Activated sulfahydantoin as Boc-glycine enolate equivalent: highly diastereoselective α-hydroxyalkylation and application to the synthesis of aldopentonate analogues

Article abstract of DOI:10.1016/j.tetlet.2008.12.070

N-Boc-activated sulfahydantoin can be seen as glycine enolate equivalent. It appeared as a convenient starting material for the stereocontrolled preparation of threonine homologues through an alkaline syn aldolization involving a Boc migration. The method

Full text of DOI:10.1016/j.tetlet.2008.12.070

Tetrahedron Letters 50 (2009) 1100–1104
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Tetrahedron Letters
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Activated sulfahydantoin as Boc-glycine enolate equivalent: highly
diastereoselective
a-hydroxyalkylation and application to the synthesis of
aldopentonate analogues
Djamel Bouchouk a,b, Evelina Colacino a, Loïc Toupet c, Noureddine Aouf b, Jean Martinez a,
Georges Dewynter a,
*
a Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS-UMI-UMII, Groupe Synthèse Asymétrique et Aminoacides, Université de Montpellier 2,
place E. Bataillon 34095 Montpellier cedex 5, France
b LCOA Groupe de Chimie Bio-Organique, Université Badji Mokhatar, Annaba, Algeria
c Groupe Matière Condensée et Matériaux, UMR 6626, Université de Rennes I, Campus de Beaulieu 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Boc-activated sulfahydantoin can be seen as glycine enolate equivalent. It appeared as a convenient
starting material for the stereocontrolled preparation of threonine homologues through an alkaline syn
aldolization involving a Boc migration. The methodology allowed the one-pot preparation of constrained
analogues of polyoxamic acid.
Received 24 November 2008
Revised 10 December 2008
Accepted 15 December 2008
Available online 24 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
C–C activation
Sulfahydantoin
Diastereoselectivity
transSulfamoylation
Polyoxamic acid analogues
b-hydroxy
a-aminoacids
Rearrangement
Sulfahydantoins (3-oxo-1,2,5-thiadiazole-1,1-dioxides) 1 (Fig. 1)
R1
4
O
3
constitute as an emergent class of heterocycles, claimed as prote-
ase inhibitors (especially matrix proteinases) and ligand of MHC
class II,1–4 aglygones in pseudonucleoside analogues,5 phosphate
mimetic,6 or substructure in the constrained peptides.7
2
N 1 N
R3
R2
S
5
O
O
1
The synthesis of sulfahydantoins (in racemic and optically
active series) has been described starting from aldehydes, via a
Bucherer–Berg reaction,8 or by sulfamoylation and ring-closure of
Figure 1. General structure for sulfahydantoins.
a
-amino acid esters.5,9 A huge diversity of sulfahydantoins was
ence of benzylamine or (S)-(ꢀ)-
a
-methylbenzylamine, the corre-
thus obtained in solution or on solid support.10–12 We report,
herein, a new and efficient method for the preparation of 2-N-
substituted sulfahydantoins in three steps. The first step is a trans-
sulfamoylation13–15 ring-closure reaction, achieved in the presence
of chlorosulfonyl isocyanate (CSI), an amino acid such as glycine
methylester (H-Gly-OMe), and chloroethanol, to afford the corre-
sponding oxazolidinone-sulfonyl-amino acid esters 2 (Scheme 1).
In this particular system, the oxazolidinone moiety behaves as a
good leaving group under the action of a nucleophile. In the pres-
sponding sulfahydantoin skeleton has been obtained, and the
protection at the 5-N-position was easily carried out with Boc2O
in the presence of DMAP, to afford activated sulfahydantoins 316
and the optically active (S)-417 in a satisfactory 50% overall yield
starting from CSI (Scheme 1).
Orthogonal groups such as benzyl or BOC can be selectively
removed in appropriate conditions (hydrogenolysis and acidic
treatment, respectively) to afford 2-N or 5-N-deprotected sulfa-
hydantoins, for further derivatisation. Sulfahydantoins can be
considered as glycine equivalents for stereocontrolled synthesis
of modified
a-aminoacids. In this respect, the Boc-glycine het-
* Corresponding author. Tel.: +33 467144819; fax: +33 467144866.
E-mail address: dewynter@univ-montp2.fr (G. Dewynter).
erocyclic derivative 316 was chosen as a convenient starting
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.070

D. Bouchouk et al. / Tetrahedron Letters 50 (2009) 1100–1104
1101
1. PhCHRNH2
OMe
O
Cl
OH
O
CH3CN, reflux
O
Ph
N
N
S N C O
Cl
Boc
S
EtONa / EtOH
3. Boc2O / DMAP
2.
Gly-OMe
TEA exc.
HN
N
O
O O
O
CSI
R
S
O
O
O
3 R = H 50%
S) - 4 R = Me 50%
2
(
Scheme 1. Improved synthesis of Boc-activated sulfahydantoins.
material to explore C–C condensation reactions. No examples are
reported on the synthesis of C-4-substituted sulfahydantoins via
an ionic condensation reaction involving the nucleophilic charac-
ter of glycine enolate equivalent. Various reaction conditions
were explored with the aim to achieve a C–C condensation reac-
tion on the C-4 position of the sulfahydantoin ring (e.g., alkyl-
This hypothesis may account the fact that the b-elimination
reaction leading to crotonization products (Perkin–Sasaki-like
reaction)19–22 is defavored, since the heterocycle is deactivated.
After Boc migration, the most acidic proton is the 5-N-hydrogen
and not more than one at the a-position, which would have been
pulled out by the base only if the Boc group was still present on
the 5-N-position. The reaction is irreversible by virtue of the differ-
ent roles played by the Boc residue: it behaves as an activating sys-
tem at the beginning of the reaction (N-Boc), and as a protecting
group (O-carbonate) after its migration. The mechanism is tenta-
tively presented below (Scheme 3). The process might be initiated
from intermediate A by the concerted aldolization/intramolecular
attack of the formed alkoxide onto the N-Boc-carbonyl moiety.
The unstable cyclic entity B might then rapidly evolve through
cleavage of the C–N and formation of C–O bond to form a stable
carbonate C.
ation,
a-and b-hydroxyalkylation, acylation, and Michael
reaction). We also investigated the reaction by changing the nat-
ure of the group on the 5-N position of the heterocyclic system.
When a silyl group such as TBDMS was introduced, the enolate
formation in the same alkaline conditions was not allowed. The
aldolization reaction was successful when the 5-N position was
substituted with an activating electron-withdrawing group such
as Boc, in the presence of DBU (2.0 equiv) as a base and in
dichloromethane as solvent (from 0 °C to room temperature).
The scope of the reaction was investigated using different achiral
and chiral aldehydes with a stereocenter at the
a
-position, in or-
It is noteworthy that the rearrangement involved the transition
a
a
der to explore their possible effect on the stereochemical course
of the reaction, as reported in Scheme 2. In our hands, no alkyli-
denation-deacylation (Perkin–Sasaki-like reaction)18–22 reaction
was observed, in contrast with the previously described reac-
tions having N-acyl or N-Boc diketopiperazines (DKPs) as sub-
strates. Interestingly, the expected aldolization products 5 were
not detected in the crude, but recovered in the form of stable
products 6–12 (Scheme 2).
from N-sp2 to a N-sp3 hybridization state, with a cis H –C –N–H
configuration, as shown by NMR data. In all cases and relatively
to CH –CHb mutual relationship, the major (or exclusive) diaste-
a
3
reoisomer was the syn aldol,25 established on the basis of
J CH –CHb values (1.46–2.90 Hz) and consistent with the small val-
a
ues already reported in the literature for similar systems26–29
(Fig. 2).
In the aldol reaction, it is usually assumed that the transition
states are rather ‘reactant-like’, however in our case the reaction
went through a ‘product-like’ non-chelated transition state. Three
contiguous chiral centers were formed starting from a prochiral
E-enolate to afford the syn-unlike products 6–12, conformation-
ally similar to the transition state, according to a diastereofacial
homoprochiral approach (Si–Si/Re–Re) conditioned by steric fac-
tors. In the case of propanal (compound 6, syn/anti 9:1, referred
The presence of compounds of type 5 was excluded because the
H -proton appeared as a doublet of doublets (in the range of 4.14–
a
5.95 ppm for all the compounds in the series), characterized by two
coupling constants, suggesting that a supplementary adjacent nu-
cleus should be present. The possibility of a coupling through four
bonds with the OH-proton was not probable, and a vicinal coupling
would have been possible only if the adjacent nitrogen atom would
be deprotected. Therefore, we speculated on the N–O acyl migra-
tion of the protecting group from the 5-N-position to the OH-
function, as already described.23,24
to CH –CHb relationship), variation of the reaction temperature,
a
reaction time or by introducing an asymmetric element on the
2-N position of sulfahydantoin nucleus as in 4 did not provide
OH
R
O
α
β
N
O
N
Bn
Boc
S
R - CHO
DBU (2 equiv.)
CH2Cl2, rt
O
O
5
N
N
Bn
Boc
S
O O
γ
R
OBoc
overnight
3
O
α
β
N
N
Bn
H
S
O O
6-12
55-70 %
6
7
8
9
R = Et
10 R = 2 - Thiophenyl
R = i - P r
R = Cyclohexyl
R = Ph
11 R = (
R
R
) - (+) - 2,2-dimethyl - 1,3 - dioxolane - 4 - yl
12 R = (
) - (+) - 3 - Boc - 2,2 - dimethyloxazolidine - 4 - yl
Scheme 2. Synthesis of selected threonine-like sulfahydantoin derivatives.

1102
D. Bouchouk et al. / Tetrahedron Letters 50 (2009) 1100–1104
R
H
R
H
S i - face
S i - face
O
R
O
R
O
H
H
O
O
H
H
S
O
N
O
DBUH
O
O
H
O
O
O
HN
S N
O
N
DBUH
N
N
S
S
O
O
O
O
O
Ph
Ph
Ph
syn - unlike product
'product-like'
Diasterofacial
S i - S i => (2S α, 3R β)
transition state of a-hydroxyalkylation
and concomittant Boc-carboxyl opening
homoprochiral approach
R e -R e => (2R α, 3S β)
S i -S i : R e - R e
C
B
A
Scheme 3. Mechanism for a-hydroxyalkylation/Boc-migration reaction.
14,32 respectively, starting from 7 (only this example is reported
here, Scheme 4).
The isosteric similarity between the free sulfahydantoin moiety
and the carboxylate group is noteworthy in such last compound.
The putative mechanism of the stereocontrolled non-chelated
3J = 1.46 -2.90 Hz
BocO
β
H
O
R
H
α
3J = 7.30 - 9.60 Hz
N
N
Bn
H
S
O
O
a-hydroxyalkylation, involving an opposite position of R group of
[Cβ-Cα] anti
[Cβ-Cα] syn
aldehyde and the bulky 5-N-Boc group leading to a syn diastereo-
facial preference observed under thermodynamic control condi-
tions, can be exemplified on compound 12 obtained from
vs
syn : anti = 9 : 1
7-10 syn > 98%
6
Garner’s
(R)-(+)-3-Boc-2,2-dimethyloxazolidine-4-carboxyalde-
hyde, and justified to the Felkin–Ahn type model I and II (Fig. 3).
It would appear that the combination of a prochiral enolate and
a chiral aldehyde leads to a facial discrimination for the aldoliza-
tion reaction, in favor of a Si–Si or Re–Re approach for the two reac-
tion partners, to afford only a single product (1R,2S,3R,4R)-12 and
(1S,2R,3S,4S)-12 as a racemic mixture, instead of the predicted
eight compounds. The racemization reaction involving the Garner’s
OBoc
OBoc
O
O
γ
γ
α
α
β
H
Ph
Ph
β
H
O
O
N
N
X
N
O
X
N
S
O
S
O
O
vs
[Cγ-Cβ-Cα] syn : syn
[Cγ-Cβ-Cα] anti : syn
(R)-(+)-3-Boc-2,2-dimethyloxazolidine-4-carboxyaldehyde
was
anti / syn : syn / syn = 2 : 1
anti / syn : syn / syn = 3 : 1
11 X = O
12 X = N -Boc
due to the presence of 2 equiv of base, and it took place just before
the attack of the prochiral enolate. The preferred diastereoisomer
derived from a matched-pair; the totally mismatched-pair is ener-
getically not favored, being the bulky Boc groups in a sterically
demanding environment, for the exo-approach of aldehyde.
In order to confirm our hypothesis and to definitely assign the
configuration of the stereocenters, compound 12 was crystallized
at room temperature in a mixture i-PrOH/(i-Pr)2O and investigated
by X-ray structural analysis. X-ray structure of (1S,2R,3S,4S)-12
proved the favourite transition state model for a syn-unlike prod-
uct O-Boc-protected (Fig. 4).
Figure 2. Stereostructures for aldol products 6–12.
any improvement of the syn/anti diastereoselectivity observed in
the subsequent aldolization,30 which maybe due to the far dis-
tance of the chiral center and no asymmetric induction was ob-
served, since a mixture of two epimers (with a ratio 55/45) was
recovered. On the other hand, in the same reaction conditions as
for the synthesis of product 6, but by only changing the nature
of aldehyde, an excellent preference for the syn adduct was al-
ways observed (compounds 7–10, syn/anti 98:2). In the presence
of a chiral aldehyde, three chiral centers were created after the
aldolization reaction. Products 11 and 12 were recovered as a
Measured vicinal coupling constants are compatible with dihe-
dral angles in the X-ray structure: according to Karplus’ equation,
a
a
an angle /[H2–N2–C –H ] of 3.3° is consistent with a coupling con-
stant of 9.6 Hz.
In conclusion, we have developed a rapid, highly diastereocon-
trolled matched synthesis of a series of syn-unlike products 6–12 in
only one step, starting from sulfahydantoin 3 and via a concerted
c
c
a
mixture of epimers at C -position in a [C –Cb–C ] anti/syn versus
[C –Cb–C ] syn/syn, respectively, of 2:1 (for compound 11) and
c
a
a
-hydroxyalkylation/Boc-migration reaction. Compounds 6–12
3:1 (for compound 12), showing a preference for the anti adduct
c
in the [C –Cb] mutual relationship. The validation of the sequen-
can be considered as protected precursors of constrained ana-
logues of polyoxamic acid derivatives, that for their intrinsic struc-
ture, result stable and not subjected to any lactonization reaction.
Molecules 6–12 contain two or three chiral centers (depending on
tial deprotection approach was then given from the successive
acidic treatment (20% TFA in dichloromethane) followed by
hydrogenolysis (H2, Pd–C 5% in ethanol), providing 1331 and
OH
O
OBoc
OH
TFA / CH2Cl2
O
O
H2 / Pd - C 5%
2 : 8 v / v
HN NH
S
N
N
HN
N
rt
Bn
Bn
H
S
EtOH
overnight
S
O O
O O
O O
7
14
85%
13
89%
Scheme 4. Sequential deprotection of Boc and Benzyl protecting groups on 7.

D. Bouchouk et al. / Tetrahedron Letters 50 (2009) 1100–1104
1103
Transition state II
(S ) - aldehyde
Transition state I
(R ) - aldehyde
O
O
O
N
O
N
O
O
H
Si-face
Si-face
O
H
Match
Mismatch
O
O
H
H
O
DBUH
O
N
O
O
N
DBUH
N
O
S
N
O
S
O
O
Ph
O
Ph
S i -S i => (2S α, 3R β , 4R γ)
From (R ) - Aldehyde:
From (S ) - Aldehyde:
R e - R e => (2R α, 3S β, 4S γ)
Figure 3. Comparison of transition states I and II: formation of the preferential diastereomeric adduct.
7. Boudjabi, S.; Dewynter, G.; Voyer, N.; Toupet, L.; Montero, J.-L. Eur. J. Org. Chem.
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8. Lee, C.-H.; Korp, J. D.; Kohn, H. J. Org. Chem. 1989, 54, 3077–3083.
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10. Tremblay, M.; Voyer, N.; Boujabi, S.; Dewynter, G. F. J. Comb. Chem. 2002, 4,
429–435.
11. Albericio, F.; Garcia, J.; Michelotti, E. L.; Nicolas, E.; Tice, C. M. Tetrahedron Lett.
2000, 41, 3161–3163.
12. Albericio, F.; Bryman, L. M.; Garcia, J.; Michelotti, E. L.; Nicolas, E.; Tice, C. M. J.
Comb. Chem. 2001, 3, 290–300.
13. Dewynter, G.; Abdaoui, M.; Regainia, Z.; Montero, J.-L. Tetrahedron 1996, 52,
14217–14224.
14. Abdaoui, M.; Dewynter, G.; Aouf, N.; Montero, J. L. Phosphorous Sulfur Silicon
1996, 118, 39–45.
15. Abdaoui, M.; Dewynter, G.; Toupet, L.; Montero, J. L. Tetrahedron 2000, 56,
2427–2435.
16. Compound 3: Yield (N-carboxylation) 96%; Mp 85–87 °C; 1H NMR (CDCl3,
200 MHz) d (ppm): 7.32 (m, 5H, Ar-H); 4.83 (s, 2H, CH2–CO); 4.41 (s, 2H, CH2-
Ar); 1.50 (s, 9H, Boc); 13C NMR (CDCl3, 100 MHz) d (ppm): 159.95, 147.45,
133.32, 129.08, 128.80, 128.73, 86.64, 49.65, 44.33, 27.92. HRMS ESI(+):
326.0926 (calcd), 326.0961 (found).
17. Compound 4: Mp 53 °C. ½a D20
ꢁ
ꢀ27 (c = 1, dichloromethane); 1H NMR (CDCl3,
a
c
Figure 4. X-ray structure of (C -R, Cb-S, C -S)-12.
400 MHz) d (ppm): 7.60–7.30 (m, 5H, Ar-H), 5.42 (q, 1H, CH-Ar), 4.31 (dd, 2H,
AB System, CH2–CO), 1.94 (d, 3H, CH3), 1.52 (s, 9H, Boc); 13C NMR (CDCl3,
100 MHz) d (ppm): 159.66, 147.46, 137.0, 128.62, 128.59, 127.81, 86.66, 54.55,
49.11, 27.93, 17.12.
the nature of starting aldehyde), available only in one step. More
particularly, they can also be considered as useful chiral synthons
for the synthesis of optically active constrained analogues of b-hy-
18. Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.; Wilkinson, S.; Luo, Y.; Lajoie, G. A.
J. Org. Chem. 1998, 63, 3631–3646. and references cited therein.
19. Gallina, C.; Liberatori, A. Tetrahedron 1974, 30, 667–673.
20. Oba, M.; Nakajima, S.; Nishiyama, K. Chem. Commun. 1996, 1875–1876.
21. Farran, D.; Parrot, I.; Martinez, J.; Dewynter, G. Angew. Chem., Int. Ed. 2007, 46,
7488–7490.
22. Farran, D.; Parrot, I.; Toupet, L.; Martinez, J.; Dewynter, J. Org. Biomol. Chem.
2008, 6, 3989–3996.
23. Seebach, D.; Juaristi, E.; Miller, D. D.; Schickli, C.; Weber, T. Helv. Chim. Acta
1987, 70, 237–261.
droxy a-aminoacids that are potentially endowed with antibacte-
rial activity18 or as functionalized 1,2 or 1,2,3 polyhydroxylated
analogues of arabinonate, known to be potent phosphoglucoisom-
erase inhibitors.33,34
We are currently investigating the scope of this process and
applying it to the synthesis of other analogues of (+)-polyhydr-
oxyamino acids, constituting the side chain moiety of antifungal
polyoxin antibiotics, endowed with biological activity.35 Relating
results will be reported in a next communication.
24. Stork, G.; Jacobson, R. M.; Levitz, R. Tetrahedron Lett. 1979, 20, 771–774.
25. Selected data: Compound 6: HPLC and NMR data on the crude showed two
diastereoisomers, in a 9/1 ratio; overall yield 58% (not separated). Data for
major product: 1H NMR (CDCl3, 400 MHz) d (ppm): 7.30 (m, 5H, Ar-H), 5.15 (m,
3
1H, CHb), 5.00 (d, 1H, NH, J(H -NH) = 8.0 Hz), 4.15 (dd, 1H, 3J
-NH) = 8.0 Hz,
a
(Ha
3J(H -Hb) = 2.9 Hz, CH ), 4.70 (d, 2H, 2J = 15.2 Hz, CH2-Ar), 1.70 (m, 2H, CH2–
a
a
CH3), 1.40 (s, 9H, Boc), 0.90 (t, 3H, CH2–CH3); 13C NMR (CDCl3, 100 MHz) d
(ppm): 166.36, 152.04, 133.88, 128.60, 128.38, 83.51, 73.83, 62.24, 44.87,
27.56, 24.90, 19.47. Compound 7: Yield 65%; Mp 125–126 °C; 1H NMR (CDCl3,
Acknowledgment
This work was partially supported by grant from Algerian
MESRS.
400 MHz) d (ppm): 7.30 (m, 5H, ArH), 5.08 (m, 1H, CHb), 4.94 (d, 1H, NH,
3J(H -NH) = 8.1 Hz), 4.65 (dd, 2H, 2J = 15.4 Hz, CH2-Ar), 4.25 (dd, J(H
=
3
a
a-NH)
3
8.1 Hz, J(H -Hb) = 2.3 Hz, CH ), 1.40 (s, 9H, Boc), 0.95 (dd, 6H, 3J = 6.7 Hz,
a
a
CH(CH3)2); 13C NMR (CDCl3, 100 MHz) d (ppm): 166.95, 152.10, 133.97, 128.69,
128.38, 122.67, 83.46, 66.20, 53.43, 44.87, 30.55, 27.51, 18.41, 18,11. Compound
8: Yield 58%; Mp 140–142 °C; 1H NMR (CDCl3, 400 MHz) d (ppm): 7.24 (m, 5H,
References and notes
3
3
1. Groutas, W. C.; Kuang, R.; Venkataraman, R.; Epp, J. B.; Ruan, S.; Prakash, O.
Biochemistry 1997, 36, 4739–4750.
2. Groutas, W. C.; Kuang, R.; Ruan, S.; Epp, J. B.; Venkataraman, R.; Truong, T. M.;
Ruan, S. Bioorg. Med. Chem. 1998, 6, 661–667.
3. Groutas, W. C.; Kuang, R.; Venkataraman, R.; Truong, T. M. Bioorg. Med. Chem.
2000, 8, 1713–1717.
4. Ducry, L.; Reinelt, S.; Seiler, P.; Diederich, F.; Bolin, D. R.; Campbell, R. M.; Olson,
G. L. Helv. Chim. Acta 1999, 82, 2432–2447.
5. Dewynter, G.; Aouf, N.; Criton, M.; Montero, J.-L. Tetrahedron 1993, 49, 65–76.
6. Black, E.; Breed, J.; Breeze, A. L.; Embrey, K.; Garcia, R.; Gero, T. W.; Godfrey, L.;
Kenny, P. W.; Morley, A. D.; Minshull, C. A.; Pannifer, A. D.; Read, J.; Rees, A.;
Russell, D. J.; Toader, D.; Tucker, J. Bioorg. Med. Chem. Lett. 2005, 15, 2503–2507.
Ar-H), 5.95 (d, 1H, J(H -NH) = 8.2 Hz, NH), 5.13 (dd, 1H, J(Hb-H ) = 8.1 Hz, CHb),
a
c
3
3
4.76 (dd, 2H, CH2-Ar), 4.30 (dd, 1H, J(H -NH) = 8.2 Hz, J(H -Hb) = 2.1 Hz, CH ),
a
a
a
1.90–1.45 (m, 11H, c-Hex), 1.40 (s, 9H, Boc); 13C NMR (CDCl3, 100 MHz) d
(ppm): 167.1, 152.09, 134.0, 128.70, 128.33, 126.47, 83.40, 61.02, 44.85, 39.61,
28.57, 28.40, 27.53, 25.80, 25.61, 25.50. Compound 9: Yield 70%; Mp 144–
146 °C; 1H NMR (CDCl3, 400 MHz) d (ppm): 7.4–7.2 (m, 10H, 2 Ar-H), 6.15 (d,
3
3
1H, J(H
= 2.4 Hz, CHb), 4.95 (d, 1H, J(H -NH) = 7.3 Hz, NH), 4.60 (dd, 2H,
a
3 3
a
-Hb)
CH2-Ar), 4.41 (dd, 1H, J(H -NH) = 7.3 Hz, J(H
= 2.4 Hz, CH ), 1.40 (s, 9H,
a
a
a
-Hb)
Boc); 13C NMR (CDCl3, 100 MHz) d (ppm): 165.20, 159.94, 135.38, 133.74,
129.22, 128.73, 128.54, 125.81, 83.84, 73.79, 64.64, 44.85, 29.71, 27.93, 27.58.
Compound 10: Yield 54%; Mp 146–148 °C; 1H NMR (CDCl3, 400 MHz) d (ppm):
7.50–7.30 (m, 6H, Ar-H, and 1H, C4H-Het), 7.25 (d, 2H, C2H-Het), 7.05 (d, 1H,

1104
D. Bouchouk et al. / Tetrahedron Letters 50 (2009) 1100–1104
3
C3H-Het), 6.51 (m, 1H, CHb), 5.24 (d, 1H, J(H -NH) = 7.7 Hz, NH), 4.80 (dd, 2H,
Union Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223/336 033 or by e-mail:
deposit@ccdc.cam.ac.uk.
26. House, H. O.; Crumrine, D. S.; Teranishi, A. Y.; Olmstead, H. D. J. Am. Chem. Soc.
1973, 95, 3310–3324.
27. Fesko, K.; Giger, L.; Hilvert, D. Bioorg. Med. Chem. Lett. 2008, 18, 5987–5990.
28. Sagui, F.; Conti, P.; Roda, G.; Contestabile, R.; Riva, S. Tetrahedron 2008, 64,
5079–5084.
29. Steinreiber, J.; Fesko, K.; Mayer, C.; Reisinger, C.; Schurmann, M.; Griengl, H.
Tetrahedron 2007, 63, 8088–8093.
a
2J = 15.5 Hz, CH2-Ar), 4.75 (d, 1H, 3J(H -NH) = 7.7 Hz, 3J(H -Hb) = 2.5 Hz, CH ), 1.43
a
a
a
(s, 9H, Boc). 13C NMR (CDCl3, 100 MHz) d (ppm): 164.95, 151.32, 137.22,
133.69, 128.44, 128.59, 128.75, 127.20, 127.07, 84.13, 70.09, 64.31, 44.93,
27.59. Compound 11: HPLC and NMR data on the crude showed two
diastereoisomers, in a 2/1 ratio; overall yield 47% (not separated). Data for
major product: 1H NMR (CDCl3, 400 MHz)
d (ppm): 7.40 (m, 5H, Ar-H),
3
3
5.28 (dbr
,
1H, J(Hb-NH) = 7.20 Hz, NH), 5.13 (dd, 1H, J(Hb-H ) = 7.5 Hz,
c
3J(H -Hb) = 1.60 Hz, CHb), 4.75 (d, 1H, 2J = 15.5 Hz, CH2-Ar), 4.58 (dd, 1H,
a
3
3
3J(H -NH) = 7.2 Hz, J(H
= 1.6 Hz, CH ), 4.25 (ddd, 1H, J(H
CH ), 4.13 (dd, 1H, J(Hd ) = 4.6 Hz, J(Hd’-Hd”) = 9.10 Hz, CHd’), 3.93 (dd, 1H,
= 7.5 Hz,
30. HPLC and NMR measurements showed a mixture of both syn diastereoisomers
a
a
-Hb)
a
c
-Hb)
3
3
in equimolar quantities starting from this chiral sulfahydantoin
propanal, isobutanal or benzaldehyde.
4 and
c
Hc
CHd”), 1.48 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.35 (s, 9H, Boc), 1.30 (s, 3H, Boc);
Compound 12: (equimolar mixture of two enantiomers) Yield 50%; 1H NMR
(CDCl3, 400 MHz) d (ppm): 7.35 (m, 2H, Ar-H), 7.25 (m, 3H, Ar-H), 6.5 (sbr, 1H,
31. Compound 13: Yield 89%; Mp 105 °C. 1H NMR (CDCl3, 400 MHz) d (ppm): 7.40–
3
7.20 (m, 6H, Ar-H and OH), 5.12 (d, 1H, J(NH-H ) = 8.2 Hz, NH), 4.61 (dd, 2H,
a
NH), 5.07 (dbr, 1H, 3J(Hb-H ) = 9.6 Hz, CHb), 4.68 (d, 1H, 2J = 15.3 Hz, CH2-Ar), 4.63
2J = 15.4 Hz, CH2-Ar), 4.15 (m, 1H, CHb), 4.02 (d, 1H, J(NH-H ) = 8.2 Hz, J(H
a c
3
3
c
a a-
3
3
(d, 1H, 2J = 15.3 Hz, CH2-Ar), 4.28 (dd, 1H, J(H -NH) = 6.7 Hz, J(H -Hb) = 1.46 Hz,
Hb) = 1.6 Hz, CH ), 1.73 (m, 1H, CH ), 0.85 (s, 6H, CH(CH3)2); 13C NMR (CDCl3,
a
a
3
3
CH ), 4.75 (dd, 1H, J(H -Hb) = 9.71 Hz, J(H -Hd) = 4.51 Hz, CH ), 3.86 (dd, 1H,
100 MHz) d (ppm): 168.63, 133.96, 128.76, 128.54, 128.40, 73.47, 62.57, 44.91,
31.66, 18.63, 17.57.
a
c
c
c
3J(Hd-H ) = 9.71 Hz, J(Hd’-Hd”) = 4.83 Hz, CHd’), 3.83 (dd, 1H, CHd”), 1.55 (s, 3H,
3
c
CH3), 1.45 (s, 3H, CH3), 1.40 (s, 9H, Boc), 1.30 (s, 9H, Boc); 13C NMR (CDCl3,
400 MHz) d (ppm): 163.80, 153.2, 151.29, 132.89, 127.88, 127.66, 127.30,
93.82, 82.59, 81.39, 71.26, 64.83, 63.48, 60.05, 55.98, 43.48, 29.30, 28.68, 27.28,
26.75, 26.50, 23.01. C25H37N3O9S, Mr = 555.64, Monoclinic P21/n,
a = 9.8020(10), b = 21.506(3), c = 13.863(2) Å, V = 2835.7(6) Å3, Z = 4,
32. Compound 14: Yield 85%; Mp 113 °C; 1H NMR (DMSO-d6, 400 MHz) d (ppm):
3
7.80 (s, 1H, N2H), 4.31 (m, 1H, CHb), 3.62 (s, 1H, OH), 3.53 (d, 1H, J(H
a
-
2
H) = 8.8 Hz, CH ), 1.70 (m, 1H, CH ), 0.85 (d, 3H, CH3), 0.62 (d, 3H, CH3);
N
a
c
13C NMR (DMSO-d6, 100 MHz) d (ppm): 170.94, 74.22, 64.25, 30.75, 19.14,
18.77.
Dx = 1.302 Mg mꢀ3, k(Mo K
a
) = 0.71069 Å,
l
= 0.168 mmꢀ1, F(000) = 1184.0,
33. Ogawa, T.; Mori, H.; Tomita, M.; Yoshino, M. Res. Microbiol. 2007, 158, 159–163.
34. Walls, A. B.; Sickmann, H. M.; Brown, A.; Bouman, S. D.; Ransom, B.; Schousboe,
A.; Waagepetersen, H. S. J. Neurochem. 2008, 105, 1462–1470.
35. Joo, J.-E.; Pham, V.-T.; Tian, Y.-S.; Chung, Y.-S.; Oh, C.-Y.; Lee, K.-Y.; Ham, W.-H.
Org. Biomol. Chem. 2008, 6, 1498–1501. and references cited therein.
T = 120(2) K. Crystallographic data for the structure in this Letter have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication Nos. CCDC No. 705481. Copies of the data can be obtained free of
charge, on application to the Cambridge Crystallographic Data Center, 12