosyl azide (1.2 equiv.) in the organic
solvent (0.1 M), neat isocyanate (1.2 equiv.) followed by a solution
of Ph3P (1.2 equiv.) in a minimum amount of the same solvent were
added at rt. After the formation of the corresponding carbodiimide
was complete (TCL monitoring), TMP (1 equiv.) followed by a
solution of the acid (1 equiv.) in a minimum amount of the same
solvent were added. The resulting solution was stirred until the
reaction was complete (TLC monitoring) leaving the temperature
at rt. A 1 N HCl aqueous solution was added and the mixture
extracted three times with AcOEt. The combined organic layers
were dried over anhydrous Na2SO4, filtered, concentrated under
vacuum and the crude purified by flash chromatography.
Scheme 4 Synthesis of sugar-pseudopeptide conjugates.
Conclusions
In conclusion, we have developed an efficient process for the
synthesis of libraries of glyco-hydantoin conjugates through a MC
sequential process involving simple and readily accessible starting
materials such as glyco-azides, isocyanates and suitable carboxylic
acids. The reaction is totally regioselective in almost all cases when
both strongly and weakly carbodiimide intermediates are involved.
These multifunctional compounds could be used to increase
the diversity of sugar frameworks and may find applications as
potential glycomimetics and/or peptidomimetics. For instance, it
is worth noting that b-ribofuranose is the central sugar of many
aminoglycoside antibiotics, such as neomycin and paromomycin,
and that their 5¢¢ position (5 position of ribofuranose) has been
often functionalized in order to obtain more potent/selective
antibiotics.29 The functionalization of such a position by our MC
methodology is currently in progress in our laboratories.
General procedure for the three-component sequential synthesis of
glyco-hydantoin conjugates, METHOD B
To a stirred solution of glycosyl azide (1.2 equiv.) in the organic
solvent (0.1 M), neat isocyanate (1.2 equiv.) followed by a solution
of Ph3P (1.2 equiv.) in a minimum amount of the same solvent were
added at rt. After the formation of the corresponding carbodiimide
was complete (TCL monitoring), TMP (1 equiv.) followed by
a solution of the acid (1 equiv.) in a minimum amount of the
same solvent were added. The resulting solution was stirred until
the reaction was complete and the formation of the N-acylurea
derivative was detected (TLC monitoring). The solution was
cooled to 0 ◦C and a 2 N aqueous solution of NaOH (10% in
volume) was added and the mixture stirred for 30 min at the same
temperature. A 1 N HCl aqueous solution was added until acidic
pH was obtained, the temperature raised to rt, and the mixture
extracted three times with AcOEt. The combined organic layers
were dried over anhydrous Na2SO4, filtered, concentrated under
vacuum and the crude purified by flash chromatography.
Finally, we have also demonstrated that glyco-hydantoin conju-
gates arising from fumaric acid monoesters are intriguing synthons
for the synthesis of a novel class of glycosyl-pseudopeptides
through a simple chemoselective hydrolysis–coupling procedure.
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3-tert-Butyl-5-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1-(((3aR,5aS,
8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
b:4¢,5¢-d]pyran-5-yl)methyl)imidazolidine-2,4-dione, 4a
5.49 (d, J = 4.8 Hz, 1H), 5.16 (s, 1H), 4.63 (dd, J = 7.6 and 2.4
Hz, 1H), 4.33 (dd, J = 4.9 and 2.4 Hz, 1H), 4.27 (d, J = 10.0 Hz,
1H), 4.20 (dd, J = 8.0 and 1.8 Hz, 1H), 3.94 (m, 2H), 3.55 (dd,
J = 15.2 and 10.4 Hz, 1H), 1.46 (s, 6H), 1.35 (s, 3H), 1.31 (s, 3H);
13C-NMR (100.6 MHz, CDCl3): d = 169.2, 155.9, 131.4, 129.3,
128.8, 126.3, 110.1, 109.2, 96.3, 71.5, 70.9, 70.5, 66.8, 57.5, 49.6
(septet, J = 28.4 Hz), 42.5, 25.9, 25.8, 25.0, 24.6, the CF3 signal was
obscured due to its low intensity; ESI (m/z) 591.0 [M++Na, (100)],
569.1 [M++1, (20)]; HRMS calcd for [C24H26F6N2O7]: 568.1644,
found: 568.1650. Minor diast.: Rf 0.27 (hexane : AcOEt 80 : 20);
Major diastereoisomer, Rf 0.52 (hexane : AcOEt 80 : 20); [a]2D5:
1
-34.3 (c 0.5, CHCl3); FTIR (neat) n 1789, 1727 cm-1; H-NMR
(400 MHz, CDCl3): d = 5.40 (d, J = 5.2 Hz, 1H), 4.51 (dd, J =
7.6 and 2.0 Hz, 1H), 4.37 (s, 1H), 4.19–4.12 (m 2H), 4.09 (dd, J =
8.0 and 1.6 Hz, 1H), 3.79 (m, 1H), 3.75 (septet, J = 8.8 Hz, 1H),
3.20 (dd, J = 15.2 and 3.6 Hz, 1H), 1.51 (s, 9H), 1.41 (s, 3H), 1.34
(s, 3H), 1.23 (s, 3H), 1.22 (s, 3H); 13C-NMR (100.6 MHz, CDCl3):
d = 170.3, 157.9, 122.9 (q, J = 280.7 Hz), 122.3 (q, J = 282.7),
109.5, 108.5, 96.3, 71.4, 71.1, 70.4, 64.6, 58.6, 55.1, 49.7, 49.4, 49.1,
42.1, 28.3, 25.9, 25.8, 24.7, 24.1; ESI (m/z) 571.2 [M++Na, (100)],
549.1 [M++1, (32)]; HRMS calcd for [C22H30F6N2O7]: 548.1957,
found: 548.1944. Minor diast.: Rf 0.30 (hexane : AcOEt 70 : 30);
1
[a]2D5: -12.6 (c 0.5, CHCl3); FTIR (neat) n 1792, 1727 cm-1; H-
NMR (400 MHz, CDCl3): d = 7.46 (m, 2H), 7.37 (m, 3H), 5.50
(d, J = 4.9 Hz, 1H), 4.82 (s, 1H), 4.61 (d, J = 8.0 Hz, 1H), 4.41
(dd, J = 15.2 and 6.9 Hz, 1H), 4.28 (m, 2H), 4.04 (m, 1H), 3.97
(septet, J = 8.7 Hz, 1H), 3.42 (dd, J = 15.2 and 3.1 Hz, 1H), 1.50 (s,
3H), 1.41 (s, 3H), 1.32 (s, 6H); 13C-NMR (125.7 MHz, CDCl3); d =
168.8, 156.6, 131.6, 129.2, 128.5, 128.2, 109.6, 108.7, 96.4, 71.6,
71.3, 70.6, 70.5, 64.8, 55.7, 49.5 (septet, J = 28.4 Hz), 42.7, 25.9,
24.7, 24.3, the CF3 signal was obscured due to its low intensity;
ESI (m/z) 591.0 [M++Na, (100)], 569.1 [M++1, (13)]; HRMS calcd
for [C24H26F6N2O7]: 568.1644, found: 568.1652.
1
[a]2D5: -15.4 (c 0.3, CHCl3); FTIR (neat) n 1775, 1726 cm-1; H-
NMR (400 MHz, CDCl3): d = 5.36 (d, J = 5.0 Hz, 1H), 4.74 (s,
1H), 4.53 (dd, J = 7.6 and 2.6 Hz, 1H), 4.21 (dd, J = 5.0 and 2.3
Hz, 1H), 4.08 (d, J = 8.2 Hz, 2H), 3.73–3.69 (m, 2H), 3.34 (dd, J =
15.4 and 10.6 Hz, 1H), 1.50 (s, 9H), 1.37 (s, 3H), 1.35 (s, 3H), 1.26
(s, 3H), 1.21 (s, 3H); 13C-NMR (125.7 MHz, CDCl3): d = 170.7,
157.5, 109.9, 109.0, 96.1, 71.5, 70.8, 70.3, 66.6, 58.8, 56.9, 49.4,
49.1, 41.9; ESI (m/z) 571.2 [M++Na, (100)], 549.1 [M++1, (12)];
HRMS calcd for [C22H30F6N2O7]: 548.1957, found: 548.1947.
5-(1,1,1,3,3,3-Hexafluoropropan-2-yl)-3-(4-methoxyphenyl)-1-
(((3aR,5aS,8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]-
dioxolo[4,5-b:4¢,5¢-d]pyran-5-yl)methyl)imidazolidine-2,4-dione, 4d
3-tert-Butyl-5-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1-(((3aS,4R,
6R,6aS)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-
4-yl)methyl)imidazolidine-2,4-dione, 4b
Mixture of two diast., Rf 0.22 (hexane : AcOEt 80 : 20); FTIR (neat)
1
n 1778, 1722 cm-1; H-NMR (400 MHz, CDCl3), one diast.: d =
7.11 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.39 (d, J = 4.9
Hz, 1H), 4.87 (s, 1H), 4.55 (m, 1H), 4.28–4.03 (m, 4H), 3.74 (s,
3H), 3.65 (septet, J = 7.8 Hz, 1H), 3.47 (t, J = 13.8 Hz, 1H), 1.53 (s,
1H), 1.43 (s, 3H), 1.41 (s, 3H), 1.27 (s, 3H); 1H-NMR (400 MHz,
CDCl3), other diast.: d = 7.13 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6
Hz, 2H), 5.43 (d, J = 4.9 Hz, 1H), 4.84 (s, 1H), 4.55 (m, 1H), 4.28–
4.03 (m, 4H), 3.74 (s, 3H), 3.65 (septet, J = 7.8 Hz, 1H), 3.46 (t, J =
13.8 Hz, 1H), 1.53 (s, 3H), 1.43 (s, 3H), 1.28 (s, 3H), 1.24 (s, 3H);
13C-NMR (100.6 MHz, CDCl3): d = 159.2, 159.0, 155.9, 155.4,
127.9, 127.5, 127.2, 126.8, 114.8, 114.7, 110.2, 110.1, 109.1, 96.5,
96.4, 71.7, 70.7, 64.8, 64.4, 55.7, 40.7, 40.6, 26.1, 26.0, 25.3, 25.2,
24.9, 24.8; ESI (m/z) 621.2 [M++Na, (100)], 599.1 [M++1, (19)];
HRMS calcd for [C25H28F6N2O8]: 598.1750, found: 598.1755.
Major diastereoisomer, Rf 0.25 (hexane : AcOEt 70 : 30); [a]2D5:
1
-23.4 (c 0.5, CHCl3); FTIR (neat) n 1775, 1715 cm-1; H-NMR
(400 MHz, CDCl3): d = 4.94 (s, 1H), 4.66 (dd, J = 5.9 and 1.5 Hz,
1H), 4.60 (d, J = 5.9 Hz, 1H), 4.37 (s, 2H), 4.29 (m, 1H), 3.98–3.88
(m, 2H), 3.31 (s, 3H), 3.29 (dd, J = 14.6 and 3.3 Hz, 1H), 1.58 (s,
9H), 1.47 (s, 3H), 1.32 (s, 3H); 13C-NMR (100.6 MHz, CDCl3):
d = 170.2, 157.7, 123.4 (q, J = 280.7 Hz), 121.1 (q, J = 279.7
Hz), 113.6, 110.3, 85.5, 83.4, 82.6, 56.3, 54.9, 50.0 (septet, J =
28.2 Hz), 45.9, 28.7, 26.9, 25.5; ESI (m/z) 515.0 [M++Na, (100)],
493.1 [M++1, (10)]; HRMS calcd for [C19H26F6N2O6]: 492.1695,
found: 492.1693. Minor diast.: Rf 0.30 (hexane : AcOEt 70 : 30);
1
[a]2D5: -15.0 (c 0.6, CHCl3); FTIR (neat) n 1767, 1722 cm-1; H-
NMR (400 MHz, CDCl3): d = 4.89 (s, 1H), 4.54 (d, J = 6.0 Hz,
1H), 4.49 (dd, J = 6.0 and 0.9 Hz, 1H), 4.45 (s, 1H), 4.31 (t, J =
7.2 Hz, 1H), 3.95 (dd, J = 15.2 and 6.8 Hz, 1H), 3.78 (septet, J =
8.8 Hz, 1H), 3.28 (s, 3H), 2.98 (dd, J = 15.2 and 7.6 Hz, 1H), 1.52
(s, 9H), 1.39 (s, 3H), 1.23 (s, 3H); 13C-NMR (125.7 MHz, CDCl3):
d = 169.8, 156.8, 112.9, 110.1, 84.7, 83.4, 81.9, 59.1, 54.8, 53.4,
49.3 (septet, J = 27.2 Hz), 44.3, 28.3, 26.4, 24.9, the CF3 signal was
obscured due to its low intensity; ESI (m/z) 515.1 [M++Na, (100)],
493.1 [M++1, (8)]; HRMS calcd for [C19H26F6N2O6]: 492.1695,
found: 492.1690.
3-tert-Butyl-5-phenyl-1-(((3aR,5aS,8aS,8bS)-2,2,7,7-tetramethyl-
tetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-d]pyran-5-yl)methyl)-
imidazolidine-2,4-dione, 4f
Mixture of two diast., Rf 0.52 (hexane : AcOEt 70 : 30); FTIR (neat)
n 1768, 1715 cm-1; 1H-NMR (400 MHz, CDCl3): d = 7.14 (m, 10H),
5.52 (s, 1H), 5.44 (d, J = 4.8 Hz, 1H), 5.43 (s, 1H), 5.38 (d, J = 4.8
Hz, 1H), 4.55 (t, J = 2.4 Hz, 1H), 4.53 (t, J = 2.4 Hz, 1H), 4.22–3.93
(m, 8H), 3.40 (dd, J = 14.0 and 3.2 Hz, 2H), 1.47 (s, 3H), 1.41 (s,
3H), 1.40 (s, 3H), 1.37 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H), 1.25 (s,
3H), 1.24 (s, 3H), 1.23 (s, 9H), 1.22 (s, 3H), 1.20 (s, 9H); 13C-NMR
(100.6 MHz, CDCl3): d = 170.4, 170.2, 144.7, 144.5, 135.1, 134.1,
129.3, 129.1, 128.8, 128.7, 128.1, 127.2, 126.9, 126.3, 109.8, 109.7,
108.7, 108.5, 96.3, 96.2, 80.9, 80.2, 71.6, 71.0, 70.9, 70.5, 70.4, 64.7,
64.2, 52.6, 40.6, 40.5, 30.5, 30.4, 28.6, 26.4, 26.1, 26.0, 25.0, 24.9,
24.7, 24.6; ESI (m/z) 517.2 [M++Na, (100)], 475.1 [M++1, (12)];
HRMS calcd for [C25H34N2O7]: 474.2366, found: 474.2372.
5-(1,1,1,3,3,3-Hexafluoropropan-2-yl)-3-phenyl-1-(((3aR,5aS,
8aS,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-
b:4¢,5¢-d]pyran-5-yl)methyl)imidazolidine-2,4-dione, 4c
Major diastereoisomer, Rf 0.33 (hexane : AcOEt 80 : 20); [a]2D5:
1
-43.8 (c 0.9, CHCl3); FTIR (neat) n 1774, 1743 cm-1; H-NMR
(400 MHz, CDCl3): d = 7.47 (m, 2H), 7.40 (m, 1H), 7.32 (m, 2H),
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8379–8392 | 8387
©

3-tert-Butyl-5-(4-fluorophenyl)-1-(((3aS,4R,6R,6aS)-6-methoxy-
2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)imidazo-
lidine-2,4-dione, 4g
3-tert-Butyl-5,5-dimethyl-1-(((3aR,5aS,8aS,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-d]pyran-5-
yl)methyl)imidazolidine-2,4-dione, 4i
Mixture of two diast., Rf 0.45 (hexane : AcOEt 80 : 20); FTIR (neat)
n 1768, 1731 cm-1; 1H-NMR (400 MHz, CDCl3): d = 7.29 (m, 5H),
7.02 (m, 5H), 5.49 (s, 2H), 4.87 (d, J = 4.8 Hz, 2H), 4.80 (d, J = 6.0
Hz, 1H), 4.73 (d, J = 5.6 Hz, 1H), 4.54 (dd, J = 12.0 and 6.0 Hz,
2H), 4.45 (m, 2H), 3.61 (m, 4H), 3.27 (s, 3H), 3.20 (s, 3H),1.40 (s,
3H), 1.39 (s, 3H), 1.26 (s, 9H), 1.25 (s, 9H), 1.24 (s, 3H), 1.20 (s,
3H); 13C-NMR (100.6 MHz, CDCl3): d = 170.1, 163.2 (d, J = 248.5
Hz), 143.5, 143.3, 129.7, 128.0, 127.9, 115.9 (d, J = 22.1 Hz), 112.3,
109.8, 85.3, 85.2, 83.1, 82.9, 82.4, 82.3, 79.6, 55.3, 55.2, 52.8, 43.1,
43.0, 30.5, 29.6, 26.4, 24.9; ESI (m/z) 459.2 [M++Na, (100)], 437.2
[M++1, (47)]; HRMS calcd for [C22H29FN2O6]: 436.2010, found:
436.2017.
Rf 0.37 (hexane : AcOEt 80 : 20); [a]2D5: -10.5 (c 0.8, CHCl3); FTIR
(neat) n 1789, 1725 cm-1; 1H-NMR (400 MHz, CDCl3): d = 5.47
(d, J = 3.9 Hz, 1H), 4.61 (dd, J = 6.3 and 1.9 Hz, 1H), 4.27 (m,
2H), 4.23 (d, J = 6.6 Hz, 1H), 3.56 (dd, J = 11.8 and 2.1 Hz, 1H),
3.10 (dd, J = 11.8 and 6.8 hz, 1H), 1.59 (s, 9H), 1.49 (s, 3H), 1.47 (s,
3H), 1.35 (s, 3H), 1.34 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H); 13C-NMR
(100.6 MHz, CDCl3): d = 177.8, 156.5, 109.4, 108.8, 96.4, 71.9,
71.0, 70.6, 65.6, 60.7, 57.4, 41.3, 28.7, 26.0, 25.8, 25.1, 24.4, 24.1,
22.9; ESI (m/z) 449.1 [M++Na, (100)], 427.1 [M++1, (7)]; HRMS
calcd for [C21H34N2O7]: 426.2366, found: 426.2361.
1-tert-Butyl-3-(((3aS,4R,6R,6aS)-6-methoxy-2,2-dimethyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-5,5-
dimethylimidazolidine-2,4-dione, 4j
3-(4-Methoxyphenyl)-5-phenyl-1-(((3aR,5aS,8aS,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-d]pyran-5-
yl)methyl)imidazolidine-2,4-dione, 4h
Rf 0.54 (hexane : AcOEt 70 : 30); [a]2D5: -48.7 (c 0.5, CHCl3); FTIR
(neat) n 1759, 1721 cm-1; 1H-NMR (400 MHz, CDCl3): d = 4.87
(s, 1H), 4.78 (d, J = 5.9 Hz, 1H), 4.52 (d, J = 5.9 Hz, 1H), 4.38
(t, J = 7.0 Hz, 1H), 3.55 (m, 2H), 3.28 (s, 3H), 1.43 (s, 3H), 1.42
(s, 3H), 1.22 (s, 3H), 1.19 (s, 9H); 13C-NMR (100.6 MHz, CDCl3):
d = 176.2, 148.2, 112.2, 109.8, 85.3, 83.1, 82.6, 54.6, 42.7, 30.3,
26.4, 25.0, 24.9, 24.1, 23.9; ESI (m/z) 393.2 [M++Na, (52)], 371.1
[M++1, (100)]; HRMS calcd for [C18H30N2O6]: 370.2104, found:
370.2113.
One diast: Rf 0.31 (toluene : AcOEt 80 : 20); [a]2D5: -27.7 (c 0.8,
1
CHCl3); FTIR (neat) n 1757, 1717 cm-1; H-NMR (400 MHz,
CDCl3): d = 7.53 (m, 2H), 7.42 (m, 3H), 7.37 (d, J = 8.1 Hz, 2H),
6.95 (d, J = 8.1 Hz, 2H), 5.76 (s, 1H), 5.55 (d, J = 7.9 Hz, 1H), 4.61
(dd, J = 7.9 and 2.2 Hz, 1H), 4.31 (dd, J = 5.0 and 3.2 Hz, 1H), 4.25
(dd, J = 8.0 and 1.8 Hz, 1H), 3.98 (m, 1H), 3.82 (s, 3H), 3.69 (dd,
J = 14.1 and 6.9 Hz, 1H), 1.53 (s, 3H), 1.47 (s, 3H), 1.35 (s, 3H), 1.34
(s, 3H); 13C-NMR (100.6 MHz, CDCl3): d = 170.4, 159.6, 133.9,
129.7, 129.3, 128.3, 128.2, 126.4, 125.2, 114.7, 109.5, 108.9, 108.8,
96.9, 96.8, 80.3, 72.0, 71.2, 71.1, 68.5, 55.8, 46.2, 26.5, 26.4, 26.3,
25.4, 24.9, 24.8; ESI (m/z) 547.0 [M++Na, (100)], 525.1 [M++1,
(31)]; HRMS calcd for [C28H32N2O8]: 524.2159, found: 524.2153.
Other diast.: Rf 0.24 (toluene : AcOEt 80 : 20); [a]2D5: -17.9 (c 0.3,
3-tert-Butyl-1-(((3aS,4R,6R,6aS)-6-methoxy-2,2-dimethyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-5,5-dimethylimidazoli-
dine-2,4-dione, 4k
Rf 0.39 (hexane : AcOEt 70 : 30); [a]2D5: -43.7 (c 0.3, CHCl3); FTIR
(neat) n 1775, 1722 cm-1; 1H-NMR (400 MHz, CDCl3): d = 4.88
(s, 1H), 4.80 (d, J = 5.9 Hz, 1H), 4.59 (d, J = 5.9 Hz, 1H), 4.19
(dd, J = 9.8 and 5.0 Hz, 1H), 3.64 (dd, J = 14.6 and 9.9 Hz, 1H),
3.28 (s, 3H), 3.01 (dd, J = 17.2 and 5.0 Hz, 1H), 1.52 (s, 9H),
1.38 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H), 1.24 (s, 3H); 13C-NMR
(100.6 MHz, CDCl3): d = 177.2, 156.9, 112.3, 109.8, 85.8, 85.2,
82.3, 60.5, 57.8, 55.2, 42.6, 29.3, 28.6, 26.5, 25.0, 24.3, 23.0; ESI
(m/z) 393.2 [M++Na, (100)], 371.1 [M++1, (13)]; HRMS calcd for
[C18H30N2O6]: 370.2104, found: 370.2111.
1
CHCl3); FTIR (neat) n 1755, 1722 cm-1; H-NMR (400 MHz,
CDCl3): d = 7.53 (m, 2H), 7.41 (m, 3H), 7.37 (d, J = 9.0 Hz, 2H),
6. 93 (d, J = 9.0 Hz, 2H), 5.75 (s, 1H), 5.54 (d, J = 5.0 Hz, 1H),
4.61 (dd, J = 8.0 and 2.3 Hz, 1H), 4.31 (dd, J = 4.9 and 2.3 Hz,
1H), 4.26 (m, 1H), 3.81 (s, 3H), 3.54 (dd, J = 12.9 and 6.3 Hz,
1H), 1.50 (s, 3H), 1.46 (s, 3H), 1.35 (s, 3H), 1.34 (s, 3H); 13C-
NMR (100.6 MHz, CDCl3): d = 170.5, 159.6, 131.2, 129.7, 129.6,
129.3, 128.3, 128.2, 128.19, 128.11, 126.4, 114.6, 109.6, 108.8, 96.8,
80.3, 72.1, 71.3, 68.6, 67.5, 55.8, 46.2, 26.5, 26.4, 25.4, 24.9; ESI
(m/z) 547.1 [M++Na, (100)], 525.1 [M++1, (11)]; HRMS calcd for
[C28H32N2O8]: 524.2159, found: 524.2162.
Ethyl 2-(1-tert-butyl-2,5-dioxo-3-(((3aR,5aS,8aS,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-d]pyran-5-
yl)methyl)imidazolidin-4-yl)acetate, 4l
2-Bromo-N-tert-butyl-2-methyl-N-(((3aR,5aS,8aS,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-d]pyran-5-
yl)methylcarbamoyl)propanamide, 5i
Mixture of two diast., Rf 0.43 (hexane:AcOEt 70 : 30); FTIR (neat)
n 1784, 1756, 1727 cm-1; 1H-NMR (400 MHz, CDCl3), major diast:
d = 5.32 (d, J = 5.0 Hz, 1H), 4.48 (dd, J = 7.9 and 2.5 Hz, 1H),
4.16 (dd, J = 5.0 and 2.4 Hz, 1H), 4.03 (m, 4H), 3.92 (m, 1H),
3.48 (dd, J = 14.8 and 8.3 Hz, 1H), 3.31 (dd, J = 14.8 and 3.1 Hz,
1H), 3.78 (m, 2H), 1.49 (s, 9H), 1.37 (s, 3H), 1.32 (s, 3H), 1.21 (s,
Rf 0.49 (hexane : AcOEt 80 : 20); FTIR (neat) n 1776, 1711 cm-1;
1H-NMR (400 MHz, CDCl3): d = 7.51 (br s, 1H), 5.50 (d, J = 3.9
Hz, 1H), 4.62 (dd, J = 6.3 and 2.0 Hz, 1H), 4.31 (dd, J = 3.9 and 2.0
Hz, 1H), 4.24 (dd, J = 6.3 and 1.1 Hz, 1H), 4.10 (m, 2H), 3.67 (dd,
J = 12.0 and 8.1 Hz, 1H), 2.10 (s, 3H), 2.05 (s, 3H), 1.48 (s, 3H),
1.45 (s, 3H), 1.36 (s, 12H), 1.31 (s, 3H); 13C-NMR (100.6 MHz,
CDCl3): d = 174.1, 154.7, 109.6, 109.4, 96.2, 71.6, 70.9, 70.7, 66.1,
60.8, 51.0, 48.5, 33.4, 33.0, 28.3, 26.1, 26.0, 25.0, 24.4; ESI (m/z)
507.0 [M++1, (100)]; HRMS calcd for [C21H35BrN2O7]: 506.1628,
found: 506.1633.
1
3H), 1.95 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H); H-NMR (400 MHz,
CDCl3), minor diast: d = 5.33 (d, J = 5.1 Hz, 1H), 4.47 (m, 1H),
4.21 (t, J = 4.4 Hz, 1H), 4.16 (m, 1H), 4.03 (m, 4H), 3.67 (dd,
J = 15.0 and 2.4 Hz, 1H), 2.99 (dd, J = 15.0 and 9.4 Hz, 1H),
2.81 (dd, J = 17.2 and 4.3 Hz, 1H), 2.74 (dd, J = 17.2 and 5.5 Hz,
1H), 1.50 (s, 12H), 1.35 (s, 3H), 1.22 (s, 3H), 1.19 (s, 3H), 1.13 (t,
8388 | Org. Biomol. Chem., 2011, 9, 8379–8392
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The Royal Society of Chemistry 2011
©

J = 7.1 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3), major diast.: d =
173.2, 169.6, 157.6, 109.4, 108.7, 96.2, 71.6, 71.0, 70.5, 65.8, 60.7,
57.7, 56.8, 42.9, 35.1, 28.6, 25.9, 25.0, 24.3, 14.1; 13C-NMR (100.6
MHz, CDCl3), minor diast.: d = 173.3, 169.1, 157.6, 109.5, 108.8,
96.2, 71.6, 70.8, 70.4, 67.1, 60.8, 57.1, 56.8, 41.3, 33.4, 28.6, 25.8,
25.0, 24.7, 14.1; ESI (m/z) 507.1 [M++Na, (100)], 485.1 [M++1,
(41)]; HRMS calcd for [C23H36N2O9]: 484.2421, found: 484.2434.
43.0, 35.1, 28.5, 26.0, 25.0, 24.3; ESI (m/z) 547.1 [M++1, (100)];
HRMS calcd for [C28H38N2O9]: 546.2577, found: 546.2571.
(E)-tert-Butyl 4-(1-tert-butyl-3-(((3aS,4R,6R,6aS)-6-methoxy-
2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ureido)-
4-oxobut-2-enoate, 5p
Rf 0.30 (hexane : AcOEt 70 : 30); [a]2D5: -38.6 (c = 0.6, CHCl3);
FTIR (neat) n 1768, 1731, 1704 cm-1; 1H-NMR (400 MHz,
CDCl3): d = 6.92 (d, J = 15.1 Hz, 1H), 6.65 (d, J = 15.1 Hz,
1H), 6.48 (br s, 1H), 4.90 (s, 1H), 4.56 (d, J = 5.9 Hz, 1H), 4.46 (d,
J = 5.9 Hz, 1H), 4.38 (t, J = 4.6 Hz, 1H), 3.46 (m, 1H), 3.68 (m, 1H),
3.29 (s, 3H), 1.42 (s, 9H), 1.39 (s, 3H), 1.38 (s, 9H), 1.24 (s, 3H);
13C-NMR (100.6 MHz, CDCl3): d = 164.5, 162.4, 155.1, 134.2,
133.4, 112.8, 110.2, 85.5, 85.3, 82.1, 81.5, 57.9, 55.6, 44.1, 28.1,
27.9, 26.4, 24.8; ESI (m/z) 479.3 [M++Na, (100)], 457.2 [M++1,
(3)]; HRMS calcd for [C22H36N2O8]: 456.2472, found: 456.2479.
Ethyl 2-(1-tert-butyl-3-(((3aS,4R,6R,6aS)-6-methoxy-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2,5-
dioxoimidazolidin-4-yl)acetate, 4m
Mixture of two diast., Rf 0.52 (hexane : AcOEt 70 : 30); FTIR (neat)
n 1775, 1741, 1712 cm-1; 1H-NMR (400 MHz, CDCl3): d = 4.93 (s,
1H), 4.92 (s, 1H), 4.72 (dd, J = 5.9 and 1.0 Hz, 1H), 4.61 (s, 1H),
4.31 (t, J = 7.3 Hz, 1H), 4.20–4.12 (m, 4H), 4.07 (t, J = 4.8 Hz, 1H),
3.87 (dd, J = 14.6 and 7.5 Hz, 1H), 3.44 (d, J = 7.4 Hz, 1H), 3.34
(s, 3H), 3.30 (s, 3H), 2.94–2.86 (m, 4H), 1.59 (s, 9H), 1.58 (s, 9H),
1.43 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.29 (s, 3H), 1.24 (t, J = 7.2
Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3):
d = 173.0, 172.8, 169.4, 169.2, 158.0, 157.4, 112.9, 112.7, 110.4,
110.2, 85.5, 85.2, 84.8, 84.7, 82.4, 82.2, 61.4, 61.3, 58.3, 58.2, 56.8,
55.8, 55.7, 55.5, 45.3, 43.6, 35.2, 33.8, 28.7, 28.6, 28.5, 26.7, 25.3,
25.2, 14.3, 14.2; ESI (m/z) 393.2 [M++Na, (100)], 371.1 [M++1,
(13)]; HRMS calcd for [C20H32N2O8]: 428.2159, found: 428.2151.
(E)-tert-Butyl 4-(3-tert-butyl-1-(((3aS,4R,6S,6aS)-6-methoxy-
2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)ureido)-
4-oxobut-2-enoate, 5q
Rf 0.53 (hexane : AcOEt 70 : 30); [a]2D5: -27.4 (c = 1.0, CHCl3);
FTIR (neat) n 1787, 1730 cm-1; 1H-NMR (400 MHz, CDCl3): d =
8.71 (br s, 1H), 7.35 (d, J = 15.2 Hz, 1H), 6.68 (d, J = 15.2 Hz, 1H),
4.87 (s, 1H), 4.68 (d, J = 5.9 Hz, 1H), 4.54 (d, J = 5.9 Hz, 1H), 4.21
(m, 2H), 3.56 (m, 1H), 3.28 (s, 3H), 1.43 (s, 9H), 1.37 (s, 3H), 1.30
(s, 9H), 1.21 (s, 3H); 13C-NMR (100.6 MHz, CDCl3): d = 168.1,
164.0, 152.6, 135.4, 133.8, 112.5, 110.3, 85.7, 85.1, 82.1, 81.9, 55.5,
51.4, 46.5, 28.6, 27.9, 26.4, 24.9; ESI (m/z) 479.3 [M++Na, (100)];
HRMS calcd for [C22H36N2O8]: 456.2472, found: 456.2462.
Ethyl 2-(1-(4-methoxyphenyl)-2,5-dioxo-3-(((3aR,5aS,8aS,8bS)-
2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-
d]pyran-5-yl)methyl)imidazolidin-4-yl)acetate, 4n
Mixture of two diast., Rf 0.36 (hexane : AcOEt 70 : 30); FTIR (neat)
n 1769, 1733, 1716 cm-1; 1H-NMR (400 MHz, CDCl3): d = 7.32–
7.22 (m, 4H), 6.96–6.89 (m, 4H), 5.48 (m, 2H), 4.76 (m, 2H),
4.61 (m, 2H), 4.30–4.25 (m, 4H), 4.17–4.01 (m, 8H), 3.81 (s, 3H),
3.79 (s, 3H), 3.59 (t, J = 3.1 Hz, 1H), 3.55 (dd, J = 4.5 and 3.1
Hz, 1H), 3.07 (m, 2H), 2.80 (m, 2H), 1.52–1.29 (m, 30H); ESI
(m/z) 557.1 [M++Na, (100)], 535.1 [M++1, (25)]; HRMS calcd for
[C26H34N2O10]: 534.2213, found: 534.2206.
tert-Butyl 2-(1-tert-butyl-3-(((3aS,4R,6R,6aS)-6-methoxy-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2,5-
dioxoimidazolidin-4-yl)acetate, 4p
Mixture of diast., Rf 0.18 (hexane : AcOEt 80 : 20); FTIR (neat)
1
n 1775, 1736, 1712 cm-1; H-NMR (400 MHz, CDCl3): d = 4.87
(s, 1H), 4.86 (s, 1H), 4.70 (d, J = 5.9 Hz, 1H), 4.56 (m, 3H), 4.25
(t, J = 7.4 Hz, 1H), 4.12 (m, 2H), 4.02 (dd, J = 5.7 and 4.2 Hz,
1H), 3.83 (dd, J = 14.6 and 8.2 Hz, 1H), 3.43 (dd, J = 14.4 and
6.7 Hz, 1H), 3.34 (dd, J = 14.4 and 7.9 Hz, 1H), 3.27 (s, 3H), 3.24
(s, 3H), 2.85 (dd, J = 14.6 and 6.5 Hz, 1H), 2.79–2.71 (m, 2H),
2.68–2.60 (m, 2H), 1.53 (s, 9H), 1.52 (s, 9H), 1.38 (s, 6H), 1.37
(s, 9H), 1.36 (s, 9H), 1.24 (s, 3H), 1.23 (s, 3H); 13C-NMR (100.6
MHz, CDCl3): d = 172.8, 172.7, 168.6, 168.3, 157.7, 157.2, 112.6,
112.5, 110.1, 109.9, 85.3, 85.1, 84.44, 84.40, 82.3, 82.1, 81.9, 81.8,
58.1, 56.8, 55.7, 55.4, 55.2, 45.1, 43.3, 36.4, 35.1, 28.6, 27.9, 26.5,
26.4, 25.1, 25.0; ESI (m/z) 479.3 [M++Na, (100)]; HRMS calcd
for [C22H36N2O8]: 456.2472, found: 456.2481.
Benzyl 2-(1-tert-butyl-2,5-dioxo-3-(((3aR,5aS,8aS,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-d]pyran-5-
yl)methyl)imidazolidin-4-yl)acetate, 4o
Mixture of two diast., Rf 0.19 (hexane : AcOEt 80C: 20); FTIR
1
(neat) n 1779, 1756, 1726 cm-1; H-NMR (400 MHz, CDCl3),
major diast: d = 7.26 (m, 5H), 5.29 (d, J = 4.9 Hz, 1H), 5.07 (d,
J = 12.3 Hz, 1H), 5.02 (d, J = 12.3 Hz, 1H), 4.49 (dd, J = 7.7 and
2.4 Hz, 1H), 4.16 (dd, J = 5.0 and 2.4 Hz, 1H), 4.10 (dd, J = 7.8
and 1.6 Hz, 1H), 4.04 (m, 1H), 3.94 (br d, J = 7.6 Hz, 1H), 3.45
(dd, J = 14.9 and 8.2 Hz, 1H), 3.36 (dd, J = 14.9 and 3.0 Hz, 1H),
2.91 (dd, J = 17.2 and 4.2 Hz, 1H), 2.83 (dd, J = 17.2 and 5.4 Hz,
1H), 1.50 (s, 9H), 1.39 (s, 3H), 1.35 (s, 3H), 1.23 (s, 3H), 1.20 (s,
3H); 1H-NMR (400 MHz, CDCl3), minor diast: d = 7.26 (m, 5H),
5.34 (d, J = 5.0 Hz, 1H), 5.02 (s, 2H), 4.48 (dd, J = 7.8 and 2.6
Hz, 1H), 4.25 (t, J = 4.4 Hz, 1H), 4.18 (dd, J = 5.0 and 2.4 Hz,
1H), 4.06–4.01 (m, 2H), 3.67 (dd, J = 16.0 and 2.4 Hz, 1H), 3.01
(dd, J = 16.0 and 9.4 Hz, 1H), 2.87 (m, 2H), 1.49 (s, 9H), 1.37 (s,
3H), 1.35 (s, 3H), 1.23 (s, 3H), 1.20 (s, 3H); 13C-NMR (100.6 MHz,
CDCl3), major diast.: d = 173.1, 169.5, 157.7, 135.7, 128.5, 128.2,
128.0, 109.4, 108.7, 96.2, 71.6, 71.0, 70.6, 66.6, 65.9, 57.8, 56.9,
tert-Butyl 2-(3-tert-butyl-1-(((3aS,4R,6R,6aS)-6-methoxy-2,2-
dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)-2,5-
dioxoimidazolidin-4-yl)acetate, 4q
Mixture of diast., Rf 0.43 (hexane : AcOEt 70C: 30); FTIR (neat)
1
n 1773, 1756, 1715 cm-1; H-NMR (400 MHz, CDCl3): d = 4.87
(s, 1H), 4.86 (s, 1H), 4.70 (d, J = 5.8 Hz, 1H), 4.68 (d, J = 5.9 Hz,
1H), 4.56 (t, J = 6.0 Hz, 2H), 4.35 (m, 2H), 4.07 (m, 2H), 3.54
(m, 4H), 3.28 (s, 3H), 3.26 (s, 3H), 2.98 (dd, J = 5.8 and 2.2 Hz,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8379–8392 | 8389
©

1H), 2.94 (dd, J = 5.8 and 2.2 Hz, 1H), 2.72 (dd, J = 6.2 and 4.6
Hz, 1H), 2.68 (dd, J = 6.2 and 4.6 Hz, 1H), 1.38 (s, 18H), 1.36 (s,
6H), 1.33 (s, 9H), 1.32 (s, 9H), 1.21 (s, 3H), 1.20 (s, 3H); 13C-NMR
(100.6 MHz, CDCl3): d = 172.5, 172.3, 167.7, 156.6, 156.4, 112.2,
109.9, 109.8, 85.4, 85.3, 83.7, 83.6, 82.5, 82.3, 81.8, 56.2, 55.7, 55.6,
55.1, 55.0, 41.6, 38.7, 38.6, 28.5, 28.4, 27.9, 26.5, 26.4, 25.1, 25.0;
ESI (m/z) 479.3 [M++Na, (100)]; HRMS calcd for [C22H36N2O8]:
456.2472, found: 456.2476.
3.74–3.61 (m, 10H), 3.46 (m, 3H), 3.32 (septet, J = 5.3 Hz, 1H), 2.98
(m, 2H), 2.02 (s, 3H), 1.99 (s, 6H), 1.96 (s, 6H), 1.90 (s, 6H), 1.89
(s, 12H), 1.87 (s, 3H), 1.86 (s, 3H), 1.80 (s, 6H), 1.72–1.60 (m, 4H),
1.44 (s, 18H); 13C-NMR (100.6 MHz, CDCl3): d = 170.1, 170.0,
169.9, 169.8, 169.5, 169.2, 168.9, 157.2, 157.1, 123.0 (q, J = 279.7
Hz), 122.2 (q, J = 283.7 Hz), 100.9, 100.6, 76.0, 72.8, 71.4, 70.9,
70.7, 69.1, 68.2, 66.9, 66.7, 61.9, 60.8, 58.7, 58.6, 54.6, 54.3, 53.9,
49.6 (septet, J = 28.7 Hz), 40.2, 39.4, 31.5, 30.2, 29.2, 28.2, 28.1,
27.0, 26.5, 20.6, 20.5, 20.4, 20.3; ESI (m/z) 1005.1 [M++Na, (100)];
HRMS calcd for [C39H52F6N2O20]: 982.3018, found: 982.3013.
tert-Butyl 2-(2,5-dioxo-1-phenyl-3-(((3aR,5aS,8aS,8bS)-2,2,7,7-
tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-d]pyran-5-
yl)methyl)imidazolidin-4-yl)acetate, 4r
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-(3-(3-tert-butyl-5-(2-ethoxy-
2-oxoethyl)-2,4-dioxoimidazolidin-1-yl)propoxy)tetrahydro-2H-
pyran-3,4,5-triyl triacetate, 6c
Mixture of diast., Rf 0.53 (hexane : AcOEt 70 : 30); FTIR (neat) n
1749, 1722 cm-1; 1H-NMR (400 MHz, CDCl3): d = 7.38 (m, 8H),
7.25 (m, 2H), 5.42 (d, J = 5.3 Hz, 1H), 5.41 (d, J = 5.5 Hz, 1H),
4.52 (m, 3H), 4.40 (t, J = 4.7 Hz, 1H), 4.22 (m, 2H), 4.17 (t, J =
8.2 Hz, 1H), 4.16 (t, J = 8.2 Hz, 1H), 4.05 (m, 2H), 3.94 (dd, J =
14.6 and 7.6 Hz, 1H), 3.89 (dd, J = 15.1 and 2.2 Hz, 1H), 3.29 (dd,
J = 14.6 and 3.7 Hz, 1H), 3.17 (dd, J = 15.0 and 9.6 Hz, 1H), 2.92
(m, 2H), 2.89 (m, 2H), 1.44 (s, 3H), 1.41 (s, 3H), 1.40 (s, 3H), 1.35
(s, 12H), 1.37 (s, 9H), 1.27 (s, 3H), 1.24 (s, 6H), 1.22 (s, 3H); 13C-
NMR (100.6 MHz, CDCl3): d = 171.8, 171.7, 168.6, 168.1, 156.0,
132.1, 128.9, 127.8, 126.0, 125.9, 109.6, 109.5, 108.9, 108.7, 96.3,
96.2, 81.8, 81.7, 71.5, 70.8, 70.4, 67.5, 65.3, 57.8, 57.0, 42.1, 41.3,
35.7, 34.4, 28.0, 27.9, 26.0, 25.96, 25.91, 24.9, 24.9, 24.4, 24.2; ESI
(m/z) 555.1 [M++Na, (100)], 533.2 [M++1, (21)]; HRMS calcd for
[C27H36N2O9]: 532.2421, found: 532.2429.
Mixture of diast., Rf 0.35 (AcOEt : hexane 60 : 40); FTIR (neat) n
1
1781, 1754, 1741, 1727 cm-1; H-NMR (400 MHz, CDCl3): d =
5.11 (t, J = 9.5 Hz, 1H), 5.10 (t, J = 9.5 Hz, 1H), 4.97 (t, J = 9.5
Hz, 2H), 4.88 (dd, J = 8.0 and 2.2 Hz, 1H), 4.86 (dd, J = 8.0 and
2.2 Hz, 1H), 4.41 (dd, J = 8.0 and 3.8 Hz, 2H), 4.18 (dd, J = 4.8
and 1.8 Hz, 1H), 4.15 (dd, J = 4.7 and 1.8 Hz, 1H), 4.04 (m, 6H),
3.94 (t, J = 4.6 Hz, 1H), 3.91 (t, J = 4.7 Hz, 1H), 3.78 (m, 2H), 3.61
(m, 2H), 3.50–3.35 (m, 4H), 3.10 (m, 1H), 2.98 (m 1H), 2.75 (m,
4H), 2.00 (s, 6H), 1.97 (s, 3H), 1.96 (s, 3H), 1.93 (s, 6H), 1.91 (s,
6H), 1.75 (m, 4H), 1.51 (s, 18H), 1.16 (t, J = 7.1 Hz, 3H), 1.59 (t,
J = 7.2 Hz, 3H); 13C-NMR (100.6 MHz, CDCl3): d = 172.8, 170.6,
170.2, 169.3, 169.2, 169.1, 157.3, 157.2, 100.75, 100.72, 72.8, 72.7,
71.8, 71.2, 68.4, 67.3, 66.9, 61.9, 61.8, 61.1, 61.0, 57.9, 57.8, 56.1,
55.7, 38.7, 37.8, 34.4, 34.1, 29.2, 28.6, 28.5, 27.9, 20.66, 20.61, 20.5,
14.1; ESI (m/z) 653.1 [M++Na, (100)], 631.2 [M++1, (13)]; HRMS
calcd for [C28H42N2O14]: 630.2636, found: 630.2625.
(3R,4S,5S,6R)-2-(acetoxymethyl)-6-(3-(3-tert-butyl-5-
(1,1,1,3,3,3-hexafluoropropan-2-yl)-2,4-dioxoimidazolidin-1-
yl)propoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate, 6a
(3S,4S,5S,6S)-2-(Acetoxymethyl)-6-((3R,4S,5S,6R)-4,5-
diacetoxy-2-(acetoxymethyl)-6-(3-(3-tert-butyl-5-(2-ethoxy-2-
oxoethyl)-2,4-dioxoimidazolidin-1-yl)propoxy)tetrahydro-2H-
pyran-3-yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate, 6d
Mixture of diast., Rf 0.38 (hexane : AcOEt 70 : 30); FTIR (neat) n
1
1788, 1765, 1735, 1721 cm-1; H-NMR (400 MHz, CDCl3): d =
5.11 (m, 2H), 4.99–4.90 (m, 2H), 4.83 (t, J = 8.4 Hz, 2H), 4.39
(dd, J = 13.0 and 7.9 Hz, 2H), 4.24 (m, 2H), 4.15 (m, 2H), 4.04
(m, 2H), 3.77 (m, 6H), 3.60 (m, 2H), 3.51 (m, 1H), 3.40 (m, 1H),
3.06 (m, 2H), 2.00 (s, 3H), 1.98 (s, 3H), 1.95 (s, 3H), 1.94 (s, 3H),
1.93 (s, 3H), 1.91, (s, 3H), 1.78–1.70 (m, 4H), 1.51 (s, 9H), 1.50
(s, 9H); 13C-NMR (100.6 MHz, CDCl3): d = 170.5, 170.1, 170.0,
169.9, 169.3, 169.2, 169.0, 157.3, 157.2, 101.1, 100.9, 100.7, 72.7,
72.6, 71.9, 71.8, 71.2, 71.0, 68.4, 68.0, 67.3, 65.5, 63.3, 61.8, 58.9,
58.7, 54.6, 54.2, 49.7 (septet, J = 28.2 Hz), 49.4 (septet, J = 28.9
Hz), 40.2, 39.5, 28.3, 28.2, 27.1, 26.6, 20.5, 20.4, the CF3 signal was
obscured due to its low intensity; ESI (m/z) 555.1 [M++Na, (100)],
533.2 [M++1, (21)]; HRMS calcd for [C27H36F6N2O12]: 694.2172,
found: 694.2177.
Mixture of diast., Rf 0.45 (AcOEt : hexane 70 : 30); FTIR (neat)
1
n 1787, 1753, 1727 cm-1; H-NMR (400 MHz, CDCl3): d = 5.26
(d, J = 3.0 Hz, 2H), 5.11 (t, J = 9.3 Hz, 1H), 5.10 (t, J = 9.2 Hz,
1H), 5.02 (dd, J = 10.4 and 7.9 Hz, 2H), 4.89 (dd, J = 10.4 and
3.4 Hz, 2H), 4.78 (m, 2H), 4.42–4.38 (m, 6H), 3.99 (m, 10H), 3.94
(q, J = 4.6 Hz, 2H), 3.78–3.70 (m, 6H), 3.52–3.40 (m, 5H), 3.06
(m, 1H), 2.98 (m,1H), 2.74 (m, 3H), 2.06 (s, 6H), 2.03 (s, 6H),
1.98 (s, 6H), 1.97 (s, 6H), 1.96 (s, 12H), 1.87 (s, 6H), 1.80–1.68 (m,
4H), 1.52 (18H), 1.17 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H);
13C-NMR (100.6 MHz, CDCl3): d = 172.7, 170.1, 170.0, 169.8,
169.5, 168.9, 157.2, 101.0, 100.5, 77.2, 76.1, 72.7, 71.8, 70.9, 70.7,
69.2, 66.6, 61.9, 61.0, 60.8, 56.0, 55.7, 38.6, 37.9, 34.4, 34.1, 28.5,
28.0, 20.6, 20.4, 20.3, 14.1; ESI (m/z) 941.1 [M++Na, (100)], 957.3
[M++K, (21)]; HRMS calcd for [C40H58N2O22]: 918.3481, found:
918.3486.
(3S,4S,5S,6S)-2-(Acetoxymethyl)-6-((3R,4S,5S,6R)-4,5-
diacetoxy-2-(acetoxymethyl)-6-(3-(3-tert-butyl-5-(1,1,1,3,3,3-
hexafluoropropan-2-yl)-2,4-dioxoimidazolidin-1-yl)propoxy)tetra-
hydro-2H-pyran-3-yloxy)tetrahydro-2H-pyran-3,4,5-triyl
triacetate, 6b
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-(3-(5-(2-(benzyloxy)-2-
oxoethyl)-3-tert-butyl-2,4-dioxoimidazolidin-1-yl)propoxy)tetra-
hydro-2H-pyran-3,4,5-triyl triacetate, 6e
Mixture of diast., mixture of diast., Rf 0.36 (AcOEt : hexane
1
50 : 50); FTIR (neat) n 1759, 1747, 1725, 1708 cm-1; H-NMR
(400 MHz, CDCl3): d = 5.19 (d, J = 2.9 Hz, 2H), 5.03 (t, J = 9.2
Hz, 1H), 5.02 (t, J = 9.2 Hz, 1H), 4.94 (m, 2H), 4.82 (m, 2H), 4.66
(m, 2H), 4.37–4.28 (m, 6H), 4.23 (s, 1H), 4.12 (s, 1H), 3.96 (m, 6H),
Mixture of diast., Rf 0.20 (AcOEt : hexane 50 : 50); FTIR (neat) n
1
1782, 1773, 1754, 1729 cm-1; H-NMR (400 MHz, CDCl3): d =
7.25 (m, 10H), 5.10 (m, 2H), 5.03 (s, 4H), 4.96 (t, J = 9.8 Hz, 2H),
8390 | Org. Biomol. Chem., 2011, 9, 8379–8392
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4.86 (t, J = 8.4 Hz, 2H), 4.38 (d, J = 3.9 Hz, 1H), 4.35 (d, J = 3.8
Hz, 1H), 4.16 (dd, J = 12.3 and 4.6 Hz, 2H), 4.02 (m, 4H), 3.93
(m, 2H), 3.72 (m, 2H), 3.57 (m, 2H), 3.46–3.29 (m, 4H), 3.08 (m,
1H), 2.93 (m, 1H), 2.81 (m, 2H), 1.98 (s, 3H), 1.97 (s, 3H), 1.94
(s, 6H), 1.93 (s, 6H), 1.92 (s, 3H), 1.90 (s, 3H), 1.48 (s, 18H); 13C-
NMR (100.6 MHz, CDCl3): d = 172.7, 170.6, 170.2, 169.4, 169.2,
157.3, 135.2, 128.6, 128.5, 100.7, 100.6, 72.7, 72.6, 71.8, 71.2, 67.3,
66.8, 61.8, 56.1, 55.7, 38.7, 37.8, 34.4, 28.5, 27.9, 20.7, 20.6, 14.2;
ESI (m/z) 715.1 [M++Na, (100)]; HRMS calcd for [C33H44N2O14]:
692.2793, found: 692.2784.
1H), 5.08 (d, J = 12.4 Hz, 1H), 5.03 (d, J = 12.4 Hz, 1H), 4.47 (m,
2H), 4.13 (dd, J = 4.9 and 2.3 Hz, 1H), 4.08 (m, 1H), 4.02 (m, 2H),
3.52 (dd, J = 15.0 Hz, 1H), 3.30 (dd, J = 15.0 and 2.6 Hz, 1H),
2.66 (m, 2H), 1.49 (s, 9H), 1.36–1.16 (m, 15H);13C-NMR (100.6
MHz, CDCl3), major diast.: d = 173.8, 172.6, 167.6, 157.3, 135.3,
128.5, 128.3, 128.1, 109.5, 108.8, 96.2, 71.6, 70.8, 70.4, 67.0, 57.8,
57.6, 48.2, 41.4, 35.5, 28.6, 25.8, 24.9, 24.3, 18.4; 13C-NMR (100.6
MHz, CDCl3), minor diast.: d = 173.2, 172.7, 168.1, 157.6, 135.3,
128.4, 128.3, 128.1, 109.3, 108.7, 96.2, 71.6, 70.9, 70.6, 65.8, 57.8,
56.8, 48.2, 42.9, 36.8, 28.6, 25.9, 24.9, 24.2, 18.4;ESI (m/z) 618.1
[M++1, (100)]; HRMS calcd for [C31H43N3O10]: 617.2948, found:
617.2956.
(3S,4S,5S,6S)-2-(Acetoxymethyl)-6-((3R,4S,5S,6R)-4,5-
diacetoxy-2-(acetoxymethyl)-6-(3-(5-(2-(benzyloxy)-2-oxoethyl)-
3-tert-butyl-2,4-dioxoimidazolidin-1-yl)propoxy)tetrahydro-2H-
pyran-3-yloxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate, 6f
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-(3-(5-(2-((S)-1-(benzyloxy)-
4-methyl-1-oxopentan-2-ylamino)-2-oxoethyl)-3-tert-butyl-2,4-
dioxoimidazolidin-1-yl)propoxy)tetrahydro-2H-pyran-3,4,5-triyl
triacetate, 12
Mixture of diast., Rf 0.28 (AcOEt : hexane 70 : 30); FTIR (neat) n
1
1784, 1765, 1735, 1727 cm-1; H-NMR (400 MHz, CDCl3): d =
Mixture of diast., Rf 0.35 (AcOEt : hexane 60 : 40); FTIR (neat)
7.32 (m, 10H), 5.25 (d, J = 3.3 Hz, 2H), 5.08 (t, J = 9.4 Hz, 1H),
5.07 (t, J = 9.2 Hz, 1H), 5.03 (m, 5H), 4.91–4.85 (m, 4H), 4.78–4.70
(m, 2H), 4.41–4.33 (m, 5H), 4.04–4.94 (m, 10H), 3.78 (m, 2H), 3.67
(m, 3H), 3.53–3.36 (m 5H), 3.21 (m, 1H), 3.05–2.90 (m, 2H), 2.78
(m, 3H), 2.03 (s, 6H), 2.01 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3H), 1.94
(s, 9H), 1.93 (s, 9H), 1.92 (s, 6H), 1.90 (s, 3H), 1.85 (s, 6H), 1.65
(m, 4H), 1.47 (s, 18H); 13C-NMR (100.6 MHz, CDCl3): d = 172.7,
170.2, 170.0, 169.9, 169.6, 168.9, 157.2, 135.9, 135.3, 133.1, 132.1,
131.9, 131.8, 128.6, 128.5, 128.4, 125.4, 101.0, 100.4, 72.7, 71.0,
70.0, 69.2, 68.3, 66.9, 66.7, 61.9, 60.8, 60.2, 57.9, 55.8, 34.2, 30.3,
28.5, 22.8, 20.9, 20.8, 20.5, 20.4, 14.1; ESI (m/z) 1003.3 [M++Na,
(100)]; HRMS calcd for [C45H60N2O22]: 980.3638, found: 980.3643.
1
n 1783, 1755, 1717 cm-1; H-NMR (400 MHz, CDCl3): d = 7.25
(10H), 6.32 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 8.2 Hz, 1H), 3.14
(t, J = 9.5 Hz, 1H), 5.12 (t, J = 9.4 Hz, 1H), 5.06 (m, 2H), 5.05
(m, 2H), 4.97 (t, J = 9.8 Hz, 1H), 4.96 (t, J = 9.6 Hz, 1H), 4.88
(t, J = 9.8 Hz, 1H), 4.86 (t, J = 8.0 Hz, 1H), 4.53 (m, 2H), 4.41
(d, J = 5.2 Hz, 1H), 4.39 (d, J = 5.3 Hz, 1H), 4.14 (m, 2H), 4.06–
3.95 (m, 4H), 3.75 (m, 2H), 3.61 (m, 2H), 3.52 (m, 1H), 3.42 (m,
3H), 3.07 (m, 1H), 2.97 (m, 1H), 2.75 (dd, J = 15.9 and 4.8 Hz,
1H), 2.62 (m, 3H), 1.97 (s, 3H), 1.96 (s, 3H), 1.95 (s, 3H), 1.94
(s, 3H), 1.93 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H), 1.90 (s, 3H), 1.72
(m, 4H), 1.55-1.46 (m, 6H), 1.51 (s, 9H), 1.50 (s, 9H), 0.84–0.80
(m, 6H); 13C-NMR (100.6 MHz, CDCl3): d = 172.6, 170.5, 170.1,
169.8, 169.5, 169.3, 168.1, 167.9, 157.2, 157.1, 135.4, 128.5, 128.3,
128.1, 100.8, 72.7, 72.6, 71.9, 71.4, 66.8, 61.9, 60.3, 56.04, 56.00,
50.9, 41.3, 37.4, 35.5, 28.6, 28.0, 24.8, 21.8, 20.6, 20.5, 14.1; ESI
(m/z) 828.1 [M++Na, (100)], 806.1 [M++1, (2)]; HRMS calcd for
[C39H55N3O15]: 805.3633, found: 805.3625.
(3R,4S,5S,6R)-2-(Acetoxymethyl)-6-(3-(3-tert-butyl-5,5-
dimethyl-2,4-dioxoimidazolidin-1-yl)propoxy)tetrahydro-2H-
pyran-3,4,5-triyl triacetate, 6g
Rf 0.33 (AcOEt : hexane 60 : 40); [a]2D5: -52.0 (c 0.4, CHCl3); FTIR
(neat) n 1777, 1752, 1727 cm-1; 1H-NMR (400 MHz, CDCl3): d =
5.10 (t, J = 9.4 Hz, 1H), 4.97 (t, J = 9.8 Hz, 1H), 4.88 (t, J = 9.5
Hz, 1H), 4.42 (d, J = 7.9 Hz, 1H), 4.15 (m, 1H), 4.02 (m, 1H), 3.94
(m, 1H), 3.84 (m, 1H), 3.59 (m, 1H), 3.48 (m, 2H), 1.98 (s, 6H),
1.95 (s, 3H), 1.92 (s, 3H), 1.91 (s, 3H), 1.90 (s, 3H), 1.85 (s, 3H),
1.28 (s, 9H); 13C-NMR (100.6 MHz, CDCl3): d = 174.0, 170.5,
170.1, 169.3, 169.1, 153.4, 100.7, 72.9, 72.8, 71.9, 71.8, 71.3, 68.5,
67.5, 62.0, 58.6, 51.3, 44.0, 32.8, 30.7, 29.2, 28.6, 28.4, 20.6; ESI
(m/z) 595.1 [M++Na, (57)], 573.1 [M++1, (100)]; HRMS calcd for
[C26H40N2O12]: 572.2581, found: 572.2596.
Notes and references
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(2S)-Benzyl 2-(2-(1-tert-butyl-2,5-dioxo-3-(((3aR,5aS,8aS,8bS)-
2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4¢,5¢-
d]pyran-5-yl)methyl)imidazolidin-4-yl)acetamido)propanoate, 11
Mixture of two diast., Rf 0.32 (hexane : AcOEt 60 : 40); FTIR (neat)
n 1774, 1724 cm-1; 1H-NMR (400 MHz, CDCl3), major diast: d =
7.23 (m, 5H), 6.47 (d, J = 7.2 Hz, 1H), 5.34 (d, J = 5.0 Hz, 1H),
5.09 (d, J = 12.3 Hz, 1H), 5.04 (d, J = 12.3 Hz, 1H), 4.47 (m, 2H),
4.25 (dd, J = 5.6 and 3.9 Hz, 1H), 4.16 (dd, J = 4.9 and 2.4 Hz,
1H), 4.08 (m, 1H), 4.02 (m, 1H), 3.66 (dd, J = 15.1 and 2.0 Hz,
1H), 3.07 (dd, J = 15.1 and 9.6 Hz, 1H), 2.66 (m, 2H), 1.49 (s, 9H),
1
1.36–1.16 (m, 15H); H-NMR (400 MHz, CDCl3), minor diast:
d = 7.23 (m, 5H), 6.39 (d, J = 7.2 Hz, 1H), 5.31 (d, J = 4.9 Hz,
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astereoisomer was assessed to be (R) on the basis of the structure of the
corresponding peptide-sugar conjugate incorporating hexafluorovaline
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25 In this reaction a small amount of the other regioisomers (less than
15%) were formed and detected by 1H NMR spectroscopy.
26 The stereochemistry of the newly formed stereocenter of the major
diastereoisomer was assessed to be (R) by comparison with the reaction
products arising from acid 3a and taking into account that the reaction
mechanism is the same.
27 Also in this reaction a small amount of the others regioisomers (less
than 15%) were formed and detected by 1H NMR spectroscopy.
28 Probably, deprotonation at the new stereogenic carbon occurred during
the cyclization step promoted by the use of the NaOH solution,
rendering the reaction completely not diastereoselective.
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©