Asymmetric Memory at Labile, Stereogenic Boron
J. Am. Chem. Soc., Vol. 121, No. 11, 1999 2469
of a 98:2 25:24 mixture. Recrystallization from cold CH2Cl2/Et2O
upgraded the material to >99:1 dr, mp 206-7 °C. Analytical TLC on
silica gel, 2:1 EtOAc/hexane: Rf ) 0.23. Analytical HPLC (silica gel
column, 250H4.6 mm, Gilson): 1.5 mL/min, 1392 psi, 1:3 EtOH/
hexane, tR ) 13.3 min (24) and tR ) 15.4 min (25). Molecular ion
calcd for C16H18BFN2O2: 300.14456; found m/e ) 300.1450, error )
1 ppm. IR (KBr, cm-1): 1744, CdO; 1676, CdN. 300 MHz NMR
(9:1 mixture of amidine E/Z isomers; CD2Cl2, ppm): δ 8.45-8.43 (1H,
m), 7.83-7.75 (2H, m), 7.51-7.32 (5H, m), 4.64 (0.1H, q, J ) 7.2
Hz), 4.29 (0.9H, q, J ) 7.2 Hz), 3.27 (0.3H, s), 3.19 (2.7H, s), 3.15
(0.3H, s), 2.99 (2.7H, d, J ) 3.4 Hz), 1.59 (3H, d, J ) 7.2 Hz).
(2R,4R)-4-Benzyl-3-(dimethylaminomethylidene)-2-fluoro-4-methyl-
2-(1-naphthyl)-1,3,2-oxazaborolidin-5-one (27). Alkylation of 25 (97
mg, 0.32 mmol, de) was performed according to alkylation method A
with the following quantities of reagents: THF, 4 mL; tBuOK/THF,
0.48 mL, 0.75 M, 0.36 mmol; benzyl bromide,0.38 mL, 3.2 mmol.
The material obtained after aqueous workup (121 mg, 0.31 mmol, 249:1
dr and >99.5% ee by HPLC assay) was recrystallized from CH2Cl2/
Et2O, yielding 98 mg (0.25 mmol, 78%, g99.5% ee) 27, mp 217-9
°C (dec). Analytical TLC on silica gel, 2:1 EtOAc/hexane: Rf ) 0.25.
Analytical HPLC (5 µm silica gel column, 250 × 4.6 mm, Gilson),
1.5 mL/min, 1290 psi, 3:1 hexane/ethanol: tR ) 5.8 min (27) and tR )
6.9 min (28). Analytical HPLC (Chiralpak AS column, 250 × 4.6 mm,
Daicel), 1.0 mL/min, 406 psi, 7:3 hexane/ethanol: tR) 6.0 min (ent-
27), 7.4 min (28), 10.8 min (ent-28), 13.8 min (27; major). Molecular
ion calcd for C23H24BFN2O2: 390.19153; found m/e ) 390.1919, error
) 1 ppm. IR (KBr, cm-1): 1746, CdO; 1672, CdN. 200 MHz NMR
(CD3CN, ppm): δ 8.29-8.23 (1H, m), 7.82-7.72 (2H, m), 7.42-7.17
(10H, m), 3.19 (2H, ABq, J ) 14.0 Hz), 3.01 (3H, s), 2.72 (3H, s),
1.63 (3H, s).
psi, tR ) 5.3 min (31) and tR ) 7.2 min (32)]. Pure material was
obtained by crystallization from CH2Cl2/ether, mp 217 °C (dec).
Analytical TLC on silica gel, 2:1 EtOAc/hexane: Rf ) 0.23. Molecular
ion calcd for C22H22BFN2O2: 376.1758; found m/e ) 376.1758, error
) 0 ppm; base peak ) 249 amu, M - 127 (-C10H7). IR (KBr, cm-1):
1733, CdO; 1678, CdN. 200 MHz NMR (CD2Cl2, ppm): δ 8.45-
8.39 (1H, m), 7.82-7.73 (2H, m), 7.49-7.30 (9H, m), 6.63 (1H, s),
4.36 (1H, dd, J ) 10.5, 3.9 Hz), 3.37 (1H, dd, J ) 14.0, 3.9 Hz), 2.96
(1H, dd, J ) 14.0, 10.5 Hz), 2.90 (3H, d, J ) 3.7 Hz), 2.80 (3H, s).
(2R,4S)-4-Allyl-4-benzyl-3-(dimethylaminomethylidene)-2-fluoro-
2-(1-naphthyl)-1,3,2-oxazaborolidin-5-one (34). Alkylation of 32 (202
mg, 0.537 mmol) was performed according to method A with the
following quantities of reagents: THF, 5.5 mL; tBuOK/THF, 0.79 mL,
0.75 M, 0.593 mmol; allyl bromide, 0.450 mL, 5.20 mmol. The material
obtained after aqueous workup was recrystallized from CH2Cl2/Et2O,
yielding 162 mg (0.389 mmol, 73%) of pure 34, mp 148-9 °C.
Analytical TLC on silica gel, 2:1 EtOAc/hexane: Rf ) 0.38. Analytical
HPLC (5 µm silica gel column, 250 × 4.6 mm, Gilson), 1.5 mL/min,
1363 psi, 3:1 hexane/ethanol: tR) 5.2 min. Molecular ion calcd for
C25H26BFN2O2: 416.2072; found m/e ) 416.2079, error ) 2 ppm. IR
(KBr, cm-1): 1731, CdO; 1667, CdN. 500 MHz NMR (CD2Cl2,
ppm): δ 8.48 (1H, d, J ) 8.2 Hz), 7.76 (1H, dd, J ) 8.2, 1.5 Hz),
7.65 (1H, d, J ) 7.4 Hz), 7.44 (1H, ddd, J ) 8.2, 6.7, 1.5 Hz), 7.41
(1H, ddd, J ) 8.2, 6.7, 1.5 Hz), 7.35-7.32 (3H, m), 7.28-7.25 (2H,
m), 7.10 (1H, dd, J ) 7.4, 7.4 Hz), 6.93 (1H, s), 6.45 (1H, d, J ) 7.4
Hz), 5.87 (1H, dddd, J ) 17.0, 10.1, 7.1, 7.1 Hz), 5.29 (1H, dddd, J )
10.1, 1.3, 1.3, 1.3 Hz), 5.19 (1H, dddd, J ) 17.0, 1.3, 1.3, 1.3 Hz),
3.46 (1H, d, J ) 14.4 Hz), 3.13 (1H, d, J ) 14.4 Hz), 3.00 (3H, s),
2.92 (1H, dddd, J ) 14.4, 7.1, 1.3, 1.3 Hz), 2.82 (3H, d, J ) 1.1 Hz),
2.59 (1H, dddd, J ) 14.4, 7.1, 1.3, 1.3 Hz).
(2R,4R)-4-Allyl-3-(dimethylaminomethylidene)-2-fluoro-4-meth-
yl-2-(1-naphthyl)-1,3,2-oxazaborolidin-5-one (29). Alkylation of 25
(99 mg, 0.33 mmol) was performed according to alkylation method A
with the following quantities of reagents: THF, 4 mL; tBuOK/THF,
0.48 mL, 0.75 M, 0.36 mmol; allyl bromide, 0.28 mL, 3.3 mmol. The
material (100 mg, g97:3% dr) obtained after aqueous workup was
recrystallized from CH2Cl2/Et2O, yielding 75 mg (0.22 mmol, 67%)
29, mp 163-5 °C. Analytical TLC on silica gel, 2:1 EtOAc/hexane:
Rf ) 0.20. Analytical HPLC (5 µm silica gel column, 250 × 4.6 mm,
Gilson), 1.5 mL/min, 1290 psi, 3:1 hexane/ethanol: tR) 7.2 min.
Molecular ion calcd for C19H22BFN2O2: 340.1759; found m/e )
340.1763, error ) 1 ppm. IR (KBr, cm-1): 1754, CdO; 1669, CdN.
500 MHz NMR (CD2Cl2, ppm): δ 8.45 (1H, d, J ) 7.7 Hz), 7.80 (1H,
dd, J ) 7.7, 1.9 Hz), 7.75 (1H, d, J ) 7.9 Hz), 7.46 (1H, ddd, J ) 7.7,
7.2, 1.9 Hz), 7.43 (1H, ddd, J ) 7.7, 7.2, 1.9 Hz), 7.36 (1H, dd, J )
7.9, 7.9 Hz), 7.30 (1H, s), 7.21 (1H, d, J ) 7.9 Hz), 5.83 (1H, dddd,
J ) 17.0, 10.3, 7.2, 7.2 Hz), 5.28 (1H, dddd, J ) 10.3, 1.5, 1.0, 1.0
Hz), 5.21 (1H, dddd, J ) 17.0, 1.5, 1.5, 1.5 Hz), 3.14 (3H, s), 2.89
(3H, d, J ) 1.1 Hz), 2.85 (1H, dddd, J ) 14.6, 7.2, 1.5, 1.5 Hz), 2.54
(1H, dddd, J ) 14.6, 7.2, 1.0, 1.0 Hz), 1.60 (3H, s).
(2R,4S)-4-Benzyl-3-(dimethylaminomethylidene)-2-fluoro-2-(1-
naphthyl)-1,3,2-oxazaborolidin-5-one (32). To a solution of sodium
N-(dimethylaminomethylidene)phenylalaninate (1.037 g, 4.29 mmol)3c
and potassium (1-naphthyl)trifluoroborate 23 (1.111 g, 4.75 mmol) in
40 mL of anhydrous THF under nitrogen was added excess chloro-
trimethylsilane (Aldrich; 1.4 mL, 11.0 mmol) in one portion. After
several minutes, formation of a fine white precipitate was observed.
The mixture was stirred for 1 h and then concentrated to a white solid
(rotary evaporator, 30 °C). The residue was triturated with 10 mL of
H2O, filtered, washed with additional portions of water and ether, and
pumped dry to yield 1.432 g (3.81 mmol) of a 5:1 mixture of
diastereomeric oxazaborolidinones 32:31. The asymmetric transforma-
tion procedure was performed on 355 mg of this material. Thus, the
mixture was dissolved in 20 mL of anhydrous 1,2-dichloroethane at
65 °C in a septum-capped 115 × 25 mm test tube equipped with a
magnetic stir bar. The solvent was slowly evaporated under a nitrogen
stream with continuous stirring, while dry CCl4 was added periodically.
The resulting slurry was cooled to room temperature, filtered, washed
with H2O and ether, and dried. The transformed product (309 mg) was
composed of a 96.5:3.5 32:31 mixture according to HPLC assay [5
µm silica gel, 250 ×4.6 mm, 1:3 ethanol/hexane, 1.5 mL/min, 1392
Cleavage of Oxazaborolidones. Conversion of 6a into (R)-r-
Methylphenylalanine (37). The boron complex 6a (150 mg, 0.441
mmol) was refluxed in anhydrous methanol (2 mL) for 2 h, at which
time TLC analysis indicated complete disappearance of the starting
material. Conversion to the amino acid could be effected by prolonged
heating in methanol, but complete conversion of the N-formyl
intermediate could not be achieved reproducibly. The following method
gave better yields. Ethylenediamine (0.06 mL, 0.9 mmol) was added
to the methanol solution when no more 6a could be detected, and
heating was continued for 1.5 h, until the amidino acid was completely
consumed according to TLC analysis using 4:1:0.1 CH2Cl2/CH3OH/
concentrated NH4OH on silica gel: Rf 0.34 (amidino acid), Rf 0.2
(amino acid), Rf 0.57 (phenylboric anhydride). The mixture was allowed
to cool, 15 mL of deionized water was added, and the aqueous phase
was washed with ether (3 × 15 mL). The ether layer was washed once
with brine, dried (MgSO4), and concentrated (aspirator) to give 40 mg
(87%) phenylboric anhydride. If desired, the latter can be recycled to
KPhBF3.4b
The aqueous phase from above was stirred with 15 g of Amberlite
IRC-50S (H+) ion-exchange resin (Aldrich; pretreated with 2 N NaOH,
washed with H2O until the eluent was neutral, acidified with 2 N HCl,
and washed again with H2O until neutral). To absorb basic amines,
stirring was continued until the pH of the water layer had dropped
from pH 10 to pH 6 (ca. 15 min). The mixture was filtered through a
glass frit, and the resin was washed with more deionized water (ca.
100 mL) until the presence of 37 could no longer be detected by
ninhydrin stain. The combined water eluent was evaporated (aspirator),
and the residue was dissolved in methanol (10 mL) and filtered through
Celite to remove inorganic salts. Evaporation of methanol and drying
under vacuum to constant weight gave (R)-R-methylphenylalanine, 79
mg (100%), >97% pure by 1H NMR comparison with literature data;23
mp 300 °C (dec). [R]D ) +21 (c ) 0.1, H2O); lit. for (S)-enantiomer:
[R]D ) +20 (c ) 0.1, MeOH).23
Conversion of 6b or 34 into (R)- or (S)-r-Allylphenylalanine (35
or ent-35). Hydrolysis of the phenylalanine-derived complexes was
performed as described for 6a. Thus, 34 (435 mg, 1.05 mmol) was
cleaved using 0.210 mL (3.14 mmol) of ethylenediamine for amidine
hydrolysis and 20 g of Amberlite IRC-50S resin for purification,
yielding 152 mg (0.741 mmol, 71%) crude amino acid ent-35 [R]D
)
(23) Seebach, D.; Fadel, A. HelV. Chim. Acta 1985, 68, 1243.