Notes
J . Org. Chem., Vol. 65, No. 8, 2000 2617
eluent 80% CH3CN/0.1% aqueous trifluoroacetic acid @ 1 mL/
min monitored at 210 nM).
11. Furthermore, it was observed that the action of
triethylamine alone, in DCM at room temperature,
resulted in a 1.8:1 ratio of 11B to 11A, presumably
reflecting thermodynamic control. Hence, iterative treat-
ment of the undesired diastereomer with triethylamine
resulted in almost complete conversion of the material
to the desired diastereoisomer.17
N-{2-[(N-ter t-Bu t oxyca r b on yl-4-p h en ylp ip er id in -4-yl)-
m eth oxy]-2-(3,5-bis(tr iflu or om eth yl)p h en yl)a cetyl}-4(R)-
ben zyl-2-oxa zolid in on e (11). To a solution of methyl ester 3
(11 g, 0.019 mol) in methanol (100 mL) at 0 °C was added KOH
(3.2 g, 0.057 mol), followed by water (3 mL). The homogeneous
solution was stirred at 0 °C for 1 h. The methanol was removed
in vacuo and pH 4 buffer (100 mL) added to the residue. The
product was extracted into Et2O, dried (MgSO4), and evaporated
in vacuo. The resulting white foam (10.6 g) was dissolved in
anhydrous DCM (50 mL). DMF (0.5 mL) was added followed by
oxalyl chloride (2.23 mL, 25.7 mmol) dropwise. After stirring at
25 °C for 0.5 h, the solvent was removed in vacuo. The resulting
residue was azeotroped with toluene (50 mL) and then, as a
solution in anhydrous toluene (40 mL), added at -78 °C to the
lithium anion of (4R)-4-benzyl-2-oxazolidinone (generated by
adding n-BuLi (11.8 mL, 1.6 M, 18.8 mmol) to a solution of (4R)-
(+)-4-benzyl-2-oxazolidinone (3.34 g, 18.8 mmol) in THF (100
mL) at -78 °C and stirring for 0.5 h). The resulting colorless
solution was stirred at -78 °C for a further 0.75 h and quenched
by addition of Et2O (400 mL), and sat. NH4Cl aq (30 mL). The
organic layer was dried (MgSO4). The clear oil obtained after
removal of solvent in vacuo was chromatographed on silica gel
(eluent 20% ethyl acetate/hexane to obtain diastereomer 11A
(3.4 g, 25%), and then 30% ethyl acetate/hexane to obtain
diastereomer 11B (4.0 g, 29%), as colorless foams.
Dia ster eoisom er 11A. 1H NMR (400 MHz, CDCl3) δ 7.81
(1H, s), 7.70 (2H, s), 7.34-7.19 (10H, m), 5.94 (1H, s), 4.58 (1H,
m), 4.17 (2H, m), 3.77 (2H, m), 3.67 (1H, d, J ) 9 Hz), 3.31 (1H,
d, J ) 9 Hz), 3.28 (1H, m), 3.02 (2H, m), 2.79 (1H, m), 2.19 (2H,
m), 1.90 (2H, m) 1.43 (9H, s). 13C NMR (100 MHz, CDCl3) δ
168.91, 154.97, 152.82, 141.81, 138.38, 134.69, 131.74 (q, J C-F
) 33 Hz), 129.41, 129.06, 128.56, 128.50, 127.58, 127.15, 126.63,
123.08 (q, J C-F ) 273 Hz), 122.81 (m), 79.37, 79.21, 78.20, 66.69,
55.45, 41.63, 40 (br m, CH2N), 37.74, 31.84 (br m), 31.37 (br m),
28.42. 19F NMR (376.36 MHz, CDCl3) δ -63.14. m/e (ES+) 721
(MH+), 665 (MH+ - (CH3)2CCH2)), 621(MH+ - Boc). Anal. Calcd
for C37H38F6N2O6: C, 61.66; H, 5.31; N, 3.88%. Found: C, 61.97;
H, 5.28; N, 3.88%.
In summary we have described a practical and high-
yielding route to multigram quantities of 1, relying on a
diazo-insertion strategy which permits a highly conver-
gent synthesis, followed by an effective resolution protocol
which exploits the acyloxazolidinone moiety as a sur-
rogate for a primary alcohol.
Exp er im en ta l Section
Gen er a l P r oceed u r es. NMR spectra were recorded at 300
K. Flash column chromatography was carried out on silica gel
(E. Merck Art 7734). “Petroleum ether” refers to petroleum ether
with bp 60-80 °C. Reagents and dry solvents were purchased
from Fluka or Aldrich and used without further purification.
Glassware was dried at 130-150 °C prior to use, and reactions
were performed under an atmosphere of dry nitrogen unless
otherwise specified. Organic solvents were evaporated on a
rotary evaporator at reduced pressure. Elemental analyses were
determined by Butterworth Laboratories Ltd., Teddington,
England.
Meth yl 2-Dia zo-2-(3,5-bis(tr iflu or om eth yl)p h en yl)a ce-
t a t e (4). To a solution of methyl 3,5-bis(trifluoromethyl)-
phenylacetate (5) (53.0 g, 184 mmol) and 4-nitrobenzenesulfonyl
azide (42 g, 184 mmol) in dry acetonitrile (250 mL), cooled to
-10 °C, was added DBU (30.0 g, 196 mmol) dropwise over 30
min with stirring, and the mixture was stirred at -10 °C for a
further 0.5 h. The solvents were evaporated at reduced pressure,
and the residue was partitioned between ether and water. The
organic layer was washed with sat. NaHCO3 aq, dried (Na2SO4),
and evaporated, and residue was chromatographed on silica gel
(eluent 2.5% Et2O/ hexane) to afford 4 (52.8 g, 92%) as yellow
prisms (significant exotherm when oil crystallizes). 1H NMR (400
MHz, CDCl3) δ 7.95 (2H, s), 7.65 (1H, s), 3.91 (3H, s). 13C NMR
(100 MHz, CDCl3) δ 164.3, 132.3(q, J C-F 33 Hz), 129.1, 123.1(q,
J C-F 271 Hz), 123.0(m), 119.1(m), 52.4. 19F NMR (376.36 MHz,
CDCl3) δ -63.55. m/e (ES+) 284 (M - N2). IR (film, NaCl) 1740,
2140 cm-1. HPLC purity > 99.2% by two systems (TSKgel Super
ODS 100 × 4.6 mm column [supplied by Fisher Scientific], eluent
40% H2O/ CH3CN @ 1 mL/min; Supelco Discovery 150 × 4.6 mm
column [supplied by Supelco U.K.], eluent 35% H2O/ CH3CN @
1 mL/min monitored at 210 nM).
Dia ster eoisom er 11B. 1H NMR (400 MHz, CDCl3) δ 7.85
(1H, s), 7.77 (2H, s), 7.34-7.16 (8H, m), 6.95 (2H, m), 5.93 (1H,
s), 4.69 (1H, m), 4.25 (1H, m), 4.17 (1H, m), 3.77 (2H, m), 3.61
(1H, d, J ) 8.7 Hz), 3.29 (1H, d, J ) 8.7 Hz), 3.04 (3H, m), 2.62
(1H, m), 2.17 (2H, m), 1.89 (2H, m) 1.43 (9H, s). 13C NMR (100
MHz, CDCl3) δ 168.97, 154.95, 152.86, 141.78, 138.43, 134.28,
131.81 (q, J C-F ) 33 Hz), 129.21, 128.88, 128.52, 127.49, 127.17,
126.61, 123.09 (q, J C-F ) 273 Hz), 122.78 (m), 79.37, 79.27, 78.24,
66.77, 55.11, 41.63, 40 (br m, CH2N), 37.31, 31.80 (br m), 31.39
(br m), 28.42. 19F NMR (376.36 MHz, CDCl3) δ -63.14. m/e (ES+)
721 (MH+), 665 (MH+ - (CH3)2CCH2)), 621 (MH+ - Boc). Anal.
Calcd for C37H38F6N2O6: C, 61.66; H, 5.31; N, 3.88%. Found:
C, 61.57; H, 5.32; N, 3.75%.
Meth yl 2-[(N-ter t-Bu toxyca r bon yl-4-p h en ylp ip er id in -4-
yl)m eth oxy]-2-(3,5-bis(tr iflu or om eth yl)p h en yl)a ceta te (3).
Slow addition (over 60 h via syringe pump) of the R-diazo ester
4 (49.26 g) as a solution in benzene (50 mL) to alcohol 27 (80 g,
1.75 equiv) in benzene (150 mL) at reflux under nitrogen, in the
presence of catalytic rhodium acetate (100 mg, 0.15 mol %),
afforded, after evaporation and chromatography of the residue
on silica gel (eluent 25% to 40% Et2O/ hexane), ester 3 (62.5 g,
70%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.79 (1H,
s), 7.70 (2H, s), 7.35 (4H, m), 7.25 (1H, m), 4.67 (1H, s), 3.79
(2H, m), 3.69 (3H, s), 3.67 (1H, d, J ) 9 Hz), 3.37 (1H, d, J ) 9
Hz), 3.04 (2H, m), 2.31 (1H, m), 2.19 (1H, m), 1.91 (2H, m), 1.44
(9H, s). 13C NMR (100 MHz, CDCl3) δ 169.87, 154.97, 141.79,
138.97, 131.73(q, J C-F ) 33 Hz), 128.58, 127.17, 126.96 (m),
126.66, 123.14 (q, J C-F ) 273 Hz), 122.37 (m), 79.96, 79.53, 79.39,
52.60, 41.72, 40 (br m, CH2N), 31.88, 31.4, 28.4. 19F NMR (376.36
Diastereomer 11A (3.0 g) and dry triethylamine (5 mL) in
DCM (50 mL) was allowed to stand at 25 °C for 16 h. The
solvents were evaporated, and the mixture was separated by
chromatography as described above to obtain diastereomer 11B
(1.85 g). Diastereomer 11A (1.0 g) was also recovered.
(+)-2-[(N-ter t-Bu toxyca r bon yl-4-p h en ylp ip er id in -4-yl)-
m eth oxy]-2-(3,5-bis(tr iflu or om eth yl)p h en yl)eth a n ol (+1).
Diastereomer 11B (1.8 g, 2.5 mmol) was dissolved in diethyl
ether (50 mL) and cooled to 0 °C under a nitrogen atmosphere.
Water (0.05 mL, 2.75 mmol) was added, followed by lithium
borohydride (0.054 g, 2.5 mmol). The reaction was stirred at 0
°C for 0.75 h and quenched by addition of 1 N NaOH (50 mL).
The mixture was extracted with ethyl acetate, and the organic
solutions were washed with brine, dried (MgSO4), filtered and
evaporated in vacuo. The residue was purified by chromatog-
raphy on silica gel eluting with 20% ethyl acetate/hexane to
obtain (+)-1 (1.2 g, 88%, 97% ee) as a white foam: RD +31.1° (c
) 1; CH2Cl2), 1H NMR (400 MHz, CDCl3) δ 7.78 (1H, s), 7.52
(2H, s), 7.40-7.32 (4H, m), 7.27 (1H, m), 4.29 (1H, m), 3.76 (2H,
m), 3.50 (2H, m), 3.41 (1H, d, J ) 8.8 Hz), 3.34 (1H, d, J ) 8.8
Hz), 3.04 (2H, m), 2.24 (2H, m), 1.83 (3H, m), 1.44 (9H, s). 13C
NMR (100 MHz, CDCl3) δ 154.94, 142.03, 141.53, 131.88 (q, J C-F
MHz, CDCl3) δ -63.29. m/e (ES+) 576 (MH+), 520 (MH+
-
(CH3)2CCH2)), 476 (MH+ - Boc). HPLC purity > 97.8% by two
systems (TSKgel Super ODS 100 × 4.6 mm column [supplied
by Fisher Scientific], eluent 70% CH3CN/0.1% aqueous trifluo-
roacetic acid @ 1 mL/min; ACE 3C18 150 × 4.6 mm column
(17) As yet we have been unable to prepare crystalline derivatives
of 11 or 1 suitable for X-ray structural determination of the absolute
configuration.
) 33 Hz), 128.70, 126.95, 126.78, 126.68 (m), 123.13 (q, J C-F
)