Notes
J . Org. Chem., Vol. 61, No. 22, 1996 7957
{3.89 (d, J ) 4.4 Hz), 3.98 (br s), 4.02 (br s), 4.17 (d, J ) 5.3
Hz), 4.22 (d, J ) 5.3 Hz), ca. 2H combined}, {4.52 (d, J ) 8.4
Hz) and 4.88 (m, J ) 4.2, 4.9 Hz), ca. 1H combined}, {5.24 (t, J
) 4.5 Hz) and 5.40 (br m), 1H combined}, 7.43-7.56 (m, 5 H).
13C NMR [75 MHz, CDCl3 + drop of CD3OD]: δ 34.7, 37.4, 37.7,
37.9, 52.3, 54.2, 56.7, 59.6, 77.1, 82.5, 126.5, 128.2, 129.9, 130.3,
134.8, 135.4, 170.3, 171.2, 172.0, 172.4. IR (KBr): 1745 (br),
1595, 1570, 1335, 1165 cm-1. Anal. Calcd for C13H15NO6S: C,
49.83; H, 4.83; N, 4.47; S, 10.23. Found: C, 49.74; H, 4.73; N,
4.38; S, 10.38.
redox byproducts, eliminating the need for chromatog-
raphy. No more than 0.1% of the trans-isomer is found
in the product 3. These conditions have been extended
to the preparation of two other sulfonates.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. All
reagents and solvents were reagent grade. All reactions were
conducted under nitrogen, except for hydrolyses.
Tr ip h en ylp h osp h in e Oxid e-Diisop r op yl Hyd r a zin ed i-
ca r boxyla te. This byproduct was generally not dried or
characterized. A batch was found suitable for single-crystal
X-ray analysis: mp 111-113 °C. 1H NMR [400 MHz, CDCl3]:
δ 1.16 (d, 12H, J ) 6.3 Hz), 4.88 (m, 2H, J ) 6.3 Hz), 6.5 (brm,
2H), 7.62-7.19 (m, 15H). 13C NMR [100 MHz, CDCl3]: δ 21.9,
69.9, 128.4, 128.5, 131.88, 131.90, 132.1, 133.0, 156.4. IR
Mitsu n obu Su lfon a tion . Meth od A. A slurry of methane-
sulfonic acid (7.8 mL, 120 mmol) and triphenylphosphine (32.8
g, 125 mmol) in 250 mL of toluene was cooled to about 20 °C,
and DIAD24 (27.1 g, 140 mmol) was added, keeping the temper-
ature below 35 °C. Then the alcohol (100 mmol) was added,
followed by triethylamine (5.5 mL, 40 mmol). The slurry was
heated to 60-70 °C and held at that temperature until the
formation of the sulfonate was complete by HPLC, generally
about 3 h. The reaction was cooled to about room temperature
for workup.
(KBr): 3220 (br), 1710 (br), 1110 cm-1
26H31N2O5P: C, 64.72; H, 6.48; N, 5.81; P, 6.42. Found: C,
64.75; H, 6.30; N, 5.78; P, 6.39.
. Anal. Calcd for
C
N-Ben zoyl-4-cis-(m eth a n esu lfon yloxy)-L-p r olin e Meth yl
Ester (2). The ester generated by the Mitsunobu reaction was
not routinely isolated. A reference sample was prepared by
adding 3 (40.0 g, 142 mmol) to a solution of thionyl chloride (11.2
mL, 154 mmol) in methanol (400 mL) that had been prepared
at -15 °C and stirred 17 h at room temperature. The esterifi-
cation was quenched into water (200 mL) at 10 °C and adjusted
to pH 7.1 with aqueous NaHCO3 (saturated, 520 mL). The
slurry was cooled to 4 °C and filtered, and the product was
washed with ice water (2 × 200 mL) and dried to afford 30.68 g
Mitsu n obu Su lfon a tion . Meth od B. For use with hydrated
sulfonic acids. The reactor was fitted with a Dean-Stark
apparatus and condenser and charged with the sulfonic acid and
toluene (2.1 mL/mmol). The mixture was refluxed under
nitrogen until water removal was complete and cooled to about
20 °C. Thereafter the procedure was the same as in method A.
N-Ben zoyl-4-cis-(m et h a n esu lfon yloxy)-L-p r olin e (3).
Method A was used for the Mitsunobu condensation, with alcohol
125 (25.0 g, 100 mmol). The orange-brown solution was cooled
to 5 °C and mixed with aqueous NaOH (150 mmol, 90 mL). The
triphasic mixture was stirred vigorously at 5 °C until hydrolysis
was complete by HPLC assay,26 about 2 h, and acidified to pH
6-7 with HCl (concentrated, ca. 8 mL). The suspension was
stirred at 5 °C for 1 h, and the solids of triphenylphosphine
oxide-diisopropyl hydrazinedicarboxylate (see experimental
below) were filtered off and washed with cold water (2 × 35 mL).
The organic layer of the filtrate was extracted with distilled
water (2 × 15 mL). Glacial acetic acid was added in two portions
to the combined aqueous phases, first to adjust to pH 3.8-3.9
at 25 °C (ca. 10 mL) to initiate crystallization. The crystal
slurry was stirred at room temperature for 30 min and adjusted
to pH 4 (glacial acetic acid, ca. 6 mL). The mixture was adjusted
to pH 2 by the slow addition of HCl (concentrated, ca. 7 mL),
held at 20-25 °C for 30 min, and stirred at 0-5 °C for 1 h. The
product was isolated by filtration and washed with cold water
(2 × 30 mL). Drying in a vacuum oven at 50 °C/30 mmHg
returned 25.8 g (84%) of 3. By HPLC analysis the purity of this
material was at least 98% relative to a standard of 3. No more
than 0.1% each of the trans-isomer 5, triphenylphosphine oxide,
or other individual organic impurites was detectable. The
product contained about 0.1-0.2% water and acetic acid.
A reference standard was prepared by recrystallization from
10 volumes of 1:1 EtOAc:95% EtOH to provide material with
(73.5%) of white solid: mp 90-91 °C, [R]20 -51.6° (c ) 1.0,
D
MeOH). 1H NMR [400 MHz, CDCl3, a mixture of rotamers due
to the tertiary amide]: δ {2.59 and 2.67 (brm, 2H)}, 3.07 (s, 3H),
3.74-4.26 (brm, 2H), {3.86 (s) and 3.94 (s), 3H}, {4.57 (brm)
and 5.00 (brm), 1H}, {5.26 (brm) and 5.40 (brm), 1H}, 7.48-
7.59 (m, 5H). 13C NMR [75 MHz, CDCl3]: δ 35.0, 38.0, 38.4,
52.5, 54.3, 56.7, 59.6, 126.5, 126.9, 128.4, 130.1, 130.4, 135.2,
135.8, 169.5, 170.9, 171.2. IR (KBr): 1746, 1640, 1346, 1169
cm-1. Anal. Calcd for C14H17NO6S: C, 51.36; H, 5.23; N, 4.28;
S, 9.79. Found: C 51.45; H, 5.00; N, 4.29; S, 9.49.
N-Ben zoyl-4-tr a n s-(m eth a n esu lfon yloxy)-L-p r olin e (5)
(Sod iu m Sa lt). A suspension of 47a (200 g, 0.61 mol) in water
(1 L) was treated with NaOH (10 M, 73.3 mL) at room
temperature for 2.5
h and acidified to pH 1.5 with HCl
(concentrated). The reaction was extracted with CH2Cl2 (3 ×
500 mL), and the combined extracts were polish-filtered through
Hyflo. The solvent was removed under reduced pressure, and
the residue was taken up into absolute EtOH (1.0 L). Over 30
min sodium 2-ethylhexanoate (0.61 mol in absolute EtOH, 522
mL) was added, followed by absolute EtOH (0.50 L). The
suspension was stirred at 0-4 °C for 1 h, and the product was
filtered and washed with absolute EtOH (3 × 250 mL). The
crystals were reslurried in absolute EtOH (1.5 L) at 4 °C for 1
h, filtered, washed with absolute EtOH (2 × 250 mL), and dried
to afford 144.7 g (70.6%): mp 136 °C (endotherm, differential
mp 172-174 °C (lit.7a mp 173-174 °C), [R]20 -55.0° (c ) 1.0,
D
scanning calorimetry), [R]20 -79.5° (c ) 1.0, H2O). 1H NMR
MeOH) (lit.7a [R]20 -50.6° (c ) 1.0, MeOH)). 1H NMR (300
D
D
[400 MHz, DMSO-d6, a mixture of rotamers due to the tertiary
amide]: δ 2.2-2.45 (brm, 2H), {3.16 (s) and 3.23 (s), (3H
combined}, {3.51 (d, J ) 12.1 Hz), 3.72 (d, J ) 6.0 Hz), 3.76 (d,
J ) 6.0 Hz), 3.84-3.91 (m), 4.03 (dd, J ) 4.1 and 4.2 Hz), 4.42
(t, J ) 8.0 Hz), 5.22-5.25 (m), 4H total}, 7.34-7.50 (m, 5H).
13C NMR [75 MHz, DMSO-d6]: δ 35.8, 37.56, 37.64, 37.68, 39.7,
51.3, 55.3, 59.1, 61.8, 127.2, 127.9, 128.3, 128.5, 129.3, 129.9,
136.6, 137.0, 168.0, 169.2, 174.0, 174.3. IR (KBr): 1619, 1356,
1171 cm-1. Anal. Calcd for C13H14NO6SNa‚0.5H2O: C, 45.35;
H, 4.39; N, 4.07; S, 9.31; H2O, 2.62. Found: C, 45.52; H, 4.19;
N, 4.03; S, 9.46; H2O, 2.52 (Karl Fischer titration).
MHz, CDCl3 + drop of CD3OD) showed a mixture of rotamers
due to the tertiary amide: δ 2.51-2.76 (m, 2H), 3.07 (s, 3H),
(23) Seven of eight such trans-4-hydroxyproline structures have an
axial OH (e.g. Koetzle, T. F.; Lehmann, M. S.; Hamilton, W. C. Acta
Crystallogr., Sect. B 1973, 29, 231 (HOPROL12). Hospital, M.; Courseille,
C.; Leroy, F.; Roques, B. P. Biopolymers, 1979, 18, 1141 (NAHYPL, or
N-acetyl-trans-4-hydroxyproline). Garbay-J aureguiberry, C.; Arnoux,
B.; Prange, T.; Wehri-Altenburger, S.; Pascard, C.; Roques, B. P. J .
Am. Chem. Soc. 1980, 102, 1827 (GLHPRC, or prolylhydroxyproline)).
The last reference also contains the exception: the hydroxyl is
pseudoequatorial in glycyl-L-4-hydroxyproline (GLHPRA). Intermediate
conformations occur in two mono- and di-N-alkylated derivatives:
J ones, G. P.; Naidu, B. P.; Paleg, L. G.; Tiekink, E. R. T. Acta
Crystallogr. Sect. C 1988, 44, 2208 (GOJ MAT and GOJ MEX).
(24) DIAD purity may be determined by dissolving a standardized
amount of triphenylphosphine in acetonitrile containing 0.2% acetic
acid and titrating with DIAD until the yellow-orange color remains.
(25) Portoghese, P. S.; Turcotte, J . G. Tetrahedron 1971, 27, 961.
The ester was dried to moisture levels of not more than 0.1%.
(26) Waters 30 cm µ-Bondapak C-18 column held at 31 °C, eluted
at 1.0 mL/min with 28:72 methanol:(0.05 M KH2PO4 acidified to pH
3.0 with 3 M H3PO4), 215 nm. Typical retention times: 1, 10.4 min; 2,
16.7 min; 3, 7.6 min; 4, 18.0 min; 5, 8.0 min.
N-Ben zoyl-4-cis-(p -t olu en esu lfon yloxy)-L-p r olin e (6).
Method B was used for the Mitsunobu condensation, with alcohol
125 (25.0 g, 100 mmol). The reaction was stirred at 65 °C for 6
h and then without heat overnight. By HPLC27 the ratio of
intermediate tosylate ester to starting material was 40:1. The
yellow solution was stirred vigorously with aqueous NaOH (0.15
(27) YMC Basic 25 cm column, eluted at 1.0 mL/min with 50:50
acetonitrile:0.01 M ammonium phosphate, acidified to pH 4 after
mixing, monitored at 210 nm. Typical retention times: 1, 3.7 min; ester
intermediate, 8.5 min; 6, 5.6 min.