872 J . Org. Chem., Vol. 66, No. 3, 2001
Clapham et al.
distilled from calcium hydride. The ion-exchange resins, Dowex
50WX2-200 and Dowex 1X2-400, were washed with distilled
water, acetone, methanol, and CH2Cl2 prior to use. A batch of
mixed-bed resin was prepared by mixing equal quantities of
these acidic and basic resins. The filtration/workup cartridges
were prepared by placing 1.0 g of the mixed-bed resin in a 5
mL plastic syringe, equipped with a polyethylene frit; an
additional frit was then placed over the top of the resin. The
enantiomeric excess of resolved compounds was determined
using a Hitachi 655A liquid chromatograph equipped with a
Chiracel OD-H chiral column. Premixed isocratic mixtures of
2-propanol/hexanes were used throughout. Compounds were
injected at 10 mM in a solution of hexanes, and products were
detected at 254 nm. Optical rotations were determined at 598
nm in a conventional 10 cm cell using a Perkin-Elmer 241 MC
polarimeter.
made alkaline by the addition of NaOHaq (4 M, 50 mL). The
alkaline solution was extracted with ether (3 × 50 mL), and
the combined ether extracts were dried (Na2SO4) and concen-
trated under reduced pressure to give a yellow oil. Purification
using bulb to bulb distillation (130-135 °C, 0.85 mmHg) gave
the desired allyl ether 10 as a colorless oil (9.11 g, 91%): [R]D
22
-76.0 (c ) 1, MeOH); IR 993 and 922 cm-1; 1H NMR (500 MHz,
CDCl3) δ 1.75-1.81 (m, 1H), 2.01-2.05 (m, 1H), 2.20 (s, 3H),
2.23-2.30 (m, 1H), 2.38 (s, 3H), 2.53 (dd, 1H, J ) 12.1, 4.3),
2.59-2.62 (m, 1H), 3.38 (dd, 1H, J ) 9.9, 6.3), 3.43 (d, 1H, J
) 13.2), 3.55 (d, 1H, J ) 13.2), 3.91-3.93 (m, 1H), 3.94-3.98
(m, 1H), 4.02-4.04 (m, 1H), 5.13 (ddd, 1H, J ) 10.7, 3.0, 1.5),
5.27 (ddd, 1H, J ) 17.3, 3.3, 1.5), and 7.22-7.29 (m, 5H); 13C
NMR (75 MHz, CDCl3) δ 38.2, 41.1, 43.0, 61.8, 62.2, 63.1, 63.6,
70.2, 76.4, 116.9, 126.8, 128.1, 128.9, 134.8, and 139.1; HRMS
calcd for C17H26N2O 274.2045, found 274.2045.
BOC Hyd r oxyp r olin e Meth ylben zyla m id e 5. A solution
of BOC hydroxyproline 4 (10.0 g, 43.3 mmol), HOBt (5.85 g,
43.3 mmol), benzylmethyamine (5.60 mL, 43.4 mmol), and
CH2Cl2 (300 mL) was cooled in a salt/ice bath. To this solution
was added DCC (8.92 g, 43.3 mmol) in CH2Cl2 (150 mL) in a
dropwise fashion over a period of 30 min. The resulting
mixture was allowed to warm to room temperature over 6 h,
during which time the urea precipitate was formed. The
mixture was filtered and the precipitate washed with CH2-
Cl2. The organic liquors were evaporated to dryness under
reduced pressure and dissolved in ethyl acetate (300 mL). The
ethyl acetate solution was washed with saturated sodium
carbonate, 10% citric acid, and brine, dried (MgSO4), and
concentrated to give amide 5 as an oil which solidified on
Hyd r oxyp r op yl Eth er Dia m in e 11. A solution of 9-BBNH
(0.5 M, 11 mL, 5.5 mmol) was cooled to 0 °C, and a solution of
allyl ether 10 (312 mg, 1.14 mmol) in THF (10 mL) was added.
The resultant mixture was allowed to warm to room temper-
ature and stirred overnight. An alkaline solution of hydrogen
peroxide (10 mL, 4 M NaOH, 30% H2O2, 2:1) and EtOH (10
mL) were slowly added, and the resulting mixture was stirred
for an additional 30 min. The organic layer was separated and
the aqueous layer extracted with ether (2 × 30 mL). The
organic extracts were combined, dried (Na2SO4), and concen-
trated under reduced pressure to give a yellow oil. Purification
by flash chromatography (90% CH2Cl2, 9.5% MeOH, 0.5%
concd NH4OHaq) gave the desired hydroxy ether diamine 11
as a colorless oil (247 mg, 74%). Larger scale reactions gave
similar yields of product which were purified by bulb to bulb
standing (14.2 g, 98%): mixture of rotamers; [R]D -14.1 (c
22
) 1, MeOH); IR 3411, 1681, and 1648 cm-1
;
1H NMR (500
distillation (145-150 °C, 0.75 mmHg): [R]D -49.2 (c ) 1,
22
MHz, CDCl3) δ 1.35 and 1.46 (s, 9H), 1.86-1.92 (m, 1H), 2.09-
2.28 (m, 2H), 2.99 and 3.04 (s, 3H), 3.44-3.62 (m, 1H), 3.69-
3.79 (m, 1H), 4.42-4.60 (m, 2H), 4.68-4.89 (m, 1H) and 7.19-
7.28 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 28.2, 28.4, 34.5,
34.8, 38.2, 38.8, 51.5, 54.9, 55.1, 55.2, 69.5, 70.4, 79.9, 126.5,
126.6, 127.2, 127.7, 128.4, 128.5, 128.6, 128.9, 136.9, 154.0,
154.6, 172.8, and 173.0; HRMS calcd for C18H26N2O4 334.1893,
found 334.1893.
MeOH); IR 3382 cm-1 1H NMR (500 MHz, CDCl3) δ 1.74-
;
1.81 (m, 3H), 1.94-2.01 (m, 1H), 2.20 (dd, 1H, J ) 9.9, 6.2)
2.21 (s, 3H), 2.27 (dd, 1H, J ) 12.1, 7.7), 2.36 (s, 3H), 2.52 (dd,
1H, J ) 12.1, 4.8), 2.56-2.60 (m, 1H), 3.37 (dd, 1H, J ) 9.6,
6.3), 3.42 (d, 1H, J ) 13.2), 3.50-3.53 (m, 1H), 3.54 (d, 1H, J
) 13.2), 3.56-3.60 (m, 1H), 3.56-3.60 (m, 1H), 3.73 (t, 2H, J
) 5.5), 3.93-3.98 (m, 1H), 7.20-7.24 (m, 1H), and 7.28-7.31
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 31.9, 36.1, 38.0, 40.9,
42.8, 61.5, 62.0, 63.0, 63.3, 68.2, 76.4, 126.7, 127.9, 128.7, and
138.8; HRMS calcd for C17H28N2O2 292.2151, found 292.2151.
P olym er -Su p p or ted Ca ta lyst 12. A suspension of potas-
sium hydride (35% in mineral oil, 1.00 g, 8.73 mmol) in THF
(50 mL) was cooled to 0 °C, and a solution of hydroxypropyl
ether 11 (1.54 g, 5.27 mmol) in THF (50 mL) was slowly added.
The resultant mixture was stirred at room temperature for 1
h and then added to a suspension of chloromethyl J andaJ el
(5.00 g, 0.70 mmol g-1, 3.5 mmol), 18-crown-6 (100 mg, cat.),
and potassium iodide (100 mg, cat.) in THF (50 mL). The
reaction was stirred at reflux for 48 h. After cooling, the resin
was filtered and washed with THF, dioxane/water (3:1), THF,
THF/Et3N (9:1), CH2Cl2, THF, ether, and pentane. Drying
under vacuum overnight gave the polymer-supported catalyst
12 as a free-flowing white powder (5.91 g, 100%). A loading of
0.59 mmol g-1 was calculated from the mass increase of the
Hyd r oxy Dia m in e 6. A solution of amide 5 (14.0 g, 41.9
mmol) in THF (200 mL) was cooled to 0 °C, and a solution of
LiAlH4 (1 M in THF, 90.0 mL, 90.0 mmol) was added over 30
min. Caution: Hydrogen gas evolved! After being stirred for 1
h, the mixture was heated to reflux for 5 h and was then cooled
in a salt/ice bath. The flask was opened to the atmosphere,
and a stream of argon was passed over the reaction. Next,
NaSO4‚10H2O was added in small portions until no further
hydrogen gas was evolved. The solid material was isolated by
filtration and extracted in a Soxhlet apparatus using dioxane
overnight. The organic extracts were combined and concen-
trated under reduced pressure to give a yellow oil. Purification
by bulb to bulb distillation (175-180 °C, 2.5 mmHg) gave the
desired hydroxy diamine 6 as a colorless oil (8.71 g, 89%):
[R]D -80.9 (c ) 1, MeOH); 1H NMR (500 MHz, CDCl3) δ
22
1.75-1.87 (m, 2H) 2.12 (dd, 1H, J ) 9.9, 5.9), 2.13 (s, 3H),
2.20 (dd 1H J ) 12.1, 7.3), 2.31 (s, 3H), 2.45 (dd, 1H, J ) 12.1,
4.8), 2.57-2.61 (m, 1H), 3.31 (dd, 1H, J ) 9.9, 6.3), 3.35 (d, 1
H, J ) 13.2), 3.45 (d, 1H, J ) 13.2), 4.25-4.29 (m, 1H), 7.22-
7.25 (m, 1H), and 7.29-7.30 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 41.2, 41.5, 43.1, 61.7, 62.2, 63.1, 65.9, 69.5, 126.9,
128.1, 129.0, and 139.1; HRMS calcd for C14H22N2O 234.1732,
found 234.1732.
polymer. IR 1119 and 976 cm-1
.
Gen er a l P r oced u r e for Kin etic Resolu tion Usin g P oly-
m er -Su p p or ted Ca ta lyst 12. Catalyst 12 (250 mg, 0.15
mmol, 15 mol %), 4 Å molecular sieves (500 mg), and trans-
2-phenyl-1-cyclohexanol (13) (176 mg, 1.00 mmol) were placed
in a 10 mL Wheaton vial equipped with a small stir bar. A
stream of argon was purged into the flask, and CH2Cl2 (5 mL)
was added. An inlet septum cap was fitted, the flask was cooled
to -78 °C, Et3N (70 µL, 0.50 mmol) and benzoyl chloride (87
µL, 0.75 mmol) were added, and the mixture was stirred at
-78 °C for 11 h. The mixture was filtered through the ion-
exchange resin cartridge, washed with CH2Cl2 and ether, and
concentrated under reduced pressure. The resolved products
were separated on a silica gel column (10 cm × 2.5 cm) which
was eluted with 10% ethyl acetate in hexanes (200 mL) and
50% ethyl acetate in hexanes (100 mL), giving ester 13a (123
mg, 44%) and alcohol 13b (79 mg, 45%).
Dia m in e Allyl Eth er 10. A suspension of potassium
hydride (35 wt % in mineral oil, 5.00 g, 43.7 mmol) in THF
(100 mL) was cooled to 0 °C, and a solution of hydroxy diamine
6 (8.53 g, 36.4 mmol) in THF (50 mL) was slowly added. The
mixture was warmed to room temperature and stirred for an
additional 2 h. Next, allyl bromide (3.15 mL, 36.4 mmol) was
added, and the resulting mixture was heated at reflux for 3
h. After cooling, excess potassium hydride was destroyed by
the slow addition of water (20 mL) followed by HClaq (1 M, 50
mL). The phases were separated, and the organic layer was
extracted with HClaq (1 M, 2 × 50 mL). The acidic aqueous
extracts were combined, washed with ether (2 × 50 mL), and
Gen er a l P r oced u r e for th e An a lysis of En a n tiom er ic
Excess for Ester s 13-19. Ester 13a (100 mg) was dissolved