Short and highly stereoselective total synthesis of d-ribo-configured ureido sugars

Article abstract of DOI:10.1016/j.tet.2008.09.080

An highly stereoselective, flexible and very short synthetic approach to d-ribo-configured ureido monosaccharides of the aldose, aldonic acid and alditol series has been performed starting from the 5-(alditol-1-C-yl)-hydantoin intermediates, obtained via aldol-type addition reaction of hydantoin based building blocks to enantiomerically pure aldehydes. A study to assess the stereoselectivity of this reaction has been undertaken and a very high increase of diastereoselectivity was observed depending on the hydantoin protecting group. The imidazolidinone ring elaboration of 5-(alditol-1-C-yl)-hydantoin intermediates to give ureido sugar derivatives was studied.

Full text of DOI:10.1016/j.tet.2008.09.080

Tetrahedron 64 (2008) 11768–11775
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Short and highly stereoselective total synthesis of -ribo-configured ureido sugars
D
*
*
Fausta Ulgheri , Daniela Giunta, Pietro Spanu
Istituto di Chimica Biomolecolare del CNR, Trav. La Crucca 3, 07040 Sassari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An highly stereoselective, flexible and very short synthetic approach to
D-ribo-configured ureido
Received 16 June 2008
Received in revised form
11 September 2008
Accepted 25 September 2008
Available online 7 October 2008
monosaccharides of the aldose, aldonic acid and alditol series has been performed starting from the 5-
(alditol-1-C-yl)-hydantoin intermediates, obtained via aldol-type addition reaction of hydantoin based
building blocks to enantiomerically pure aldehydes. A study to assess the stereoselectivity of this reaction
has been undertaken and a very high increase of diastereoselectivity was observed depending on the
hydantoin protecting group. The imidazolidinone ring elaboration of 5-(alditol-1-C-yl)-hydantoin in-
termediates to give ureido sugar derivatives was studied.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Streptomyces containing an ureido sugar in its structure exhibits
antigastrin- and gastric-mucosal protective activity.11
Because of their relevant biological properties a few naturally
occurring carbohydrate-based ureas awakened interest during the
eighties with the discovery of antibiotic activity in a family of gly-
cocinnamoylspermidines pseudooligosaccharides 11 incorporating
an urea–glycosyl linkage, in CV-1 22 and in N-carbamoylglucos-
amine SF-1993 33 uerido monosaccharides (Fig. 1). But only in re-
cent years a renewed interest in ureido sugar derivatives has been
observed, and a few sugar ureas with new and interesting biological
properties were synthesized. Some azasugar ureas such as 4 or 5
showed glycosidase inhibition activity.4 Ureido glycuronate de-
rivatives 6 were proposed as novel antibacterial agents because of
their ability to inhibit ligases distinguishing between NADþ and
ATP-dependent ligases,5a as antifilarial agents because they are
inhibitors of filarial glutathione-S-transferases.5b,c Furthermore,
In contrast to the increasing interest in biological properties of
these sugar mimics, a relatively scarce number of synthetic strategies
have been used for the synthesis of ureido sugars. The first approach
to carbohydrate-based ureas was the condensation of mono-
saccharides with ureas.12 More recent procedures were mainly based
on the condensation of sugar-derived isocyanates1c,4c,13 and
isothiocyanates,14 sugar-derived carbamates15 or oxazolidinones4b,16
with amines or aminosugars in order to obtain ureido mono-
saccharides and pseudodisaccharides, respectively. Other methods
involve the condensation of aminosugars with isocyanates,5d,17
hydrolysis ofglycosylcarbodiimides obtained via iminophosphoranes
derived from glycosyl azides,4a,18 and finally modified Curtius
rearrangement of sugar carboxylic acids.19 Although these new in-
teresting procedures have been successful used for the synthesis of
ureido mono- and polysaccharides, new highly stereoselective
approaches that also replace dangerous reagents are particularly
attractive.
Searching for a new versatile and stereoselective procedure for
the synthesis of carbohydrate-based ureas, we looked at imidazo-
lidinone derivatives type A as suitable intermediates for the syn-
thesis of enantiopure ureido sugars equipped with a variable polyol
chain and different stereochemical centres (Scheme 1).20 In fact,
the elaboration of the imidazolidinone ring, via heterocycle ring
opening or reduction, could be an easy way to synthesize ureido-
aldonic acids (B) or ureido-aldoses and -alditols (C and D),
respectively. This approach requires the enantiomerically pure key
intermediate A that could be synthesized by a stereoselective
coupling reaction of enantiopure aldehydo precursors and
hydantoin derivatives21,22 as well as stereoconservative procedures
for the non-trivial chemical imidazolidinone ring elaboration.23
This very short route for the synthesis of carbohydrate-based ureas
they also show an
a-glycosidase inhibition activity and a mild
antitubercular activity.5d N-Glucopyranosyl ureido derivatives 7
exhibit a strong inhibition activity against glycogen phosphorylase,
an important biological target for the treatment of type II diabetes.6
Hydroxyalkylureas like 8 have shown antifungal activity and have
found cosmetic application for treating desquamative conditions of
the scalp particularly seborrhoeic dermatitis and dandruff.7 They
are also components of selective inhibitors of platelet-derived
growth factor and inhibitors of human ileal bile acid transporter.8
Ureido-furanosyluronic acid pyrimidine derivative 9 inhibits the
synthesis of chitin, a cell wall component of fungi.9 An ureido-
glucose analogue shows Trypanosoma brucei hexose transporter
inhibition10 and finally,
a new angucycline compound from
* Corresponding authors. Tel.: þ39 079 3961033; fax: þ39 079 3961036.
E-mail addresses: f.ulgheri@icb.cnr.it (F. Ulgheri), p.spanu@icb.cnr.it (P. Spanu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.080

F. Ulgheri et al. / Tetrahedron 64 (2008) 11768–11775
11769
O
diastereoselectivity of the aldol-type reaction and on the reactivity
of hydantoin intermediates.
CH3
O
H
N
H
N
O
N
H
HN
O
RO
O
NH
HO
O
NH2
2. Results and discussion
H2N
OH
HN
NH2
O
In order to obtain the 5-(alditol-1-C-yl)-hydantoin intermediates
of type A, we previouslyexamined the homologation of enantiopure
aldehydo sugars with 1,3-dibenzylhydantoin derivative (DBnHy) 11
prepared by N-protection of commercially available hydantoin 10
under weakly basic conditions (Scheme 2).21a
NH
Glycocinnaspermicin D 1
H
N
HOH2C
O
OH
OH
OH
O
N
H
HO
N
H
NH2
OH
Ph
OH
SF-1993 3
OH OH
CV-1 2
OH
1'
OH
O
O
O
O
O
3'
O
OH
OH
H
N
2'
5
b)
S
R
N
4
HO
HO
H
O
R
HN
N
O
3
Bn N
2
+
+ Bn
N
RN
1
N
O
N
O
NR
O
O
HO
Bn
Bn
O
4
O
H
O
O
OH
5
14
13
12
10 R=H
11 R=Bn
a)
COOEt
O
OH
NR2
H
N
H
O
Scheme 2. Synthesis of 5-(alditol-1-C-yl)-1,3-dibenzylhydantoins 13 and 14: (a) BnBr,
K2CO3, DMF, 85%; (b) LiHMDS, THF, ꢀ80 ꢁC, 80:20 isomer ratio 13/14.
HO
HO
N
R
O
O
N
OH
R1
O
O
O
RO
7
6
The synthesis of the required
D-ribo-configured 5-(alditol-1-
O
OH OH
C-yl)-hydantoin intermediate was performed by addition reaction
of the enantiopure C-3 aldehydo sugar 12 to DBnHy lithium eno-
late, derived from the reaction of 11 with 1.2 equiv of LiHMDS in
COOH
NH2
OH
H
O
N
NH
O
N
H
H
N
n
N
O
anhydrous THF at ꢀ80 ꢁC.
D
-ribo-Configured 5-(alditol-1-C-yl)-
R
R1
OH
HO
O
hydantoin 13 was obtained in good yield and diastereoselectivity
with a small amount of its C-5 epimer 14 (80:20 isomer ratio 13/14)
(Scheme 2).24 Purification of compound 13 was achieved at this
stage by crystallization of the crude reaction mixture from CH2Cl2/
hexane (1:3) to give 13 in 45% yield.25
9
8
Figure 1. Natural and synthetic ureido sugar derivatives.
Then, we have explored the reactivity of differently protected
hydantoin derivatives in the aldol-type addition reaction in order
to improve the diastereoselectivity of this reaction, and to find
a more easy elaboration of hydantoin ring of the 5-(alditol-1-
C-yl)-hydantoin intermediates. For this purpose 1,3-di-(tert-butoxy-
carbonyl)hydantoin 15 (DBocHy) was synthesized in high yield
(81%) by reaction of hydantoin 10 with Boc2O in CH3CN in
presence of a catalytic amount of DMAP (Scheme 3). Further-
more, the preparation of 1,3-di-(tert-butyldimethylsilyl)hydantoin
(DTBSHy) 18 was performed in high yield (84%) by reaction
of hydantoin 10 with TBSCl in CH2Cl2, Et3N (Scheme 4). The
is based on two steps only: (a) diastereoselective aldol-type ad-
dition and (b) efficient hydantoin ring elaboration, and in prin-
ciple offers a divergent and flexible approach too. In fact the
choice of different starting aldehydo sugars can generate products
with 2þn carbon chain atoms and different stereochemical
variants.
We wish to report here the stereoselective synthesis of D-ribo-
configured carbohydrate-based ureas, in particular the synthesis of
analogues of bioactive compounds 2 and 8, as the first application
of this new flexible synthetic approach to ureido monosaccharide
derivatives and the study of protecting group influence both on
O
O
PG N
N
*
H
OPG
PG
OPG
n
O
O
O
OH
OH
*
OH
OH
*
O
*
*
*
*
*
*
HO
NH
OPG
*
OH
OH
H
N
PG N
OPG
N
OH
n
N
OH
N
n
n
PG
PG
PG
PG
A
GP
O
O
ureido-alditol series
D
ureido-aldonic acid series
B
O
OH
OH
*
HO
*
*
*
*
H
NH
*
*
OH
OH
PG N
OH
N
OH
n
n
N
PG
GP
GP
O
O
ureido-aldose series
C
PG= protecting group
Scheme 1. Retrosynthetic analysis of ureido-alditol, aldose and aldonic acid series.

11770
F. Ulgheri et al. / Tetrahedron 64 (2008) 11768–11775
aldol-type addition reaction to 2,3-O-isopropylidene-
D
-glyceral-
reaction of compound 17 in THF with a LiOH aqueous solution at
0 ꢁC to room temperature gave stereoselectively an interesting
diastereopure (Z) dehydrated ureido acid 20 (Scheme 5). The
same reaction performed at ꢀ20 ꢁC to 0 ꢁC gave only the
dehydrated product 21 indicating that the dehydrating process
was the first reaction step eventually followed by hydrolytic ring
opening.28,29
dehyde 12 was then performed with both hydantoin derivatives
15 and 18. The addition reaction of the DBocHy lithium enolate
derived from the reaction of DBocHy 15 with LiHMDS in anhy-
drous THF at ꢀ80 ꢁC to the aldehyde 12 gave, after quenching
with water at ꢀ80 ꢁC and workup, a mixture of products that
were identified by NMR analysis as the dehydrated 16 and the
product 17 (Scheme 3).
O
OBoc
O
HO
a)
b)
O
O
O
Boc
Boc
N
OR''
NH
20
O
BocHN
O
O
O
N
O
O
H
b)
O
O
O
O
H
+
Boc N
+
Boc
N
R
N
O
17
N
O
N
O
N
O
H
R'
R
OBoc
O
O
O
O
O
17 R'=H, R''=Boc
16
10
12
R= H
O
a)
N
Boc
N
N
O
H
N
O
R= Boc
15
H
O
O
Scheme 3. Synthesis of 5-(alditol-1-C-yl)-3-Boc-hydantoin 17: (a) Boc2O, CH3CN,
DMAP, 81%; (b) LiHMDS 1 M solution, THF, ꢀ80 ꢁC, 98%.
17
21
Scheme 5. Synthesis of ureido aldonic acid dehydrated 20: (a) LiOH aq, THF, 0 ꢁC to rt,
95%; (b) LiOH aq, THF, ꢀ20 ꢁC to 0 ꢁC, 90%.
OTBS
O
O
O
O
a)
b)
Acidic conditions were then investigated. By treatment of
compound 17 with 37% aqueous HCl at room temperature for
12 h, deprotected hydantoin derivative 23 was quantitatively
obtained without trace of aldonic acid 22 (Scheme 6). Un-
expectedly, the treatment of compound 17 with neat TFA at room
temperature gave, after 12 h, the desired ureido aldonic acid 24
O
+
HN
TBS
N
H
TBS N
O
N
N
O
NH
10
O
TBS
H
O
O
O
18
12
19
Scheme 4. Synthesis of 5-(alditol-1-C-yl)-3-TBS-hydantoin 19: (a) TBSCl, CH2Cl2, Et3N,
84%; (b) LiHMDS 1 M solution, THF, ꢀ80 ꢁC, 56%.
in the lactone form (2-ureido-2-deoxy-D-ribonic acid-1,5-lactone)
as single diastereomer in quantitative yield. This interesting
ureido polyoxamic acid lactone30 was completely transformed
after 24–36 h into the hydantoin derivative 23 by standing at
room temperature in methanol or water solution. A methanol
solution of lactone 24 at ꢀ15 ꢁC was slowly converted into
hydantoin 23. A 1:2 mixture of 24 and 23 was detected by NMR
analysis after 4 weeks.
To avoid the dehydration process, we repeated the experiment
under the same reaction conditions quenching the reaction at
ꢀ80 ꢁC with a saturated aqueous solution of NaH2PO4 (pH 5–6).
We observed, by NMR analysis of the crude mixture, that now
only the aldol addition product 17 was obtained without trace of
the dehydrated 16 in 98% yield. Interestingly, only one of the four
possible diastereomers was formed in the addition step (de>98%).
The substitution of the Bn protecting groups by Boc groups
generated a dramatic increase of diastereomeric excess from 60%
up to >98%, with a significant increase of the reaction yield. The
product 17 was obtained by an interesting 1,3-Boc-migration
from the N-1 nitrogen to the oxygen on C-10.26 This also
explained the easy dehydration process in the basic conditions of
the workup.
An analogous migration, although of the Bz group (1,3-benzoyl
migration), was reported by Seebach et al. for the reaction of
enantiopure 1-benzoyl-2-tert-butyl-3-methylimidazolidin-4-one
lithium enolate with achiral aldehydes.27 No evidence was reported
for Boc group, but interestingly this 1,3-migration was not observed
when Bz group was substituted with Cbz group. Furthermore the
1,3-benzoyl migration proceeds with retention of configuration at
the LiO-substituted C-atom.
OH
OBoc
O
HOOC
H2N
O
b)
OH
O
Boc
N
N
OH
N
O
H
H
17
O
22
a)
OH
O
O
O
O
OH
HN
N
H
NH2
HO
NH OH
. HX
23
. CF3COOH
OH
O
24
X= Cl, CF3COO
Scheme 6. Synthesis of ureido aldonic acid 24: (a) HCl 37%, rt, 12 h, quantitative; (b)
The addition reaction of 1,3-di-(tert-butyldimethylsilyl)hy-
TFA, rt, 12 h, quantitative.
dantoin 18 to 2,3-O-isopropylidene-D-glyceraldehyde was finally
investigated (Scheme 4). The aldehyde 12 was added to the DTBSHy
lithium enolate obtained by the addition of LiHMDS to 18 in an-
hydrous THF at ꢀ80 ꢁC.
Starting from the
a
-carbamoylamino acid intermediate 22 the
-lactone 24 was kinetically
formation of the -carbamoylamino-
a
d
After quenching and aqueous workup we obtained a crude
material that was composed by a mixture of starting material 18
(44%) and the aldol addition product 19 (56%). Although the
DTBSHy addition reaction to 12 shows a good diastereoselectivity
the reaction yield was low.
favoured in these acidic conditions with respect to a new cycliza-
tion to hydantoin.31 On the contrary, the same reaction with neat
TFA performed at room temperature on the benzyl derivative 13
gave the 1,3-dibenzyl polyhydroxylated hydantoin without forma-
tion of lactone intermediate.
In order to synthesize the ureido sugar targets of the three
series, we have investigated the imidazolidinone ring reactivity
of 5-(alditol-1-C-yl)-hydantoin intermediates 17 and alternati-
vely of 13 towards basic, acidic and reductive conditions. The
Reduction of imidazolidinone ring of compounds 17 and 13 was
then studied to obtain aldose and alditol ureido sugars by using
a series of reductive conditions. Treatment of the derivative 17 with
NaBH4 in CH2Cl2 and CH3OH (3 equiv) at room temperature gave

F. Ulgheri et al. / Tetrahedron 64 (2008) 11768–11775
11771
the desired reductive opening of imidazolidinone ring. The
D
-ribo-
have been examined although many previous studies of the con-
formation of -lactones in solution consider only the half-chair and
configured 2-deoxy-2-ureido alditol 25, analogous to the bioactive
compound 8, was obtained in 94% yield as single diastereomer
(Scheme 7). On the contrary, when compound 13 was submitted to
the same NaBH4 reductive conditions we obtained a mixture of
unidentifiable products.
d
boat as main types.33 At first we attempted to distinguish between
these conformations on the basis of 1H NMR coupling constants, the
diagnostic parameters being J3,4¼1.6 Hz, J4,5¼9.2 Hz, J5,6a¼2.8 Hz
and J5,6b¼5.6 Hz. Established the stereochemistry of C-5 carbon
atom of 24 because derived from the stereochemistry of the C-2
carbon atom of the glyceraldehyde progenitor, the conformations
4H5, E5 and 2C5 are excluded because they require a not found trans
biaxial J5,6 coupling constant. We analyzed then the remaining
OBoc
OH
OBoc
O
a)
O
O
O
O
O
Boc
N
N
N
O
NH
O
BocHN
three conformations B3,6,
2S6, 1S3 for the possible four di-
H
17
O
O
25
OBoc
astereomers 24 (3R,4S,5R), 28 (3R,4R,5R), 29 (3S,4R,5R) and 30
(3S,4S,5R) (Scheme 8). On the basis of diagnostic J4,5 and J3,4 values
we excluded the (3R,4R,5R) and (3S,4R,5R) configurations of 28 and
29. Furthermore, only the B3,6 conformation for both 24 and 30 fit
with the J measured values. The stereochemistry of both di-
astereomers 24 and 30 derives from the expected Felkin approach
of the Re or Si face of the enolate of 15 to the Si face of the iso-
propylidene protected glyceraldehyde 12 (unlike or like ap-
proach).32 Finally, a diagnostic small positive NOE effect between
H-3 and H-5 permits to confirm the previous assigned (2R,3S,4R)
configuration of the lactone 24 and then the (5R,10S,20R) configu-
ration of 17.34
OBoc
HO
O
b)
c)
Boc
Bn
N
Boc
Bn
N
NH
O
O
H
17
O
O
26
OH
OH
HO
N
O
O
N
N
O
N
O
Bn
13
Bn
27
O
O
Scheme 7. Synthesis of ureido alditol 25 and ureido aldose 26 and 27: (a) NaBH4,
CH2Cl2, MeOH (3 equiv), 85%; (b) Super HÒ (3 equiv), THF, ꢀ18 ꢁC, quantitative; (c)
LiBH4, THF, rt, 96%.
O
O
O
O
NH2
NH
NH2
NH
NH2
NH
NH2
NH
O
O
O
O
The synthesis of ureido aldose derivatives was then inves-
tigated starting from compounds 17 and 13. Addition of a THF
solution of Super HÒ to compound 17 at low temperature (ꢀ18 ꢁC)
2
5
O
O
O
O
3
4
1
6
OH
OH
OH
OH
OH
29
OH
OH
OH
in anhydrous conditions gave the desired
D-ribo-configured
2-deoxy-2-ureido aldose 26, analogous of bioactive compound 2,
in quantitative yield without evidence of the ring opened aldose.
Interestingly, the reaction was diastersoselective too, furnishing
only compound 26 with (R)-configuration to C-1 as detected from
the coupling constant value (J1–2¼2.0 Hz). Alternatively, reduction
of compound 13 performed in anhydrous THF with LiBH4 at room
28
24
30
HO
OH
HO
H
OH
O
O
H
H
H
N
O
H
O
NH2
H
H
H
H
H
O
H
HN
B3,6
NH2
temperature gave D-ribo-configured 2-deoxy-2-ureido aldose 27 in
B3,6
high yield as a mixture of C-1 epimers. The reduction of compound
17 under the same reaction conditions gave a mixture of not
identifiable products.
The protecting group of the hydantoin building block has then
a great influence both on the diastereoselectivity of the aldol-type
reaction and on the reactivity of the imidazolidinone ring towards
basic, acidic and reductive conditions.
O
Scheme 8. Boat conformations of 2-deoxy-2-ureido-D-ribonic acid-1,5-lactone
diastereomers 24 and 30.
3. Conclusion
The (5R,10S) stereochemistry of the two new stereocentres of the
preferential 1,3-dibenzyl-imidazolidine-2,4-dione derivative 13
was unambiguously established by single crystal X-ray analysis of
13 on the basis of the known (R) configuration of the 20 carbon
atom.21a In analogy with the product 13, we assumed that
compound 17 could be derived by the same unlike (Re enolate, Si
aldehyde) approach of the reaction partners in the addition step
and that the 1,3-Boc-migration step, observed in the case of
DBocHy addition reaction, proceeds with retention of configuration
at the C-10 carbon atom.27 The same (5R,10S) stereochemistry of the
two new stereocentres was then tentatively assigned at this stage
to compound 17 also on the basis of a similar value of the indicative
J H(5)–H(10) coupling constant for 13 and 17. A confirmation of the
stereochemistry previously assigned to 17 was possible at this stage
by NMR analysis of the lactone 24. We started from an analysis of
We have developed the first highly stereoselective total syn-
thesis of biologically important ureido sugar derivatives in only two
steps and in very high yield. This method realizes the access to
ureido monosaccharides not by a simple modification of preformed
sugars, aminosugars or their derivatives but by building the skel-
eton of carbon atoms of the target molecules and their chirality.
This approach offers a divergent, stereoselective and flexible
procedure. In fact the simple modification of the protecting groups
of hydantoin building block introduces variability in the reactivity
of the condensed product A and in the stereoselectivity of the aldol-
type addition reaction. Furthermore, a different choice of the
aldehyde precursors can generate products with 2þn carbon atoms
chains (2 derived from hydantoin building block and n furnished by
the aldehyde). Exploiting the reactivity of differently protected
5-(alditol-1-C-yl)-hydantoin derivatives, new stereoconservative
procedures for chemical imidazolidinone ring elaborations are also
performed. As an example of the potentiality of this approach the
energy-minimized ideal d-lactone conformations that, respect to
the classical boat (B), chair (C), envelope (E), half-chair (H) and
skew (S) conformations for nonplanar six-membered rings, con-
siders conformational restrictions due to the strong preference of
the C(6)–O(1)–C(2)–C(3) unit to be close to planar (Scheme 8).33
highly stereoselective synthesis of different
ido aldose and alditol, analogues of bioactive molecules 2 and 8,
and -ribo-configured aldonic acid have been performed and
D-ribo-configured ure-
Energy-minimized ideal conformations B3,6
,
4H5, E5, 2C5, 2S6, 1S3
D

11772
F. Ulgheri et al. / Tetrahedron 64 (2008) 11768–11775
further investigations are in progress in our laboratory to extend
this approach to the synthesis of other biologically interesting
ureido sugar derivatives.
127.8, 109.7, 74.0, 71.0, 66.8, 61.2, 45.3, 42.6, 26.6, 24.8. Anal. Calcd
for C23H26N2O5: C, 67.30; H, 6.38; N, 6.82. Found C, 67.42; H, 6.42; N,
6.70. IR (Nujol, cmꢀ1): 1709 (C]O), 3453 (OH).
4. Experimental
4.1. General
4.4. 1,3-Di-(tert-butoxycarbonyl)hydantoin (15)
To a suspension of hydantoin 10 (1 g, 10 mmol) in CH3CN
(30 mL), Boc2O (4.8 g, 22 mmol) and DMAP (122 mg, 1 mmol) were
added at room temperature. The formation of a limpid solution was
observed followed by CO2 evolution. The reaction was monitored
by TLC (CH2Cl2/AcOEt 9:1). The reaction mixture was stirred for
12 h, then the solvent was evaporated under reduced pressure. The
crude reaction mixture was then purified by flash chromatography
eluting with CH2Cl2/AcOEt 9:1 to give 2.4 g of compound 15 (81%
All organic solvents were dried and freshly distilled before use
according to the literature procedures. All moisture sensitive
reactions were carried out under a positive nitrogen pressure. For
thin layer chromatography (TLC) analysis, Merck precoated TLC
plates (silica gel 60 F254, 0.25 mm) were used. Column chroma-
tography was performed on silica gel (silica gel 60). Melting
points are uncorrected. 1H NMR spectra and 13C NMR spectra
were recorded on a Varian Mercury (1H 400 MHz, 13C 100 MHz)
or Varian XL-300 (1H 300 MHz, 13C 75.4 MHz) spectrometer.
Optical rotation were measured with a Perkin–Elmer 341 digital
yield) as a white solid, mp 141–143 ꢁC. 1H NMR (400 MHz, CDCl3)
t
d
4.23 (s, 2H, H-5), 1.58 (s, 9H, tBu), 1.56 (s, 9H, Bu). 13C NMR
(100 MHz, CDCl3)
d 163.9, 148.2, 147.3, 145.0, 86.8, 85.1, 48.2, 27.9,
27.7. Anal. Calcd for C13H20N2O6: C, 51.99; H, 6.71; N, 9.33. Found C,
51.88; H, 6.76; N, 9.27. IR (Nujol, cmꢀ1): 1733, 1755, 1772, 1827
(C]O).
polarimeter using a sodium lamp (
units of 10ꢀ1 deg cm2 gꢀ1. 2,3-O-Isopropylidene-
12 was prepared from 1,2-5,6-di-O-isopropylidene-
l
589, D-line) and are given in
-glyceraldehyde
-mannitol
D
D
(Fluka) by periodate fission and used immediately. The IR spectra
4.5. (5R,10S,20R)-5-(10-tert-Butoxycabonyloxy-20,30-
isopropylidenedioxypropyl)-3-tert-butoxycarbonyl-
hydantoin (17)
were recorded on a Nicolet Avatar 330 FT-IR; nmax is expressed
in cmꢀ1
.
4.2. 1,3-Dibenzylhydantoin (11)
To a solution of DBocHy 15 (500 mg, 1.67 mmol) in anhydrous
THF (30 mL), 1.67 mL of a 1 M LiHMDS solution in THF was added
at ꢀ80 ꢁC under a nitrogen atmosphere. The reaction mixture
was stirred at this temperature for 45 min, then 2,3-O-iso-
To a suspension of hydantoin 10 (1 g, 10 mmol) in anhydrous
DMF (80 mL), K2CO3 (2.76 g, 20 mmol) was added. The suspen-
sion was stirred at room temperature for 6 h, then BnBr (2.96 mL,
20 mmol) was added. After a further 19 h, the TLC (CH2Cl2/Et2O
9:1) showed the disappearance of the starting material. Water
was added and the solution was extracted with CH2Cl2
(3ꢂ40 ml). The organic layers were dried over MgSO4 and con-
centrated under reduced pressure, the crude material obtained
was purified by flash chromatography on silica gel eluting with
CH2Cl2/Et2O 9:1 to afford 2.1 g of compound 11 (DBnHy) in 83%
yield. White solid, mp 146–148 ꢁC. 1H NMR (300 MHz, CDCl3)
propilidene-D-glyceraldehyde 12 (217 mg, 1.67 mmol) was added.
The reaction mixture was stirred at ꢀ80 ꢁC for 3.5 h, then an
NaH2PO4 saturated solution was added. The solution was
extracted with Et2O (3ꢂ40 mL), the organic layers were dried
over Na2SO4 and after filtration concentrated under reduced
pressure to give 718 mg (98%) of a pale yellow solid that was, by
20
NMR analysis, the pure product 17, mp 56–59 ꢁC. [
a
]
ꢀ25.0 (c
D
1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d 5.93 (br s, 1H, NH), 4.98
(dd, J¼4.8, 2.0 Hz, 1H, H-10), 4.34–4.29 (m, 1H, H-20), 4.26 (t,
d
7.44–7.20 (m, 10H, 2ꢂPh), 4.66 (s, 2H, CH2Ph), 4.52 (s, 2H,
J¼1.6 Hz, 1H, H-5), 4.19 (dd, J¼9.2, 7.5 Hz, 1H, H-30a), 3.86 (dd,
CH2Ph), 3.68 (s, 2H, H-5). 13C NMR (75.4 MHz, CDCl3)
d
169.4,
t
J¼9.2, 5.6 Hz, 1H, H-30b), 1.58 (s, 9H, Bu), 1.50 (s, 3H, CH3), 1.46
156.4, 135.9, 135.2, 128.9, 128.6, 128.5, 128.0, 127.8, 49.0, 46.6,
42.5. Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found
C, 72.91; H, 5.81; N, 9.89. IR (Nujol, cmꢀ1): 1701 (C]O).
(s, 9H, Bu), 1.34 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d 167.9.0,
t
152.5, 152.3, 145.8, 110.6, 85.6, 83.9, 75.2, 73.9, 66.6, 56.5, 27.8,
27.6, 26.4, 24.6. Anal. Calcd for C19H30N2O9: C, 53.02; H, 7.02; N,
6.51. Found: C, 53.18; H, 7.08; N, 6.43. IR (Nujol, cmꢀ1): 1776
(C]O), 3286 (NH).
4.3. (5R,10S,20R)-5-(10-Hydroxy-20,30-isopropylidene-
dioxypropyl)-1,3-dibenzyl hydantoin (13)
To a solution of DBnHy 11 (1 g, 3.6 mmol) in anhydrous THF
(60 mL), 1 M LiHMDS solution (4.3 mL) was added at ꢀ80 ꢁC under
nitrogen. The solution was stirred at this temperature for 30 min,
4.6. 1,3-Di-(tert-butyldimethylsilyl)hydantoin (18)
To a suspension of hydantoin 10 (1 g, 10 mmol) in anhydrous
CH2Cl2 (40 mL), Et3N (3.62 mL) and TBSCl (3.92 g, 26 mmol) were
added under nitrogen at room temperature. The reaction mixture
was stirred for one night and monitored by the TLC (hexane/Et2O
1:1), further TBSCl (1.8 g, 11.9 mmol) and Et3N (3 mL) were added.
The reaction mixture was stirred for another 3 h, then water was
added, and the mixture was extracted with CH2Cl2 (3ꢂ40 mL). The
organic layers were dried over Na2SO4 and after filtration concent-
rated under reduced pressure. The crude reaction mixture (w6 g)
was purified by flash chromatography eluting with hexane/Et2O 1:1
to give 5 g of a mixture of compound 18 containing TBSOH. This
material was further purified via flash chromatography eluting
with CH2Cl2/AcOEt 9:1 to give 2.75 g of product 18 as a white solid
then
2,3-O-isopropylidene-
D
-glyceraldehyde
12
(600 mg,
4.61 mmol) was added. The reaction mixture was stirred at ꢀ80 ꢁC
for 3 h, then was quenched at ꢀ80 ꢁC with H2O (10 mL). The solu-
tion was extracted with Et2O (2ꢂ50 mL) and CH2Cl2 (2ꢂ50 mL). The
organic layers were dried over MgSO4 and concentrated under re-
duced pressure to give a crude mixture containing 13 and 14 in
a 80:20 isomer ratio. Enantiopure compound 13 was obtained via
crystallization of the crude reaction mixture from CH2Cl2/hexane
20
1:3 (0.650 g, 45%). White solid, mp 182–184 ꢁC, [
a
]
þ44 (c 0.6,
D
CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.40–7.22 (m, 10H, 2ꢂPh), 5.03
(d, J¼14.8 Hz, 1H, CH2Ph), 4.69 and 4.64 (AB system, JAB¼14.4 Hz,
2H, CH2Ph), 4.40–4.32 (m, 1H, H-10), 4.24 (d, J¼15.2 Hz, 1H, CH2Ph),
4.09 (d, J¼1.6 Hz, 1H, H-5), 4.02 (dd, J¼8.4, 6.4 Hz, 1H, H-30a), 3.93
(dd, J¼8.8, 4.4 Hz, 1H, H-30b), 3.91–3.85 (m, 1H, H-20), 2.72 (d,
J¼4.8 Hz, 1H, OH), 1.22 (s, 3H, CH3), 1.17 (s, 3H, CH3). 13C NMR
in 84% yield, mp 65–67 ꢁC. 1H NMR (400 MHz, CDCl3)
d 3.86 (s, 2H,
t
H-5), 0.96 (2s, each 9H, 2ꢂ Bu), 0.45 (s, 6H, 2ꢂCH3), 0.31 (s, 6H,
2ꢂCH3). 13C NMR (100 MHz, CDCl3)
d 178.3, 163.9, 52.3, 26.4, 26.3,
19.4, 18.8, ꢀ4.6, ꢀ5.3. Anal. Calcd for C15H32N2O2Si2: C, 54.83; H,
(75.4 MHz, CDCl3)
d
170.2, 157.3, 135.8, 135.6, 129.0, 128.6, 128.3,

F. Ulgheri et al. / Tetrahedron 64 (2008) 11768–11775
11773
9.82; N, 8.53. Found C, 54.78; H, 9.91; N, 8.61. IR (Nujol, cmꢀ1): 1700
(C]O).
53.84; H, 6.45; N, 8.97. Found: C, 53.71; H, 6.55; N, 9.01. IR (KBr,
cmꢀ1): 1734 (C]O), 3326 (NH).
4.7. (5R,10S,20R)-5-(10-tert-Butyldimethylsilyloxy-20,30-
isopropylidenedioxypropyl)-3-tert-butyldimethyl
silylhydantoin (19)
4.10. (5R,10S,20R)-5-(10,20,30-Trihydroxypropyl)hydantoin
hydrochloride (23)
To compound 17 (47 mg, 0.11 mmol), 7 mL of 37% aqueous HCl
To a solution of 18 (500 mg, 1.52 mmol) in anhydrous THF
(30 mL), 1.52 mL of a 1 M LiHMDS solution in THF was added at
ꢀ80 ꢁC under a nitrogen atmosphere. The reaction mixture was
stirred at this temperature for 45 min, then 2,3-O-isopropilidene-
was added. The mixture was stirred for 12 h at room temperature,
then HCl was removed under vacuum to give compound 23 as
20
a white solid in quantitative yield, mp 197–199 ꢁC. [
a
]
ꢀ28.8 (c
D
1.25, H2O). 1H NMR (400 MHz, CD3OD)
d
4.43 (d, J¼1.6 Hz, 1H, H-5),
D-glyceraldehyde 12 (197 mg, 1.52 mmol) was added. The reaction
3.93 (dd, J¼8.8, 1.6 Hz, 1H, H-10), 3.79 (dd, J¼10.8, 3.2 Hz, 1H, H-30a),
mixture was stirred at ꢀ80 ꢁC for 3.5 h, then a citric acid solution
was added to pH¼8. The solution was extracted with Et2O
(3ꢂ40 mL), the organic layers were dried over Na2SO4 and after
filtration concentrated under reduced pressure to give 690 mg of
crude product as a pale yellow oil. The crude product was purified
3.66–3.54 (m, 2H, H-20, H-30b). 13C NMR (100 MHz, CD3OD)
d 179.1,
161.7, 73.1, 71.0, 64.1, 62.4. Anal. Calcd for C6H11ClN2O5: C, 31.80; H,
4.89; N, 12.36. Found: C, 31.64; H, 4.77; N, 12.28. IR (KBr, cmꢀ1):
1653 (C]O), 3447 (OH, NH).
by flash chromatography (SiO2, Hexane/Et2O 6:4) to give 391 mg
4.11. 2-Deoxy-2-ureido-
trifluoroacetate (24)
D-ribonic acid-1,5-lactone
20
(56%) of product 19 as pale yellow foam. [
a
]
ꢀ81.4 (c 1.5, CHCl3).
D
1H NMR (400 MHz, CDCl3)
d 5.68 (br s, 1H, NH), 4.18–4.08 (m, 4H,
H-10, H-20, H-30a, H-5), 3.70 (dd, J¼8.0, 6.0 Hz, 1H, H-30b), 1.45 (s,
To compound 17 (52 mg, 0.12 mmol), 3 mL of TFA was added.
The mixture was stirred for 12 h at room temperature, then TFA was
t
t
3H, CH3), 1.33 (s, 3H, CH3), 0.96 (s, 9H, BuSi), 0.86 (s, 9H, BuSi),
0.46 (s, 3H, CH3Si), 0.43 (s, 3H, CH3Si), 0.08 (s, 3H, CH3Si), 0.03 (s,
removed under vacuum to give compound 24 as a yellow glass in
20
3H, CH3Si). 13C NMR (100 MHz, CDCl3)
d
179.0, 161.4, 110.0, 78.6,
quantitative yield. [
CD3OD)
a]
ꢀ17.8 (c 0.9, CH3OH). 1H NMR (400 MHz,
D
71.4, 66.7, 60.5, 26.4, 26.3, 25.6, 24.6, 19.0, 18.0, ꢀ4.3, ꢀ4.5, ꢀ4.6,
ꢀ4.7. Anal. Calcd for C21H42N2O5Si2: C, 54.98; H, 9.23; N, 6.11.
Found: C, 54.87; H, 9.27; N, 6.15. IR (Nujol, cmꢀ1): 1722 (C]O),
3328 (NH).
d
4.63 (dd, J¼11.6, 2.8 Hz, 1H, H-5a), 4.47 (dd, J¼11.6, 5.6 Hz,
1H, H-5b), 4.32 (d, J¼1.6 Hz, 1H, H-2), 3.92 (dd, J¼9.2, 1.6 Hz, 1H, H-
3), 3.86–3.80 (m, 1H, H-4). 13C NMR (100 MHz, CD3OD)
d
178.1,
161.8, 71.7, 71.3, 71.1, 62.7. Anal. Calcd for C8H11F3N2O7: C, 31.59; H,
3.65; N, 9.21. Found: C, 31.45; H, 3.50; N, 9.08. IR (KBr, cmꢀ1): 1726,
1793 (C]O), 3293 (OH, NH).
4.8. (4S,Z)-2-(3-(tert-Butoxycarbonyl)ureido)-4,5-
isopropylidenedioxypent-2-enoic acid (20)
4.12. 2-Deoxy-2-(3-(tert-butoxycarbonyl)ureido)-4,5-
To a solution of 17 (82 mg, 0.19 mmol) in THF (5 mL), 1.9 mL of
an aqueous solution of 1 M LiOH was added. The reaction mixture
was stirred at room temperature for 1 h, and monitored by TLC
(AcOEt/hexane 7:3). The solution was diluted with a solution of
NaH2PO4 to pH¼5–6 and extracted with AcOEt (3ꢂ10 mL). The
organic layers were dried over Na2SO4, filtered and concentrated
under reduced pressure. The crude mixture was purified by flash
O-isopropylidene-D-ribitol (25)
To a solution of 17 (20 mg, 0.05 mmol) in CH2Cl2 anhydrous
(2 mL), CH3OH (6.1 l, 0.15 mmol) and NaBH4 (1.8 mg, 0.5 mmol)
m
were added. The mixture was stirred at room temperature for 2 h,
and a solution of NaH2PO4 was added. The aqueous layer was
extracted with CH2Cl2 (3ꢂ5 mL) and the organic layers were dried
over Na2SO4, filtered and the solvent removed under vacuum. The
crude mixture was purified by flash chromatography (AcOEt/hex-
chromatography (AcOEt/hexanes 2:1) to give 20 as a pale yellow
20
oil (59 mg, 95%). [
CD3OD)
a
]
D
ꢀ6.2 (c 2.1, CHCl3). 1H NMR (400 MHz,
d
6.41 (d, J¼8.0 Hz, 1H, H-3), 4.86–4.80 (m, 1H, H-4), 4.30
ane 1:1) to give 18 mg 85% yield of the product 25 as a colourless
20
(dd, J¼8.0, 6.0 Hz, 1H, H-5a), 3.76 (dd, J¼8.0, 6.8 Hz, 1H, H-5b),
oil. [
a
]
D
þ20 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3)
d 8.04 (d,
1.55 (s, 9H, tBu), 1.44 (s, 3H, CH3), 1.37 (s, 3H, CH3). 13C NMR
J¼8.4 Hz, 1H, NH), 6.82 (br s, 1H, NH), 4.98 (dd, J¼7.2, 2.8 Hz, 1H, H-
3), 4.37–4.31 (m, 1H, H-2), 4.24 (ddd, J¼7.6, 6.0, 6.0 Hz, 1H, H-4),
4.04 (dd, J¼8.8, 6.4 Hz, 1H, H-5a), 3.87 (dd, J¼8.8, 5.6 Hz, 1H, H-5b),
3.78–3.72 (m, 1H, H-1a), 3.63–3.57 (m, 1H, H-1b), 2.77 (br t, J¼6.0H,
1H, OH), 1.50 (s, 9H, tBu), 1.49 (s, 9H, tBu), 1.43 (s, 3H, CH3), 1.35 (s,
(100 MHz, CD3OD)
d 170.6, 155.9, 154.7, 132.0, 130.2, 111.4, 84.3,
75.4, 70.6, 29.2, 27.8, 26.4. Anal. Calcd for C14H22N2O7: C, 50.90; H,
6.71; N, 8.48. Found: C, 50.86; H, 6.68; N, 8.37. IR (Nujol, cmꢀ1):
1718 (C]O), 3421 (OH, NH).
3H, CH3). 13C NMR (100 MHz, CDCl3)
d 153.6, 153.3, 152.7, 109.8,
4.9. (20R,Z)-5-(20,30-Isopropylidenedioxypropylidene)-3-tert-
butoxycarbonylhydantoin (21)
83.5, 83.0, 74.7, 74.2, 66.2, 62.3, 52.0, 28.0, 27.6, 26.6, 25.4. Anal.
Calcd for C19H34N2O9: C, 52.52; H, 7.89; N, 6.45. Found: C, 52.63; H,
7.93; N, 6.51. IR (thin film, cmꢀ1): 1695,1722,1747 (C]O), 3327 (OH,
NH).
To a solution of 17 (20 mg, 0.05 mmol) in anhydrous THF (4 mL),
180
m
l of an aqueous solution of 0.5 M LiOH was added at ꢀ20 ꢁC,
the mixture was stirred at this temperature and monitored by TLC
(AcOEt/hexane 7:3) for 4 h but there was only starting material. The
temperature was allowed to rise to 0 ꢁC in 7 h and an aqueous
solution of NaH2PO4 was added to pH¼6. The solution was
extracted with AcOEt (3ꢂ5 mL), the organic layers were dried over
4.13. (4S,5R,10S,20R)-3-tert-Butoxycarbonyl-4-hydroxy-5-(10-
tert-butoxycabonyloxy-20,30-isopropylidenedioxypropyl)-
imidazolidin-2-one (26)
To a solution of 17 (100 mg, 0.23 mmol) in 5 mL of anhydrous
THF at ꢀ18 ꢁC under nitrogen was added dropwise a solution of
LiEt3BH (Super-HydrideÒ, 0.69 mmol in 5 mL of anhydrous THF).
The reaction mixture was stirred for 3 h at ꢀ18 ꢁC, then quenched
with saturated aqueous NaH2PO4 (to pH 5–6) and extracted with
ethyl acetate (2ꢂ10 mL) and Et2O (2ꢂ10 mL). The organic phases
were dried over MgSO4, filtered and the solvent removed under
reduced pressure to give 26 in quantitative yield as a colourless oil.
Na2SO4, filtered and concentrated under reduced pressure to give
20
21 (14 mg, 90%) as colourless glass. [
a]
ꢀ7.4 (c 0.8, CHCl3). 1H NMR
D
(400 MHz, CDCl3)
d
8.17 (br s, 1H, NH), 5.80 (d, J¼3.6 Hz, 1H, H-10),
4.92–4.84 (m, 1H, H-20), 4.25 (dd, J¼8.0, 6.8 Hz, 1H, H-30a), 3.71 (t,
t
J¼8.0 Hz, 1H, H-30b), 1.59 (s, 9H, Bu), 1.47 (s,3H, CH3), 1.43 (s, 3H,
CH3). 13C NMR (100 MHz, CDCl3)
d 159.5, 149.4, 146.0, 127.5, 110.9,
109.7, 86.2, 74.1, 69.3, 28.0, 26.3, 25.9. Anal. Calcd for C14H20N2O6: C,

11774
20
F. Ulgheri et al. / Tetrahedron 64 (2008) 11768–11775
7. (a) Lerebour, G. (L’Oreal) Cosmetic use of a hydroxyalkylurea for treating des-
quamative conditions of the scalp. PCT Int. Appl. WO 2007054883, 2007; (b)
Bernard, D.; Simonetti, L., Pelletier, P. (L’Oreal) Eur. Pat. Appl. EP 1743623, 2007.
8. (a) Aoki, K.; Koseki, J.; Hirokawa, H.; Obata, T.; Watanabe, T. Tai. J. P. (Tsumura
and Co.) Preparation of quinoxalinone derivatives as selective inhibitors of
platelet-derived growth factor. Jpn. Kokai Tokkyo Koho JP 2007099642, 2007;
(b) Frick, W.; Glombik, H.; Heuer, S.; Schaefer, H. -L.; Theis, S. (Sanofi-Aventis
Deutschland Gmbh) Ger. DE 102005033100, 2007.
[
a]
ꢀ18 (c 1.03, CHCl3). 1H NMR (400 MHz, CDCl3)
d 5.60 (d,
D
J¼2.0 Hz, 1H, H-4), 4.75 (dd, J¼6.0, 4.0 Hz, 1H, H-10), 4.19–4.09 (m,
2H, H-20, H-30a), 3.81 (dd, J¼8.4, 5.6 Hz, 1H, H-30b), 3.73 (dd, J¼3.6,
2.0 Hz, 1H, H-5), 1.55 (s, 9H, tBu), 1.47 (s, 9H, tBu), 1.34 (s, 3H, CH3),
1.27 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3)
d 153.1, 152.9, 150.8,
110.4, 83.7, 83.6, 80.7, 75.0, 74.8, 66.7, 56.3, 29.1, 27.6, 26.5, 25.0.
Anal. Calcd for C19H32N2O9: C, 52.77; H, 7.46; N, 6.48. Found: C,
52.89; H, 7.40; N, 6.40. IR (thin film, cmꢀ1): 1744, 1773 (C]O), 3327
(OH, NH).
9. Kiyoto, T.; Yotsuji, A.; Kajita, T.; Takashima, K.; Miyao, N.; Nomura, N. (Toyama
Chemical Co., Ltd.) Jpn. Kokai Tokkyo Koho JP 11029590, 2005.
10. Azema, L.; Claustre, S.; Arlic, I.; Blonski, C.; Willson, M.; Peire`, J.; Baltz, T.;
Tetaud, E.; Bringaud, F.; Cottem, D.; Opperdoes, F. R.; Barrett, M. P. Biochem.
Pharmacol. 2004, 67, 459.
11. Uesato, S.; Tokunaga, T.; Takeuchi, K. Bioorg. Med. Chem. Lett. 1998, 8, 1969.
12. Schoorl, M. N. Recl. Trav. Chim. Pays-Bas 1903, 22, 31.
4.14. (R)-1,3-Dibenzyl-4-hydroxy-5-((10S,20R)-20,30-
isopropylidenedioxypropyl) imidazolidin-2-one (27)
13. (a) Ichikawa, Y.; Ohara, F.; Kotsuki, H.; Nakano, K. Org. Lett. 2006, 8, 5009; (b)
Ichikawa, Y.; Nishiyama, T.; Isobe, M. J. Org. Chem. 2001, 66, 4200; (c)Ichikawa,Y.;
Matsukawa, Y.; Nishiyama, T.; Isobe, M. Eur. J. Org. Chem. 2004, 586; (d) Ichikawa, Y.;
Nashiyama, T.; Isobe, M. Synlett 2000, 1253; (e) Prosperi, D.; Ronchi, S.; Lay, L.; Ren-
curosi, A.; Russo, G. Eur. J. Org. Chem. 2004, 395; (f) Prosperi, D. Synlett 2006, 786; (g)
Lopez, O.; Maza, S.; Maya, I.; Fuentes, J.; Fernandez-Balan˜os, J. G. Tetrahedron 2005, 61,
9058; (h) Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.; Jimenez, J. L.; Light, M. E.;
Palacios, J. C.; Perez, E. M. S. Eur. J. Org. Chem. 2006, 657.
14. Jimenez Blanco, J. L.; Bootello, P.; Benito, J. M.; Ortiz Mellet, C.; Garcia Fer-
nandez, J. M. J. Org. Chem. 2006, 71, 5136.
15. Ichikawa, Y.; Nashiyama, T.; Isobe, M. Tetrahedron 2004, 60, 2621.
16. (a) Ichikawa, Y.; Matsukawa, Y.; Isobe, M. Synlett 2004, 1019; (b) Ichikawa, Y.;
Matsukawa, Y.; Isobe, M. J. Am. Chem. Soc. 2006, 128, 3934.
17. (a) Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.; Jimenez, J. L.; Light, M. E.;
Palacios, J. C.; Silvero, G. Tetrahedron 2005, 61, 7945; (b) Avalos, M.; Babiano, R.;
Cintas, P.; Jimenez, J. L.; Palacios, J. C.; Silvero, G.; Valencia, C. Tetrahedron 1999, 55,
4377; (c) Avalos, M.; Babiano, R.; Cintas, P.; Hursthouse, M. B.; Jimenez, J. L.; Light,
M. E.; Palacios, J. C.; Silvero, G. Tetrahedron 2005, 61, 7931; (d) Avalos, M.; Babiano,
R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C.; Valencia, C. Tetrahedron 1993, 49, 2676.
18. (a) Diez Perez, V. M.; Ortiz Mellet, C.; Fuentes, J.; Garcia Fernandez, J. M. Car-
bohydr. Res. 2000, 326, 161; (b) Bianchi, A.; Ferrario, D.; Bernardi, A. Carbohydr.
Res. 2006, 341, 1438.
19. Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Tetrahedron Lett. 2006, 47,
7219.
20. Stereoselective and isocyanate-free procedures for the synthesis of ureido
sugars are of particular interest because isocyanates are toxic and are usually
prepared from a dangerous reagent such as phosgene.
To a solution of 13 (100 mg, 0.24 mmol) in anhydrous THF
(10 mL), 2 M LiBH4 solution in THF (2.4 mL, 4.8 mmol) was added
under nitrogen at room temperature. The reaction mixture was
stirred at this temperature for 3 h following the disappearance of
the starting material by TLC (CH2Cl2/Et2O 7:3). Water was added
and the mixture was extracted with CH2Cl2 (3ꢂ10 mL) and AcOEt
(3ꢂ10 mL). The organic layers were dried over MgSO4 and con-
centrated under reduced pressure to give 27 (87 mg, 96%) as a col-
20
ourless glass. [
d
a]
þ12 (c 0.8, CHCl3). 1H NMR (400 MHz, CDCl3)
D
7.39–7.22 (m, 10H, PhCH2), 5.20 (d, J¼7.2 Hz, 1H, H-4a), 5.04 (d,
J¼2.8 Hz, 1H, H-4b), 4.92 (d, J¼15.2 Hz, 1H, CH2Ph), 4.73–4.22 (m,
3H, CH2Ph), 4.38–4.33 (m, 1H, H-20a), 4.34 (d, J¼15.2 Hz, 1H,
CH2Ph), 4.24–4.18 (m, 3H, CH2Ph), 4.03 (dd, J¼8.8, 6.0 Hz, 1H, H-
30aa), 3.99–3.96 (m, 1H, H-30ab), 3.95–3.88 (m, 2H, H-20b, H-30ba),
3.82–3.78 (m, 1H, H-10a), 3.70–3.64 (m, 2H, H-30bb, H-10b), 3.57 (dd,
J¼7.2, 2.8 Hz, 1H, H-5a), 3.48 (dd, J¼2.8, 1.6 Hz, 1H, H-5b), 1.27 (s,
3H, CH3b),1.24 (s, 3H, CH3b),1.21 (s, 3H, CH3a), 1.13 (s, 3H, CH3a). 13
C
NMR (100 MHz, CDCl3)
d 160.1, 159.1, 136.9, 136.5, 128.9, 128.6,
128.3, 128.0, 127.8, 127.5, 109.7, 109.5, 79.6, 77.9, 75.1, 74.1, 70.3, 69.1,
67.7, 66.8, 63.7, 62.7, 46.0, 45.6, 44.6, 43.6, 26.7, 25.0. Anal. Calcd for
C23H28N2O5: C, 66.97; H, 6.84; N, 6.79. Found C, 66.81; H, 6.96; N,
6.71. IR (KBr, cmꢀ1): 1704 (C]O), 3457 (OH).
21. A preliminary report on the diastereoselective synthesis of 5-(alditol-1-C-yl)-
hydantoin intermediates was previously published. (a) Ulgheri, F.; Orru` , G.;
Crisma, M.; Spanu, P. Tetrahedron Lett. 2004, 45, 1047; (b) Spanu, P.; Ulgheri, F. In
TargetsinHeterocyclicSystems:ChemistryandProperties; Attanasi,O. A., Spinelli, D.,
Eds.; Springer: 2004; Vol. 8, p 330.
22.
A previous example of aldol condensation of hydantoin derivatives with
Acknowledgements
enantiopure C-4 aldehydo sugar for the synthesis of hydantocidin was de-
scribed although a very low diastereoselectivity of the aldol addition reaction
was reported. (a) Mio, S.; Ichinose, R.; Goto, K.; Sugai, S.; Sato, S. Tetrahedron
1991, 47, 2111; (b) Mio, S.; Shiraishi, M.; Sugai, S.; Haruyama, H.; Sato, S.
Tetrahedron 1991, 47, 2121.
The authors would like to thank the Regione Autonoma della
Sardegna for post-doctoral fellowship (Master and Back) to
Dr. Giunta.
23. Hydantoin derivatives are important precursors of
and enzymatic heterocycle ring opening reactions. The chemical synthesis of
enantiomerically pure -amino acids from 5-monosubstituted hydantoins is
a-amino acids via chemical
a
difficult because hard conditions are required (high temperature and pressure)
in an acid environment while epimerisation of the C-5 stereogenic centre is
observed in basic conditions.
References and notes
1. (a) Ellestad, G. A.; Cosulich, D. B.; Broschard, R. W.; Martin, J. H.; Kunstmann, M. P.;
Morton, G. O.; Lancaster, J. E.; Fulmor, W.; Lovell, F. M. J. Am. Chem. Soc. 1978, 100,
2515; (b) Dobashi, K.; Nagaoka, K.; Watanabe, Y.; Nishida, M.; Hamada, M.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1985, 1166; For the total synthesis of 1, see:
(c) Nishiyama, T.; Isobe, M.; Ichikawa, Y. Angew. Chem., Int. Ed. 2005, 44, 4372.
2. (a) Ichimura, M.; Koguchi, T.; Yasuzawa, T.; Tomita, F. J. Antibiot. 1987, 40, 723;
(b) Yasuzawa, M.; Yoshida, M.; Ichimura, M.; Shirahata, K.; Sano, H. J. Antibiot.
1987, 40, 727.
3. (a) Shomura, T.; Omoto, S.; Yoshida, J.; Kojima, M.; Inouye S. Japanese Patent JP
54103801 19790815, 1979; (b) Shomura, T.; Yoshida, J.; Amano, S.; Kojima, M.;
Inouye, S.; Niida, T. J. Antibiot. 1979, 32, 427; (c) Omoto, S.;Shomura, T.; Suzuchi, H.;
Inouye, S. J. Antibiot. 1979, 32, 436.
24. Only a marginal amount (<7%) of the other two diastereomers was detected by
NMR analysis.
25. To demonstrate the synthetic versatility of this procedure for the diaster-
eoselective preparation of 5-(alditol-1-C-yl)-hydantoin derivatives containing
multiple stereogenic centres and different lengths of the polyol chain, the
synthesis of
was also performed. The addition of 2,3:4,5-di-O-isopropylidene-
DBnHy lithium enolate under the same reaction conditions reported for pro-
tected glyceraldehyde, furnished preferentially -glycero- -talo-configured
D-glycero-L-talo-configured 5-(alditol-1-C-yl)-hydantoin intermediate
L-xylose to
D
L
5-(alditol-1-C-yl)-hydantoin in 70% yield (a 72:28 isomeric ratio was detected
by NMR analysis of the crude material), see Ref. 21a.
4. (a) Garcia-Moreno, M. I.; Benito, J. M.; Ortiz Mellet, C.; Garcia Fernandez, J. M.
J. Org. Chem. 2001, 66, 7604; (b) McCort, I.; Fort, S.; Dureault, A.; Depezay, J.-C.
Bioorg. Med. Chem. 2000, 8, 135; (c) Diaz Perez, V. M.; Garcia Moreno, M. I.; Ortiz
Mellet, C.; Fuentes, J.; Diaz Arribas, J. C.; Canada, F. J.; Garcia Fernandez, J. M.
J. Org. Chem. 2000, 65, 136.
5. (a) Srivastava, S. K.; Tripathi, R. P.; Ramachandran, R. J. Biol. Chem. 2005, 280,
30273; (b) Arora, K.; Mishra, R. C.; Tripathi, R. P.; Srivastava, A. K.; Walter, R. D.
Med. Chem. Res. 2004, 8/9, 687; (c) Ahmad, R.; Mishra, R. C.; Tewari, N.;
Tripathi, R. P.; Srivastava, A. K.; Walter, R. D. Med. Chem. Res. 2004, 8/9, 724; (d)
Tewari, N.; Tiwari, V. K.; Mishra, R. C.; Tripathi, R. P.; Srivastava, A. K.; Ahmad, R.;
Srivastava, R.; Srivastava, B. S. Bioorg. Med. Chem. 2003, 11, 2911.
6. (a) Gyorgydeak, Z.; Hadady, Z.; Felfoldi, N.; Krakomperger, A.; Nagy, V.; Toth, M.;
Brunyanszki, A.; Docsa, T.; Gergely, P.; Somsak, L. Bioorg. Med. Chem. 2004, 12,
4861; (b) Oikonomakos, N.; Kosmopoulou, M.; Zographos, S. E.; Leonidas, D. D.;
Chrysina, E. D.; Somsak, L.; Nagy, V.; Praly, J.-P.; Docsa, T.; Toth, B.; Gergely, P. Eur. J.
Biochem. 2002, 269, 1684.
O
OH
O
O
O
O
LiHMDS
O
THF, -80 °C
BnN
H
O
+
Bn
N
NBn
O
O
N
O
O
Bn
O
O
26. N-Boc to O-Boc migration is a known although rarely observed rearrangement.
(a) Bunch, L.; Norrby, P.-O.; Frydenvang, K.; Krogsgaard-Larsen, P.; Madsen, U.
Org. Lett. 2001, 3, 433; (b) Dieltiens, N.; Stevens, C. V.; Masschelein, K. G. R.;
Rammeloo, T. Tetrahedron 2005, 61, 6749.
27. Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Helv. Chim. Acta 1987,
70, 237.

F. Ulgheri et al. / Tetrahedron 64 (2008) 11768–11775
11775
28. For the use of dehydrated hydantoins in the synthesis of hydantocydin
derivatives see Ref. 22a and Renard, A.; Kotera, M.; Brochier, M.-C.; Lhomme, J.
Eur. J. Org. Chem. 2000, 1831 and references quoted therein.
TS2 because of the increase of hindrance for the Boc group with respect to
the Bn group.
29. The (Z) stereochemistry of the compound 22 was assigned on the basis of the
chemical shift of the olefin proton in analogy with the reported data by Mio
(Refs. 22 and 28).
30. Davis, F. A.; Prasad, K. R.; Carrol, P. J. J. Org. Chem. 2002, 67, 7802.
31. Knobler, Y.; Bonni, E.; Frankel, M. Tetrahedron 1967, 23, 1557.
32. The formation of 5,10-anti-10,20-anti aldol 11 or 19 and 5,10-syn-10,20-anti aldol
12 results from an unlike (Re enolate, Si aldehyde) and like (Si enolate, Si
aldehyde) approach, respectively, of the reaction partners in the addition step.
In both cases the Si-face of aldehyde 10 reacts selectively. In fact aldol re-
O
R
N
R
N
O
O
O
O
O
O
O H
H
H
N
N
R
R
R
R
M
M
M
R
M
R
N
N
N
O
N
O
O
O
H
O
O
O
H
O
O
H
H
H
H
O
O
O
TS1
TS4
TS2
TS3
actions between a-chiral aldehydes and E(O)-enolates preferentially give the
Felkin-type adduct by abiding both the Felkin–Anh rule and the Zimmerman–
Traxler model. (a) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191; (b) Roush,
W. R. J. Org. Chem. 1991, 56, 4151; (c) Gennari, C.; Vieth, S.; Comotti, A.;
Vulpetti, A.; Goodman, J. M.; Paterson, I. Tetrahedron 1992, 48, 4439; The
diastereoselectivity observed can be explained by the preferential formation
of the cyclic transition state TS1 over TS2 and both over the more hindered
TS3 or TS4. An explanation of the observed increase of diastereoselectivity
moving from Bn- to Boc-imidazolidinone could be a TS1 stabilization over
R=Bn, Boc
33. Brandange, S.; Farnback, M.; Leijonmarck, H.; Sundin, A. J. Am. Chem. Soc. 2003,
125, 11942 and references quoted therein.
34. No NOE effect was measured from H-6a (4.62 ppm) and H-3 (4.31 ppm). The
measure of NOE between H-6b and H-3 was impossible because of their close
chemical shifts.