Cyclosulfamide as a chiral auxiliary: Application to efficient asymmetric synthesis (alkylation/aldolization)

Article abstract of DOI:10.1016/j.tetasy.2010.09.001

The chiral cyclosulfamide (S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine 1,1-dioxide was designed as a chimera of Evans and Oppolzer chiral auxiliaries. The N-propionyl derivative appeared to be very powerful for the stereocontrolled synthesis of chiral building blocks through asymmetric aldolization and alkylation reactions.

Full text of DOI:10.1016/j.tetasy.2010.09.001

Tetrahedron: Asymmetry 21 (2010) 2361–2366
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Cyclosulfamide as a chiral auxiliary: application to efficient asymmetric
synthesis (alkylation/aldolization)
Fabien Fécourt a, Gérald Lopez a, Arie Van Der Lee b, Jean Martinez a, Georges Dewynter a,
⇑
a Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Universités Montpellier 1 et 2, Bâtiment Chimie (17),
Université Montpellier 2, Place E. Bataillon, 34095 Montpellier Cedex 5, France
b Institut Européen des Membranes (IEM), UMR 5635 CNRS-Université Montpellier 2, Case Courrier 047, Place E. Bataillon, 34095 Montpellier Cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The chiral cyclosulfamide (S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine 1,1-dioxide was designed as a
chimera of Evans and Oppolzer chiral auxiliaries. The N-propionyl derivative appeared to be very power-
ful for the stereocontrolled synthesis of chiral building blocks through asymmetric aldolization and alkyl-
ation reactions.
Received 14 September 2010
Accepted 16 September 2010
Available online 18 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Me2NSO2Cl, Et3N
CH2Cl2
LAH
THF
The introduction of chirality via the use of chiral auxiliaries has
been demonstrated as an effectual means for preparing chiral
compounds.1 In particular, the importance of Evans0 1,3-oxazoli-
din-2-ones 12 and Oppolzer0s chiral sultams 23 for asymmetric car-
bon–carbon bond formation has been well documented.
Ahn et al. previously investigated titanium-mediated aldol reac-
tions using the C2 symmetric cyclosulfamide chiral auxiliary 3 in
order to prepare syn dialdols with high stereoselection (>95:5).4
However, the difficult dialdol cleavage of this bis-reactive chiral
auxiliary appeared to be the weak point of this well-thought
strategy.
Herein we report a simple access to cyclosulfamides as chiral
auxiliaries through the synthesis of (S)-2-benzyl-4-isopropyl-
1,2,5-thiadiazolidine-1,1-dioxide 7.5 The applications to asymmet-
ric aldol and alkylation reactions as well as the auxiliary recovery
process are also discussed.
HN
N
OH
COOH
O
H2N
OH
S
H2N
O
5
4
p-TsCl
KOH
THF
EtCOCl, Et3N
THF
BnNH2
DMSO
O
HN
N
N
N
N
S
O
S
O
S
N
O
O
O
O
6
8
7
2. Results and discussion
Scheme 1.
2.1. Preparation of (S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine
1,1-dioxide 7 and N-acyl compound 8
conditions. Subsequent heating of 6 with 5 equiv of benzylamine
in DMSO as previously described6 gave the desired chiral sulfon-
amide auxiliary 7 in 44% overall yield from L-valine. Starting from
Our synthetic strategy involves five steps as shown in Scheme 1.
Inexpensive L-valine was first reduced with LiAlH4 into L-valinol 4,
which was subsequently derivatized with N,N-dimethylsulfonyl
chloride to give the valinol-sulfonamide 5. Then, an APTS-mediated
conversion of the free hydroxyl function into the corresponding
leaving group afforded the sulfamoyl-aziridine 6 under basic
7, the corresponding N-propionyl compound 8 was then easily ob-
tained in high yield using propionyl chloride under basic condi-
tions (see Fig. 1).4
2.2. Diastereocontrolled aldolization
The titanium enolate of 8 was generated by reaction with
1.2 equiv of TiCl4 in CH2Cl2 at ꢀ78 °C for 30 min followed by
addition of 1.2 equiv of N-diisopropylethylamine at the same
⇑
Corresponding author. Tel.: +33 467 144 819.
E-mail address: Georges.Dewynter@univ-montp2.fr (G. Dewynter).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.001

2362
F. Fécourt et al. / Tetrahedron: Asymmetry 21 (2010) 2361–2366
R
Ph
HN
Ph
HN
O
NH
O
HN
S
S
O
O
O
O
3
1
2
HN
N
S
Figure 2. Molecular structure of compound 9a; thermal ellipsoids are drawn at the
75% probability level.
O
O
7
Figure 1.
electrophiles to afford 11a and 11b, respectively, with high diaste-
reoselectivity (>99%) whereas the yields were modest (Table 2, en-
tries 1 and 3) after elimination of the starting materials by flash
chromatography. In order to improve these results, LiHMDS was
temperature and then stirring the resulting brown solution for
30 min.7,8 The enolate thus generated was then trapped with
iso-butyraldehyde at ꢀ78 °C for 4 h and progressively warmed to
0 °C overnight (Scheme 2).
used as a base; this allowed us to obtain the a-alkylated products
11a and 11b with higher yields (entries 2 and 4). The use of allyl
iodide as an electrophile instead of allyl-bromide afforded 11b
with a maximum yield of 78% (entry 4).
Analysis of the crude product mixture by 1H and 13C NMR indi-
cated the presence of only one diastereoisomeric product 9a (dr
>99%). After silica gel chromatography purification, the syn versus
anti stereochemistry of the aldol product was assigned on the basis
of 1H NMR coupling constants. The measured value for the aldol
fragment0s vicinal protons was found to be Jsyn ꢁ3 Hz, which was
completely in accordance with previously reported values for syn
aldols.2 The absolute configuration of 2,3-syn adduct 9a was then
unambiguously established through an X-ray crystallographic
analysis (Fig. 2),9a corresponding with the stereostructures previ-
ously described in oxazolidinone and sultam series.9b
An immediate 1H and/or 13C NMR analysis of the crude products
11a and 11b indicated the presence of only one diastereoisomer in
each case (dr >99%). The absolute configuration of the new asym-
metric center was assigned after removal of the chiral auxiliary
by lithium hydroxide hydrolysis as for the aldolization reactions.
The chiral cyclosulfamide auxiliary 7 was recovered quantitatively
in this hydrolysis reaction and it could be easily recycled. The abso-
lute stereochemistry of 12b was assigned as (S) by comparison of
the known specific rotations for (S)-2-methylpent-4-enoic acid10
and (R)-2-methylpent-4-enoic acid.10b,11 Similarly we assumed
an (S)-configuration for 12a.10b,11
The reaction of 8 was then investigated with a variety of alde-
hydes, including aromatic, cyclic, and aliphatic ones, using the
same conditions as described above. The results are summarized
in Table 1. All aldol products were then easily hydrolyzed with
LiOH at 0 °C in THF/H2O to afford the corresponding carboxylic
acids 10a–d as well as the recovered auxiliary 7 without any loss
of the stereochemical integrity (Table 1). The enantiomeric purity
of the b-hydroxyacids and their absolute configurations were con-
firmed by their specific rotations, which were in complete agree-
ment with those previously reported.
3. Mechanism
The results presented above indicate a transition state involving
a metal-chelated Z-enolate (Fig. 3) within which, similar to the
Oppolzer0s sultams, the cyclosulfamide may exhibit an sp3 acylated
nitrogen. However, in contrast to an Si-face approach Oppolzer
model, using the homosteric 1-(R)-(+) camphorsultame 2, our re-
sults seem to indicate a C(a)-Re-face approach. In fact, the enoliza-
tion probably induces a quasi ꢀ90° rotation of the enolate plan,
placing it perpendicular to the average cyclosulfamide plan. This
new organization confers a gain of stability and rigidity to the
transition state through the pseudo-chair ring involving both the
2.3. Stereocontrolled alkylation
The first attempts of alkylation (Scheme 3) were carried out by
using NaHMDS as a base and benzyl bromide or allyl bromide as
1. TiCl4, DIPEA
R
N
N
-78°C, CH2Cl2
N
N
S
2. RCHO,
HO
S
O
O
O
-78°C (4 hrs) to 0°C
overnight
O
O
O
9a: R=iPr
9b: R=Ph
9c: R=nPr
9d: R=cHex
8
LiOH
THF/H2O
HN
N
S
10a: R=iPr
10b: R=Ph
10c: R=nPr
10d: R=cHex
O
O
R
OH
OH
O
Scheme 2.

F. Fécourt et al. / Tetrahedron: Asymmetry 21 (2010) 2361–2366
2363
Table 1
Entry
Aldehyde
dra
% Yieldb
Product
% Yield of recovery 7c
% Yieldc
Product
1
2
3
4
iPr-CHO
Ph-CHO
nPr-CHO
cHex-CHO
>99:1
>99:1
>99:1
>99:1
93%
88%
92%
87%
9a
9b
9c
9d
96%
98%
95%
93%
95%
96%
94%
93%
10a
10b
10c
10d
a
Diastereoisomeric ratios were determined by 1H and 13C NMR.
Isolated adducts yields after silica gel chromatography.
Crude yields after auxiliary cleavage.
b
c
1.Base, -78°C,
THF
R
N
N
N
N
2. RX
S
S
-78°C (4 hrs) to 0°C
O
O
O
O
O
O
11a: R= Bn
8
11b: R= Allyl
LiOH
THF/H2O
HN
N
S
O
O
OH
O
7
R
12a: R= Bn
12b: R= Allyl
Scheme 3.
Table 2
Entry
RX
Base
dra
% Yieldb
Product
% Yield of recovery 7c
% Yieldc
Product
1
2
3
4
5
Bn-Br
Bn-Br
Allyl-Br
Allyl-Br
Allyl-I
NaHMDS
LiHMDS
NaHMDS
LiHMDS
LiHMDS
>99:1
>99:1
>99:1
>99:1
>99:1
30%
58%
48%
60%
78%
11a
11a
11b
11b
11b
96%
97%
98%
97%
98%
95%
91%
94%
92%
96%
12a
12a
12b
12b
12b
a
Diastereoisomeric ratios were determined by 1H and 13C NMR.
Isolated adducts yields after silica gel chromatography.
Crude yields after auxiliary cleavage.
b
c
Re face of enolate
Si face of enolate
R
H
(S)
Me
N
(S)
Me
N
R
H
O
O
O
O
N
S
O
N
S
O
Bn
Cl
Ti
Cl
Cl
Bn
Cl
Ti
Cl
Cl
O
O
pro S
pro S
disfavoured state
favoured state
Figure 3.
chelated metal and the Pro-S sulfone oxygen. During the aldol
reactions, the observation of our syn-aldol products suggests a
chlorotitanium enolate proceeding through a Zimmerman–Traxler
transition state,12 within which both the aldehyde and the
cyclosulfamide are coordinated to titanium. This approach can be
realized only by the most polar and the less hindranced Re-face.
In fact, this face is more accessible than the Si-face due to the
isopropyl group (as in Evans oxazolidinones). In brief, these

2364
F. Fécourt et al. / Tetrahedron: Asymmetry 21 (2010) 2361–2366
and in the three-hypothesis of either a correct hand, a 50%/50%
Si face of enolate
racemic mixture or a wrong hand of in both cases 100%.16 Because
of the rather high standard deviation on both the Flack and the
Hooft parameters data were recollected with Cu radiation which
resulted in a Flack parameter of 0.06(1) and a Hooft parameter of
0.03(1) and a 100% chance of correct assignment of the hand for
both the two and three hypotheses.
(S)
Me
N
R
E
O
O
S
N
Bn
Metal
5.3. Preparation of N0-[(S)-2-hydroxy-1-isopropyl-ethyl]-N,N-
O
dimethylsulfonamide 5
favoured state
To a solution of L-valinol (97 mmol) in anhydrous THF (100 mL)
were added Et3N (30 mL, 213 mmol, 2.2 equiv) and N,N-dim-
ethylsulfamoyl chloride (12.4 mL, 116 mmol, 1.2 equiv). The solu-
tion was stirred overnight at room temperature. The reaction
was quenched with water. The organic layer was extracted with
ethyl acetate, dried over MgSO4, and concentrated. The crude prod-
uct was purified by flash chromatography (CH2Cl2, CH2Cl2/EtOAc:
6/4) to give N0-[(S)-2-hydroxy-1-isopropylethyl]-N,N-dimethyl-sul-
fonamide 5 as a yellow oil (Yield: 88%). 1H NMR (300 MHz, CDCl3)
d: 0.97 (d, J = 6.8 Hz, 3H); 0.99 (d, J = 6.8 Hz, 3H); 1.85–1.97 (m,
1H); 2.82 (s, 6H, NMe2); 3.07–3.16 (m, 1H); 3.67 (dd, J = 5.6,
11.5 Hz, 1H); 3.77 (dd, J = 3.8, 11.5 Hz, 1H) 13C NMR (75 MHz,
CDCl3) d: 18.9 (CH3); 19.2 (CH3); 29, 7 (CH); 38.2 (CH3); 61.5
Figure 4.
hydroxyalkylation reactions provide only syn ‘Non-Evans’ com-
pounds via a diastereofacial/heteroprochiral approach between
the enolate and the carbonyl group.
For the alkylation reactions, the same mechanism predicts a
Re-face attack (Fig. 4). This approach, after cleavage, generated only
acids with the same configuration as the stereogenic center of the
cyclosulfamide auxiliary.
4. Conclusions
(CH); 62.9 (CH2). ½a D20
¼ ꢀ35 (c 1.0, CHCl3). HRMS (Q-Tof) m/z
ꢂ
[M+H]+ calcd for C7H19N2O3S 211.1116, found 211.1121.
In conclusion, we have efficiently synthesized (S)-2-benzyl-4-
isopropyl-1,2,5-thiadiazolidine-1,1-dioxide 7 as a chimera of Evans
and Oppolzer chiral auxiliaries. Herein an N-propionyl derivative 8
of this asymmetric cyclosulfamide appeared to be very powerful
for the diastereocontrolled synthesis of chiral building blocks
through asymmetric aldolization and alkylation reactions. More-
over, the efficient workup after the hydrolysis reaction allowed a
quantitative recovery of the chiral auxiliary. We are currently
investigating the synthesis of new substituted cyclosulfamides as
well as a polymer-supported version of the asymmetric synthesis
presented in this paper.
5.4. Preparation of (S)-2-isopropyl-N,N-dimethyl-aziridine-1-
sulfonamide 6
To a solution of 5 (19.02 mmol) in anhydrous THF (100 mL)
were added TsCl (4.35 g, 22.83 mmol, 1.2 equiv) and, at 0 °C,
freshly and finely broiled KOH (5.34 g, 95 mmol, 5 equiv). The
resulting mixture was stirred for 45 min at room temperature, fil-
tered and washed with Et2O. The filtrate was concentrated and the
crude oil was purified by flash chromatography (Cyclohexane/
CH2Cl2: 1/1 to CH2Cl2) to give N,N-dimethylaziridine-1-sulfon-
amide 6 as a yellow liquid (Yield: 82%). 1H NMR (300 MHz, CDCl3)
d: 0.98 (d, J = 6.8 Hz, 3H); 1.05 (d, J = 6.7 Hz, 3H); 1.46–1.57 (m,
1H); 2.08 (d, 1H); 2.38–2.44 (m, 1H); 2.48 (d, J = 6.9 Hz, 1H); 2.92
(s, 6H, NMe2) 13C NMR (300 MHz, CDCl3) d: 18.9 (CH3); 19.7
5. Experimental section
5.1. General
(CH3); 30.1 (CH); 32.5 (CH2); 38.4 (CH3); 44.4 (CH). ½a D20
¼ þ52:7
ꢂ
All solvents were dried and freshly distilled prior to use. All
reactions were realized in a flame-dried, argon purged round-
bottomed flask. TLC was performed with Merck-Kieselgel 60 F254
plates, and spots were visualized with UV light and/or by staining
with phosphomolybdic acid solution followed by heating. Flash
chromatography was performed on Merck-Kieselgel (60–40 mesh).
Melting points were recorded on Buchi 510 melting apparatus. Opti-
cal rotations were measured with a 1 cm cell on a Perkin Elmer
Polarimeter at 20 °C with a sodium lamp (589 nm). High Resolution
Mass Spectra (HRMS) were obtained on JEOL JMSSX-102 high
resolution magnetic sector mass spectrometer. 1H NMR and 13C
were recorded with Bruker 200 MHz and Bruker Advance
300 MHz, respectively.
(c 1.1, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for C7H17N2O2S
193.1011, found 193.1013.
5.5. Preparation of (4S)-2-benzyl-4-isopropyl-1,2,5-thiadiazoli-
dine 1,1-dioxide 7
Compound 7 was prepared from the procedure described by
Hannam et al.6 Isolated product purified by flash chromatography:
cyclohexane/CH2Cl2 1/1 to CH2Cl2 to yield 7 in 68% as a white solid.
Mp = 78 °C. 1H NMR (300 MHz, CDCl3) d: 0.78 (d, J = 6.7 Hz, 3H);
0.91 (d, J = 6.6 Hz, 3H); 1.62–1.73 (m, 1H); 2.85 (dd, J = 8.8 Hz,
1H); 3.22 (dd, J = 7.23 Hz, 1H); 3.29–3.39 (m, 1H); 3.90 (d,
J = 13.8 Hz, 1H); 4.25 (d, J = 13.8 Hz, 1H); 4.35 (d, J = 7.2 Hz, 1H);
7.22–7.29 (m, 5H). 13C NMR (75 MHz, CDCl3) d: 17.9 (CH3); 19.1
(CH3); 32.4 (CH); 50.4 (CH2); 51.7 (CH2); 58.5 (CH); 128.1 (CH);
5.2. X-ray crystal structure determination of compound 9a
128.6 (CH); 128.8 (CH); 135.2 (Cq). ½a D20
¼ ꢀ36 (c 1.0, CHCl3). HRMS
ꢂ
X-ray data were collected on an Oxford-Diffraction Gemini-S
diffractometer using graphite monochromated Mo-radiation. The
crystal structure was solved with the ab initio charge flipping pro-
(Q-Tof) m/z [M+H]+ calcd for C12H19N2O2S 255.1167, found
255.1160.
13
gram SUPERFLIP and refined using non-linear least-squares imple-
14
mented in CRYSTALS
.
Molecular graphics used Vesta.15
5.6. Preparation of (3S)-5-benzyl-3-isopropyl-2-propanoyl-
The Flack parameter determined using the data collected with
Mo-radiation was 0.19(7) and the Hooft parameter 0.18(4). The
Hooft analysis resulted in a chance that the correct hand was as-
signed in the two-hypothesis model of an enantiopure material
1,2,5-thiadiazolidine 1,1-dioxide 8
To a solution of cyclosulfamide 7 (200 mg, 0.786 mmol) in
anhydrous dichloromethane (10 mL) were added successively at

F. Fécourt et al. / Tetrahedron: Asymmetry 21 (2010) 2361–2366
2365
0 °C triethylamine (133
chloride (82 L, 0.944 mmol, 1.2 equiv). The reaction mixture
was stirred overnight at room temperature and then the reaction
was quenched by the addition of saturated solution of
l
L, 0.944 mmol, 1.2 equiv) and propionyl
3.75 (m, 2H); 4.08–4.20 (m, 3H); 5.57 (br s, 1H); 7.10–7.35 (m,
8H); 7.84 (d, J = 7.6 Hz, 2H). 13C NMR (75 MHz, C6D6) d: 11.8
(CH3), 16.3 (CH3), 18.0 (CH3), 29.4 (CH), 44.1 (CH2), 46.7 (CH),
50.2 (CH2), 58.0 (CH), 72.8 (CH), 126.7 (CH), 127.5 (CH), 128.3
(CH), 128.5 (CH), 128.9 (CH), 129.0 (CH), 134.3 (Cq), 141.9 (Cq),
l
a
ammonium chloride. The organic layer was extracted with dichlo-
romethane, dried over MgSO4, and the solvent was removed under
vacuum. The crude oil was purified by flash chromatography
(cyclohexane/CH2Cl2: 1/1 to CH2Cl2) to yield 8 (222 mg, 91%) as a
white solid. Mp = 60 °C. 1H NMR (300 MHz, CDCl3) d: 0.82 (d,
J = 7.0 Hz, 3H); 0.87 (d, J = 6.9 Hz, 3H); 1.22 (t, J = 7.3 Hz, 3H);
2.25–2.36 (m, 1H); 2.78–2.94 (m, 2H); 2.99 (dd, J = 3.2, 9.9 Hz,
1H); 3.14 (dd, J = 7.23, 9.9 Hz, 1H); 3.97 (d, J = 13.6 Hz, 1H); 4.24–
4.29 (m, 1H); 4.38 (d, J = 13.7 Hz, 1H); 734–7.41 (m, 5H). 13C
NMR (75 MHz, CDCl3) d: 8.65 (CH3), 16.3 (CH3), 18.4 (CH3), 28.7
(CH2), 29.3 (CH), 44.2 (CH2), 49.9 (CH2), 58.2 (CH), 128.6 (CH),
176.2 (Cq). ½a 2D0
ꢂ
¼ þ20 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H]+
calcd for C22H29N2O4S 417.1848, found 417.1844.
5.7.3. (20S,30R,3S)-5-Benzyl-3-isopropyl-2-(30-hydroxy-20-
methyl)hexanoyl-1,2,5-thiadiazolidine 1,1-dioxide 9c
Obtained with 92% from compound 8, using the general aldol
reaction procedure (colorless oil). 1H NMR (300 MHz, CDCl3) d:
0.85 (d, J = 7.0 Hz, 3H); 0.90 (d, J = 6.9 Hz, 3H); 0.97 (t, J = 7.0 Hz,
2H); 1.36 (d, J = 7.1 Hz, 3H); 1.35–1.48 (m, 2H); 1.50–1.66 (m,
2H); 2.24–2.34 (m, 1H); 3.03 (dd, J = 3.7, 10.0 Hz, 1H); 3.11 (br d,
J = 1.8 Hz, 1H); 3.20 (dd, J = 7.3, 10.0 Hz, 1H); 3.32 (dq, J = 2.5,
7.0 Hz, 1H); 4.01–4.06 (m, 2H); 4.29–4.35 (m, 1H); 4.37 (d,
J = 13.6 Hz, 1H); 7.35–7.44 (m, 5H). 13C NMR (75 MHz, CDCl3) d:
11.7 (CH3), 14.0 (CH3), 16.3 (CH3), 18.2 (CH3), 19.1 (CH2), 29.2
(CH), 35.9 (CH2), 43.7 (CH), 44.1 (CH2), 50.0 (CH2), 57.9 (CH), 70.5
(CH), 128.7 (CH), 128.8 (CH), 138.9 (CH), 133.5 (Cq), 176.3 (Cq).
128.8 (CH), 128.9 (CH), 133.7 (Cq), 171.8 (Cq). ½a D20
¼ þ17 (c 1.0,
ꢂ
CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for C15H33N2O3S 311.1429,
found 311.1432.
5.7. General procedure for aldol reactions
At first, TiCl4 (1 M in CH2Cl2, 773
added to a solution of 8 (0.64 mmol) in anhydrous CH2Cl2 (10 mL)
at ꢀ78 °C. After 15 min, diisopropylethylamine (135 L, 0.77 mmol,
l
L, 0.77 mmol, 1.2 equiv) was
½
a 2D0
ꢂ
¼ þ30 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for
C19H31N2O4S 383.2005, found 383.2006.
l
1.2 equiv) was added. After 15 min, the appropriate aldehyde
(0.77 mmol, 1.2 equiv) was added and the solution was stirred
for 4 h at ꢀ78 °C and gradually warmed overnight. Then the reac-
tion was quenched by the addition of a saturated solution of
ammonium chloride. The organic layer was extracted with CH2Cl2,
dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by flash chromatography (CH2Cl2 to
CH2Cl2/EtOAc: 6/4) to give the desired aldol 9a–d.
5.7.4. (20S,30R,3S) 5-Benzyl-3-isopropyl-2-(30-cyclohexyl-30-hydr-
oxy-20-methyl)propanoyl-1,2,5-thiadiazolidine 1,1-dioxide 9d
Obtained with 87% from compound 8, using the general aldol
reaction procedure (colorless oil). 1H NMR (300 MHz, CDCl3) d:
0.85 (d, J = 7.0 Hz, 3H); 0.89 (d, J = 6.9 Hz, 3H); 0.97–1.08 (m,
2H); 1.41–1.28 (m, 3H); 1.33 (d, J = 7.1 Hz, 3H); 1.39–1.52 (m,
1H); 1.67 (br. d, J = 10.8 Hz, 2H); 1.78 (br d, J = 12.5 Hz, 2H); 2.16
(d, J = 12.9 Hz, 1H); 2.23–2.34 (m, 1H); 3.03 (dd, J = 3.7, 10.0 Hz,
1H); 3.19 (dd, J = 7.3, 10.0 Hz, 1H); 3.53 (dq, J = 1.9, 7.0 Hz, 1H);
3.68 (dd, J = 2.0, 8.7 Hz, 1H); 4.03 (d, J = 13.6 Hz, 1H); 4.28–4.34
(m, 1H); 4.36 (d, J = 13.6 Hz, 1H); 7.34–7.45 (m, 5H). 13C NMR
(75 MHz, CDCl3) d: 11.2 (CH3), 16.3 (CH3), 18.2 (CH3), 25.9 (CH2),
26.0 (CH2), 26.4 (CH2), 28.7 (CH2), 29.2 (CH), 29.6 (CH2), 39.8
(CH), 40.4 (CH), 44.1 (CH2), 50.0 (CH2), 57.9 (CH), 74.7 (CH),
128.7 (CH), 128.8 (CH), 129.0 (CH), 133.5 (Cq), 176.8 (Cq).
5.7.1. (20S,30R,3S)-5-Benzyl-3-isopropyl-2-(20,40-dimethyl-30-
hydroxy)pentanoyl-1,2,5-thiadiazolidine 1,1-dioxide 9a
Obtained in 93% yield from compound 8, using the general pro-
cedure aldol reaction. 1H NMR (300 MHz, CDCl3) d: 0.61 (d,
J = 7.0 Hz, 3H); 0.65 (d, J = 6.9 Hz, 3H); 0.69 (d, J = 6.8 Hz, 3H);
0.83 (d, J = 6.7 Hz, 3H); 1.10 (d, J = 7.0 Hz, 3H); 1.46–1.58 (m,
1H); 1.99–2.10 (m, 1H); 2.79 (dd, J = 3.8, 10.0 Hz, 1H); 2.95 (dd,
J = 7.4, 10.0 Hz, 1H); 3.00 (br s, 1H); 3.29 (dq, J = 2.3, 7.0 Hz, 1H);
3.37 (br d, J = 8.6 Hz, 1H); 3.79 (d, J = 13.7 Hz, 1H); 4.04–4.10 (m,
1H); 4.12 (d, J = 13.8 Hz, 1H); 7.10–7.20 (m, 5H). 13C NMR
(75 MHz, CDCl3) d: 11.4 (CH3), 16.3 (CH3), 18.2 (CH3), 18.8 (CH3),
19.2 (CH3), 29.2 (CH), 30.5 (CH), 41.0 (CH), 44.1 (CH2), 50.0 (CH2),
57.9 (CH), 75.9 (CH), 128.7 (CH), 128.8 (CH), 129.0 (CH), 133.5
½
a 2D0
ꢂ
¼ þ31 (c 1.0, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd for
C22H35N2O4S 423.2318, found 423.2313.
5.8. General procedure for alkylation reactions
At first, LiHMDS (387 lL, 0.387 mmol, 1.2 equiv) was added to a
solution of 8 (100 mg, 0.322 mmol) in anhydrous THF (7 mL) at
ꢀ78 °C. After 30 min, the appropriate alkyl halide (0.966 mmol,
3 equiv) was added and the solution was stirred for 4 h at ꢀ78 °C
and gradually warmed overnight. Then the reaction was quenched
by the addition of a saturated solution of ammonium chloride. The
organic layer was extracted with CH2Cl2, dried over MgSO4, and
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography (cyclohexane/CH2Cl2 7/3–1/1) to give
the desired alkyl product.
(Cq), 176.6 (Cq). ½a D20
¼ þ25 (c 1.0, CHCl3). Mp = 49 °C. HRMS
ꢂ
(Q-Tof) m/z [M+H]+ calcd for C19H31N2O4S 383.2005, found
383.2008.
Crystal data for 9a: Formula = C19H29N2O4S, T = 175 K,
Mr = 382.52 g molꢀ1
,
crystal size = 0.040 ꢃ 0.170 ꢃ 0.430 mm,
monoclinic, space group C2, a = 24.9190(16), b = 6.3825(3), c =
14.1290(9) Å, = 90°, b = 111.453(7)°,
= 90°, V = 2091.5(2) Å3,
Z = 4,
calcd = 1.212 g cmꢀ3 = 0.179 mmꢀ1, hmax = 28.877°, experi-
mental resolution 0.74 Å. 4214 reflections measured, 3602 unique,
3107 with I > 2 (I), Rint = 0.020, < (I)/I> = 0.0509, refined parame-
ters = 235, R1 (I > 2 (I)) = 0.0320, wR2 (I > 2 (I)) = 0.0456 R1 (all
data) = 0.0384, wR2 (all data) = 0.0456, GOF = 1.1223, (min/
max) = 0.29/0.25 e Åꢀ3
a
c
q
, l
r
r
5.8.1. (20S,3S) 5-Benzyl-3-isopropyl-2-(20-methyl-30-phenyl)pro-
panoyl-1,2,5-thiadiazolidine 1,1-dioxide 11a
r
r
D
q
Obtained in 58% yield from compound 8, using the general
alkylation adduct procedure (colorless oil). 1H NMR (300 MHz,
CDCl3) d: 0.52 (d, J = 6.9 Hz, 3H); 0.63 (d, J = 7.0 Hz, 3H); 1.17 (d,
J = 6.5 Hz, 3H); 1.89–2.06 (m, 1H); 2.66 (dd, J = 13.3, 7.5 Hz, 1H);
2.84 (dd, J = 9.9, 3.5 Hz, 1H); 2.94–3.12 (m, 2H); 3.39–3.58 (m,
1H); 3.90 (d, J = 13.7, 1H); 4.10–4.21 (m, 1H); 4.27 (d, J = 13.7 Hz;
1H); 6.95–7.46 (m, 10H).13C NMR (75 MHz, CDCl3) d: 15.9 (CH3);
16.7 (CH3); 18.2 (CH3); 29.2 (CH); 41.1 (CH2); 42.0 (CH); 43.7
(CH2); 49.9 (CH2); 58.0 (CH); 126.4 (CH); 128.3 (CH); 128.5 (CH);
.
5.7.2. (20S,30S,3S)-5-Benzyl-3-isopropyl-2-(30-hydroxy-20-methyl-
30-phenyl)propanoyl-1,2,5-thiadiazolidine 1,1-dioxide 9b
Obtained in 88% yield from compound 8, using the general aldol
reaction procedure (colorless oil). 1H NMR (300 MHz, C6D6) d: 0.57
(d, J = 7.0 Hz, 3H); 0.76 (d, J = 6.9 Hz, 3H); 1.50 (d, J = 7.0 Hz, 3H);
2.18–2.29 (m, 1H); 2.60 (s, 1H); 2.62 (d, J = 1.3 Hz, 1H); 3.70–

2366
F. Fécourt et al. / Tetrahedron: Asymmetry 21 (2010) 2361–2366
128.8 (CH); 128.9 (CH); 129.3 (CH); 133.7 (Cq); 138.6 (Cq); 174.5
(qd, J = 7.1, 3.3 Hz, 1H); 3.64 (dd, J = 8.4, 3.3 Hz, 1H). ½a D20
¼ ꢀ2 (c
ꢂ
(Cq). ½a 2D0
ꢂ
¼ ꢀ90 (c 0.3, CHCl3). HRMS (Q-Tof) m/z [M+H]+ calcd
1.2, CHCl3). ½a 2D2
ꢂ
¼ ꢀ4 (c 0.6, CH2Cl2) lit.18
for C22H29N2O3S 401.1899, found 401.1891.
5.9.5. (S)-2-Methyl-3-phenylpropanoic acid 12a
5.8.2. (20S,3S) 5-Benzyl-3-isopropyl-2-(-20-methyl)pent-40-enoyl-
1,2,5-thiadiazolidine 1,1-dioxide 11b
Obtained in 95% yield from compound 11a, using the general
procedure hydrolysis cleavage (colorless oil). 1H NMR (300 MHz,
CDCl3) d: 1.17 (d, J = 7.0 Hz, 3H), 2.71 (dd, J = 8.0, 13.5 Hz, 1H),
2.78 (m, 1H), 3.08 (dd, J = 6.5, 13.5 Hz, 2H), 7.20–7.35 (m, 5H).
Obtained in 78% yield from compound 8, using the general
alkylation adduct procedure (white solid). Mp = 56 °C. 1H NMR
(300 MHz, CDCl3) d: 0.74 (d, J = 7.0 Hz, 3H); 0.79 (d, J = 6.9 Hz,
3H); 1.15 (d, J = 6.6 Hz, 3H); 2.09–2.24 (m, 2H); 2.46 (ddd,
J = 14.8, 10.6, 6.8 Hz, 1H); 2.91 (dd, J = 10.0, 3.6 Hz, 1H); 3.06 (dd,
J = 9.9, 7.4 Hz, 1H); 3.17–3.35 (m, 1H); 3.91 (d, J = 13.7 Hz, 1H);
4.22 (ddd, J = 7.5, 4.8, 3.7 Hz, 1H); 4.28 (d, J = 13.7 Hz, 1H); 4.87–
5.12 (m, 2H); 5.74 (ddt, J = 17.1, 10.1, 7.0 Hz, 1H); 7.24–7.37 (m,
5H).13C NMR (75 MHz, CDCl3) d: 16.2 (CH3); 16.5 (CH3); 18.3
(CH3); 29.2 (CH); 39.3 (CH2); 39.8 (CH); 43.8 (CH2); 50.0 (CH2);
58.1 (CH); 117.4 (CH2); 128.6 (CH); 128.8 (CH); 128.9 (CH);
½
a 2D0
ꢂ
¼ þ25:6 (c 0.5, CHCl3). ½a D20
ꢂ
¼ þ26:3 (c 1.0, CHCl3) lit.10b
5.9.6. (S)-2-Methylpent-4-enoic acid 12b
Obtained in 96%yield from compound 11b, using the general
procedure hydrolysis cleavage (colorless oil). 1H NMR (300 MHz,
CDCl3) d: 1.12 (d, J = 6.9 Hz, 3H); 2.08–2.21 (m, 1H); 2.32–2.43
(m, 1H); 2.43–2.55 (m, 1H); 4.95–5.08 (m, 2H); 5.61–5.78 (m,
1H). ½a 2D0
ꢂ
¼ þ9:7 (c 0.4, CHCl3). ½a D20
ꢂ
¼ þ10:1 (c 1.0, CHCl3) lit.10a
133.7 (Cq); 134.9 (CH); 174.7 (Cq). ½a D20
ꢂ
¼ ꢀ0:4 (c 0.5, CHCl3).
Acknowledgment
We thank the CNRS for financial support.
References
HRMS (Q-Tof) m/z [M+H]+ calcd for C18HéèN2O3S 351.1742, found
351.1739.
5.9. General procedure for cleavage using LiOH hydrolysis
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5.9.1. (2S,3R)-3-Hydroxy-2,4-dimethylpentanoic acid 10a
Obtained in 95% yield from compound 9a, using the general
hydrolysis cleavage procedure (white solid). NMR (300 MHz,
CDCl3) d: 0.82 (d, J = 6.8 Hz, 3H); 0.95 (d, J = 6.6 Hz, 3H); 1.13 (d,
J = 7.2 Hz, 3H); 1.57–1.71 (m, 1H); 2.64 (qd, J = 7.1, 3.6 Hz, 1H);
3.57 (dd, J = 8.1, 3.6 Hz, 1H). ½a D20
ꢂ
¼ ꢀ8 (c 0.5, CHCl3). ½a D20
¼ ꢀ9:5
ꢂ
(c 0.4, CH2Cl2) lit.17
5.9.2. (2S,3S)-3-Hydroxy-2-methyl-3-phenylpropanoic acid 10b
Obtained in 96% yield from compound 9b, using the general
procedure hydrolysis cleavage (white solid). 1H NMR (300 MHz,
CDCl3) d: 1.08 (d, J = 7.2 Hz, 3H); 2.77 (qd, J = 7.2, 3.9 Hz, 1H);
5.11 (d, J = 3.9 Hz, 1H); 7.19–7.29 (m, 5H). ½a D20
¼ ꢀ31 (c 1.0 in
ꢂ
CHCl3). ½a 2D0
ꢂ
¼ ꢀ29:3 (c 0.8, CHCl3) lit.18
5.9.3. (2S,3R)-3-Hydroxy-2-methylhexanoic acid 10c
Obtained in 94% yield from compound 9c, using the general
procedure hydrolysis cleavage (colorless oil). 1H NMR (300 MHz,
CDCl3) d: 0.88 (t, J = 6.9 Hz, 3H); 1.14 (d, J = 7.2 Hz, 3H); 1.16–
1.57 (m, 5H); 2.53 (qd, J = 7.2, 3.5 Hz, 1H); 3.83–3.96 (m, 1H).
½
a 2D0
ꢂ
¼ þ12 (c 1.0, CHCl3).
5.9.4. (2S,3R)-3-Cyclohexyl-3-hydroxy-2-methyl-propanoic acid
10d
Obtained in 93% yield from compound 9d, using the general
procedure hydrolysis cleavage (colorless oil). 1H NMR (300 MHz,
CDCl3) d: 0.84–1.69 (m, 13H), 1.12 (d, J = 7.2 Hz, 2H); 2.64
18. Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 1299–1308.