CLUSTER
Improved Synthesis of Optically Pure 4-Boc-5,6-Diphenylmorpholin-2-one
695
the reaction. This modification effectively provides the Procedure for the Preparation of (5S,6R)-4-(Benzyloxy-carbon-
yl)-5,6-diphenyl-morpholin-2-one (8)
desired morpholinones after three distillation cycles. Fi-
(
1R,2S)-(–)-2-Amino-1,2-diphenylethanol [(–)-2, 106 g, 0.5 mol)
nally, the products are recrystallized from ethanol or
toluene to provide optically pure 4-Boc-5,6-diphenylmor-
pholin-2-one (6) and 4-Cbz-5,6-diphenyl-morpholin-2-
one (8) in 75% and 86% yield, respectively, over three
was dissolved in a mixture of THF (1100 mL, ACS grade) and Et N
3
(
108 mL, 78.4 g, 0.775 mol, 1.55 equiv) with gentle warming. Ethyl
bromoacetate (86 mL, 129 g, 0.775 mol, 1.55 equiv) was slowly
dropped into the vigorously stirred solution over 1 h at r.t. The re-
steps. Importantly, while the modified procedure requires action was stirred for an additional 1 h, then cooled to 0 °C and fil-
three days for completion, the previous procedure typical- tered. The filter cake was thoroughly rinsed with ice cold THF
(
2 × 100 mL). The combined filtrates were evaporated to dryness
ly required six to seven days and yielded 59% and 66% of
and 8, respectively, over three steps.
and the residue diluted with CH Cl (750 mL) and sat. NaHCO
2
2
3
6
(750 mL). The mixture was cooled in ice and benzyl chloroformate
Utilizing this convenient procedure, it is possible to pre- (83 mL, 98.8 g, 0.55 mol, 1.1 equiv) was slowly added to the stirred
pare optically pure 4-Boc-5,6-diphenyl-morpholin-2-one solution over 1 h. The reaction was stirred for an additional 1 h at
0
°C, and the layers were separated. The aqueous layer was extract-
and 4-Cbz-5,6-diphenylmorpholin-2-one on a 100 g scale
with reproducibly high yields. Exclusion of air during the
synthesis was not necessary, and the entire sequence from
benzoin was accomplished without any chromatographic
separations. The products can be stored on the shelf at
ed with CH Cl (2 × 100 mL), and the combined organic extracts
were washed with H O and dried (Na SO ). The solvent was re-
moved, the residue was dissolved in toluene (1100 mL, ACS grade),
p-TsOH·H O (9.52 g, 0.05 mol, 0.1 equiv) was added, and the ex-
2
2
2
2
4
2
cess solvent was slowly distilled at atmospheric pressure until ap-
room temperature over several years without decom- proximately 500 mL remained. The reaction was then cooled to r.t.
position.
The resulting crystals were collected by filtration, and subsequently
rinsed with toluene–hexane (1:3, 300 mL), followed by hexane (300
mL, 163 g, 84%). The mother liquor and washes were combined and
evaporated to dryness under reduced pressure, and the residue was
recrystallized from toluene to provide a second crop of product
Procedure for the Preparation of (5S,6R)-4-(t-Butoxy-carbon-
yl)-5,6-diphenyl-morpholin-2-one (6)
(
2.43 g, 2%). The combined crops afforded 166 g (86%) of white
(
1R,2S)-(–)-2-Amino-1,2-diphenylethanol [(–)-2, 106 g, 0.5 mol]
22
crystalline product. Mp 206–207 °C; [a]D –68.7 (c 1.0, CH Cl ).
IR (NaCl, paraffin oil): 1745, 1705, 1455, 1440, 1375, 1325, 1215,
2
2
was dissolved in a mixture of THF (1100 mL, ACS grade) and Et N
3
(108 mL, 78.4 g, 0.775 mol, 1.55 equiv) with gentle warming. Ethyl
–1 1
1
120, 1055 cm . H NMR (200 MHz, DMSO-d vs. TMS, 120 °C):
6
bromoacetate (86 mL, 129 g, 0.775 mol, 1.55 equiv) was slowly
dropped into the vigorously stirred solution over 1 h at r.t. The re-
action was stirred for an additional 1 h, then cooled to 0 °C and fil-
tered. The filter cake was thoroughly rinsed with ice cold THF
d = 4.60 (2 H, ABq, J = 18 Hz), 5.06 (2 H, ABq, J = 13 Hz), 5.29 (1
H, d, J = 3 Hz), 6.20 (1 H, d, J = 3 Hz), 6.66 (1 H, s), 6.60 (1 H, s),
7
.00–7.30 (13 H, m). Anal. Calcd for C H NO : C, 74.40; H, 5.46;
24 21 4
N, 3.61. Found: C, 73.85; H, 5.38; N, 3.50.
5R,6S)-4-(Benzyloxycarbonyl)-5,6-diphenyl-morpholin-2-one is
obtained from the antipode, (1S,2R)-(+)-2-amino-1,2-diphenyletha-
(
2 × 100 mL). The combined filtrates were evaporated to dryness,
(
and the solid residue was washed with warm H O (500 mL, 50 °C),
2
dissolved in toluene (600 mL), and brought to reflux temperature. A
solution of di-t-butyl dicarbonate (147 g, 0.675 mol, 1.35 equiv) in
toluene (400 mL) was slowly added to the stirred mixture over 2 h.
The reaction remained at reflux for an additional 10 h, then 300–500
mL of solvent was distilled off to remove any residual water. The
reaction volume was adjusted back to 1000 mL with fresh toluene,
2
2
nol using the procedure described above. Mp 206–207 °C; [a]
D
+
68.7 (c 1.0, CH Cl ).
2 2
Acknowledgment
p-TsOH·H O (9.52 g, 0.05 mol, 0.1 equiv) was added, and the ex-
This work was supported by a grant from the National Science
Foundation (CHE0202827).
2
cess solvent was slowly distilled until approx. 500 mL remained.
The reaction was cooled to r.t., the resulting crystals were collected
by filtration, rinsed with toluene–hexane (1:3, 200 mL), followed
by hexane (200 mL). The mother liquor and washes were combined,
and the solvent was removed by distillation (until 300 mL re-
mained). The cooling, filtration, and washing sequence was repeat-
ed to provide a second crop of crystals. The washes and mother
References
(
1) For a review, see: Williams, R. M. Aldrichimica Acta 1992,
5, 11.
2) (a) Williams, R. M.; Yuan, C. J. Org. Chem. 1992, 57, 6519.
b) Williams, R. M.; Fegley, G. J. Tetrahedron Lett. 1992,
3, 6755. (c) Williams, R. M.; Zhai, W.; Aldous, D. J.;
2
(
liquors were again combined along with additional p-TsOH·H O
2
(
3
(2.38 g, 0.012 mol, 0.025 equiv) and the sequence was repeated to
provide a third crop of crystals. The combined solids were recrys-
tallized from ethanol to give the product as a white crystalline solid
Aldous, S. C. J. Org. Chem. 1992, 57, 6527. (d) Williams,
R. M.; Fegley, G. J. J. Org. Chem. 1993, 58, 6933.
2
2
(
132 g, 75%); mp 207 °C; [a]D –87.3 (c 1.0, CH Cl ). IR (NaCl,
2
2
(
(
e) Williams, R. M.; Yuan, C. J. Org. Chem. 1994, 59, 6190.
f) Williams, R. M.; Colson, P. J.; Zhai, W. Tetrahedron
CH Cl ): 3050, 2975, 1755, 1690, 1380, 1255, 1150, 1100, 1045
cm . H NMR (200 MHz, DMSO-d vs. DMSO, 120 °C): d = 1.25
9 H, s), 4.52 (2 H, d, J = 1 Hz), 5.16 (1 H, d, J = 3 Hz), 6.17 (1 H,
2
2
–
1 1
6
Lett. 1994, 35, 9371. (g) Williams, R. M. Advances in
Asymmetric Synthesis, Vol. 1; Hassner, A., Ed.; JAI Press:
Greenwich, CT, 1995, 45. (h) Williams, R. M.; Fegley, G.
J.; Gallegos, R.; Schaeffer, F.; Pruess, D. L. Tetrahedron
(
d, J = 3 Hz), 6.63–6.68 (2 H, m), 7.00–7.30 (8 H, m). Anal. Calcd
for C H NO : C, 71.37; H, 6.56; N, 3.96. Found: C, 71.08; H,
2
1
23
4
6
.44; N, 3.98.
5R,6S)-4-(t-Butoxycarbonyl)-5,6-diphenyl-morpholin-2-one
obtained from the antipode, (1S,2R)-(+)-2-amino-l,2-diphenyletha-
1996, 52, 1149. (i) Bender, D. M.; Williams, R. M. J. Org.
(
is
Chem. 1997, 62, 6690. (j) Williams, R. M.; Liu, J. J. Org.
Chem. 1998, 63, 2130. (k) Williams, R. M.; Aoyagi, Y.
Tetrahedron 1998, 54, 10419. (l) Scott, J. D.; Tippie, T. N.;
2
2
nol, using the procedure described above. Mp 207 °C; [a] +87.3
D
(
c 1.0, CH Cl ).
2 2
Synlett 2005, No. 4, 693–696 © Thieme Stuttgart · New York