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T. Denoël et al. / Bioorg. Med. Chem. 22 (2014) 4621–4628
extracted with 3 ꢀ 100 mL CH2Cl2 and the combined organic frac-
tions were washed with water, saturated NaHCO3 and brine. The
organic layer was dried over MgSO4, filtered and evaporated in
vacuo to yield the crude product as a yellow oil which was used
without purification for the next step.
159 mg, 3 mol %). The suspension was stirred for 8 h under H2
(70 psi). TLC analysis indicated total conversion to a less mobile
product. The mixture was diluted with EtOAc, filtered on Celite
and washed with EtOAc. The solvent was evaporated in vacuo to
give a golden oil. This was dissolved in toluene (50 mL) and evap-
orated in vacuo until the start of crystallization. After 10 min, an
equal volume of hexanes was added and the crystallization was
completed at 0 °C. The crystals were filtered, washed with hexanes
and dried to constant weight in vacuo to give the title compound as
colorless needles (2.6 g, 97%). Mp 71–72 °C (dec); Rf (1:1 EtOAc/
hexanes, anisaldehyde stain) 0.3; 1H NMR (400 MHz, CDCl3) dH
4.4. General procedure for the preparation of sulfamidates
This is a modification of the protocol described in literature.30
The crude sulfamidite was dissolved in CH3CN (160 mL) and cooled
in an ice bath. RuCl3.xH2O (90 mg, 0.5 mol %) was added followed
by NaIO4 (18.8 g, 88 mmol) and water (160 mL). The green–brown
solution with a white precipitate was stirred for 15 min at 0 °C and
allowed to return to rt. After 4 h, the mixture was diluted with Et2O
(200 mL) and brine (200 mL). The aqueous layer was extracted
with Et2O (3 ꢀ 200 mL) and the pooled fractions were washed with
saturated NaHCO3 (2 ꢀ 300 mL) and brine. The organic layer was
dried over MgSO4, filtered and evaporated in vacuo to yield a beige
powder. The crude product was dissolved in the minimum amount
of CH2Cl2 and then an equal volume of Et2O was added to induce
crystallization. After 16 h at ꢁ18 °C the crystals were filtered and
dried to constant weight.
8.04 (b, 1H, OH), 4.86 (dd, J = 6.4, 1.4 Hz, 1H, H-a), 4.82 (dd,
J = 9.2, 6.6 Hz, 1H, CH2), 4.76 (dd, J = 9.2, 1.7 Hz, 1H, CH2), 1.56 (s,
9H, C(CH3)3); 13C NMR (63 MHz, CDCl3) dC 170.6 (CO), 148.4
(Boc-CO), 87.0 (C(CH3)3), 67.8 (C-b), 57.5 (C-a), 27.9 (C(CH3)3);
HRMS m/z (ES+) Calcd for C8H13LiNO7S 274.0567, found 274.0568
[MLi]+.
4.7. Enantiomeric purity: General procedure
To sulfamidate 9 or 13 (1 mmol) in degassed DMF (3 mL) was
added sodium thiophenolate (132 mg, 1 mmol). The reaction mix-
ture was stirred at rt for 2 h under nitrogen. The solution was
poured in EtOAc (20 mL) and 10% aq NaH2PO4 (20 mL). After 2 h
of stirring at 50 °C, the organic layer was decanted and the aqueous
layer was extracted with EtOAc (2 ꢀ 20 mL). The combined organic
layers were washed with water (2 ꢀ 50 mL) and brine. After drying
over MgSO4 and filtration, the solvent was evaporated in vacuo to
give an oil. The purification conducted by CC on silica with 1:1
(EtOAc/hexanes) afforded a colorless oil. Chiral HPLC conditions:
Chiralcel OD-H 9:1 (Hexanes/i-PrOH), 1.0 mL/min: tR (S)-
16 = 6.6 min, tR (R)-16 = 7.6 min, ee:>99%. The enantiomers of 17
were not separated on the Chiralcel OD-H column. Thus, the benzyl
ester 17 was converted into methyl ester 16 by refluxing with
excess 1 M methanolic HCl, followed by evaporation and reprotec-
tion of the amino group using a one-pot Boc2O/NEt3 procedure.
Compound 16 was then purified by semi-preparative HPLC and
injected on the Chiralcel OD-H column.
4.4.1. Methyl (4R)-3-(tert-butyloxycarbonyl)-2,2-dioxo-1,2,3-
oxathiazolidine-4-carboxylate (9)
Yield for two steps 68% (15.3 g); colorless crystals; mp 100–
101 °C (dec) (lit.26 71 °C); Anal (C,H,N,S) C9H15NO7S; 1H NMR
(250 MHz, CDCl3) dH 4.86–4.59 (m, 3H), 3.84 (s, 3H, OCH3), 1.53
(s, 9H, C(CH3)3); 13C NMR (63 MHz, CDCl3) dC 167.6 (CO), 148.2
(Boc-CO), 86.3 (C(CH3)3), 67.6 (C-b), 57.6 (C-a), 53.7 (OCH3), 27.9
(C(CH3)3); HRMS m/z (ES+) Calcd for C9H15LiNO7S 288.0724, found
288.0722 [MLi]+.
4.4.2. Benzyl (4R)-3-(tert-butyloxycarbonyl)-2,2-dioxo-1,2,3-
oxathiazolidine-4-carboxylate (13)
Yield for two steps 33% (9.4 g); colorless crystals; mp 121–
122 °C (dec); Rf (1:1 EtOAc/Hexanes, anisaldehyde) 0.5; 1H NMR
(400 MHz, CDCl3) dH 7.36 (s, 5H, Ar-H), 5.32 (d, J = 12.2 Hz, 1H, CH2-
Ph), 5.23 (d, J = 12.2 Hz, 1H, CH2Ph), 4.83 (br d, J = 6.5 Hz, 1H, H-a),
4.76 (dd, J = 9.2, 6.8 Hz, 1H, SerꢁCH2), 4.67 (dd, J = 9.3, 1.7 Hz, 1H,
SerꢁCH2), 1.49 (s, 9H, C(CH3)3); 13C NMR (101 MHz, CDCl3) dC
167.0 (CO), 148.1 (Boc-CO), 134.5 (Ar-C), 128.8 (Ar-C), 128.8 (Ar-
C), 128.4 (Ar-C), 86.2 (C(CH3)3), 68.5 (CH2Ph), 67.5 (C-b), 57.7 (C-
4.7.1. (S)-Methyl 2-(tert-butoxycarbonylamino)-3-
(phenylthio)propanoate ((S)-16)
Yield 80%; 1H NMR (400 MHz, CDCl3) dH 7.50–7.14 (m, 5H, Ar-
H), 5.37 (s, 1H, NH), 4.58 (s, 1H, H-a), 3.54 (s, 3H, OCH3), 3.39 (s,
a
), 27.8 (C(CH3)3); HRMS m/z (ES+) Calcd for C15H19LiNO7S
2H, CH2S), 1.43 (s, 9H, C(CH3)3); m/z (ESI) 312 [MH]+; Chiralcel
364.1037, found 364.1035 [MLi]+.
OD-H 9:1 (Hexanes/i-PrOH), 1,0 mL/min: tR (S)-16 = 6,6 min, tR
20
(R)-16 = 7,6 min, S/R:>99/1. (S)-16 [
a]
+22° (c 1, MeOH) (lit.32
D
4.5. Methyl (4R)-2,2-dioxo-1,2,3-oxathiazolidine-4-carboxylate
(10)
20
[a]
ꢁ19° (c 1, MeOH) for (R)-16).
D
4.8. 2-Phenyl-thiazoline-4-carboxylic acid (18)
A solution of 4 (1.405 g, 5 mmol) in 5 mL of CH2Cl2 and 5 mL of
TFA was refluxed for 30 min. The volatiles were removed in vacuo
and the residue was triturated in boiling Et2O (20 mL). The suspen-
sion was cooled to ꢁ18 °C for 16 h. The crystals were filtered,
washed with Et2O and dried to give the title compound as colourless
needles 735 mg (81%). Mp 102–103 °C; 1H NMR (250 MHz, D2O) dH
The literature protocol was modified as follows.35,36 A solution
of cysteine (12.1 g, 100 mmol) in degassed aqueous NaOH (0.5 M,
100 mL) was treated under nitrogen with a degassed solution of
benzonitrile (10.3 g, 100 mmol) in MeOH (200 mL). The solution
was stirred at rt for 16 h. MeOH was evaporated and 18 was pre-
cipitated at 0 °C by the addition of HCOOH (5.7 mL, 150 mmol).
The crystals were filtered, washed with cold water and dried in
vacuo to constant weight. The title compound (16.6 g, 80%) was
5.20 (b, 1H), 4.77 (dd, J = 8.9, 7.8 Hz, 1H, H-
5.3 Hz, 1H, CH2), 4.55–4.43 (m, 1H, CH2), 3.90 (s, 3H, OCH3); 13C
NMR (101 MHz, CDCl3) dC 168.8 (CO), 69.9 (C-b), 56.2 (C- ), 54.1
a), 4.61 (dd, J = 8.9,
a
(OCH3); HRMS m/z (ES+) Calcd for C4H7LiNO5S 188.0199, found
a
yellow powder. Mp 128–129 °C; 1H NMR
188.0198 [MLi]+.
obtained as
(250 MHz, D2O + NaOH) dH 8.04–7.74 (m, 2H, Ar-H), 7.74–7.21
(m, 3H, Ar-H), 4.34 (dd, J = 7.2, 4.0 Hz, 1H, H-a), 3.07 (dd, J = 13.4,
4.6. (4R)-3-(tert-Butyloxycarbonyl)-2,2-dioxo-1,2,3-
oxathiazolidine-4-carboxylic Acid (14)
3.1 Hz, 1H, CysꢁCH2), 2.92 (dd, J = 13.1, 8.2 Hz, 1H, CysꢁCH2); 13C
NMR (63 MHz, D2O + NaOH) dC 178.1 (CO), 170.1 (CN), 133.4 (Ar-
The literature protocol was modified as follows.23 To a solution
of 13 (1.785 g, 5 mmol) in EtOAc (25 mL) was added Pd/C (10%,
C), 132.2 (Ar-C), 128.8 (Ar-C), 127.2 (Ar-C), 59.3 (C-a), 27.1 (C-b);
m/z (ESI) 208 [MH]+.