EnantioselectiVe Synthesis of (S,R,R,R)-NebiVolol
J. Am. Chem. Soc., Vol. 120, No. 33, 1998 8347
aromatic CH), 6.35 (1H, dd, J ) 10.06, 1.83, ArCH), 5.90-5.77 (2H,
m, vinylic CH, ArCHCH), 5.0 (1H, dd, J ) 17.2, 1.6, trans vinyl),
4.97 (1H, dd, J ) 10.2, 0.9, cis vinyl CH), 4.73 (1H, m, ArOCH),
3.92 (1H, m, CHOTBS), 2.08 (2H, m, allylic CH), 1.70-1.44 (4H, m,
aliphatic), 0.86 (9H, s, t-BuSiMe2) 0.06 (3H, s, CH3Si), -0.02 (3H, s,
CH3Si). 13C NMR: δ 158.1 (d, J ) 238.04), 150.3, 139.5, 125.5, 124.5,
123.5 (d, J ) 8.4), 117 (d, J ) 6.9), 115.5 (d, J ) 23.6), 115.4, 113.2
(d, J ) 23.6), 78.3, 74.4, 34, 33, 26, 24.2, 18.3, -4.4, -4.5. HRMS
calcd for C21H31FO2Si (M - H): 361.1998. Found: 361.1999. Anal.
Calcd for C21H31FO2Si: C, 69.57; H, 8.62; F, 5.24. Found: C, 66.94;
this point, the mixture was diluted with 2 mL of aqueous NaHCO3 and
washed three times with 5-mL portions of CH2Cl2. Organic layers were
dried over MgSO4, and the solvent was removed in vacuo to obtain a
yellow oil. Purification was accomplished by silica gel chromatography
(5:1 hexanes/EtOAc) to obtain 16.2 mg of the desired dialkylamine as
a clear oil (0.025 mmol, 91%). IR (KBr): 2962 (w), 2928 (w), 2899
(w), 2867 (w), 1494 (m), 1269 (w), 1218 (w) 836 (w) cm-1
.
1H
NMR: δ 6.80-6.64 (8H, m, aromatic CH), 4.05-3.91 (4H, m,
ArCOCH, ArCOCHCHOSi), 2.92-2.67 (8H, m, CH2N, ArCH2), 2.08-
1.98 (2H, m, ArCH2CHH), 1.84-1.65 (2H, m, ArCH2CHH), 0.85 (9H,
s, t-BuSi), 0.83 (9H, s, t-BuSi), 0.12 (3H, s, CH3SiCH3), 0.10 (6H, s,
CH3SiCH3), 0.06 (3H, s, CH3SiCH3). 13C NMR: δ 156.6 (d, J )
236.8), 156.5 (d, J ) 238.9), 155.4 (d, J ) 6.8), 150.9 (d, J ) 15.1),
123.2 (d, J ) 7.6), 117.4 (d, J ) 9.1), 117.3 (d, J ) 8.3), 115.2 (d, J
) 22.0), 113.7 (d, J ) 22.8), 78.1, 77.2, 73.9, 73.8, 52.9, 52.1, 29.7,
25.9, 25.2, 24.8, 22.4, 22.2, 18.2, -4.3, -4.4, -4.5. HRMS calcd for
H, 8.66; F, 5.35. [R]22 ) -9.700 (THF, c ) 0.066).
589
2(S)-(1(R)-tert-Butyldimethylsiloxy-5-oxohexyl)-6-fluoro-2H-ben-
zopyran. IR (KBr): 2952 (m), 2928 (m), 2855 (m), 2898 (w), 1717
(s), 1487 (s), 1252 (m), 1218 (m), 837 (m) cm-1 1H NMR: δ 6.79-
.
6.62 (3H, m, aromatic CH), 6.36 (1H, d, J ) 10.2, ArCH), 5.82 (1H,
dd, J ) 9.9, 3.1, vinyl CH), 4.72 (1H, m, ArOCH), 3.85 (1H, dt, J )
10.2, 5.1, CHOTBS), 2.45 (2H, t, J ) 7.2, CH2COCH3), 2.14 (3H, s,
CH2COCH3), 1.78-1.48 (4H, m, aliphatic CH), 0.84 (9H, s, t-BuSi),
0.40 (3H, s, CH3Si), -0.20 (3H, s, CH3Si). 13C NMR: δ 208.7, 157.6
(d, J ) 150), 149.3, 124.6, 124.1, 123.9, 122.7 (d, J ) 8.4), 116.3 (d,
J ) 7.6), 112.7 (d, J ) 23.5), 72.5, 73.7, 43.7, 32.7, 29.7, 25.9, 19.1,
C34H53F2NO4Si (M + H): 634.3560. Found: 634.3562. [R]22
-0.740 (THF, c ) 0.0108).
)
589
(+)-[S,R,R,R]-r,r′-[Iminobis(methylene)bis[6-fluoro-3,4-dihydro-
2H,1-benzopyran-2-methanol] Hydrochloride (3‚HCl). Bis(silyl
ether) 23 (10.5 mg, 0.16 mmol) was placed in a 5-mL round-bottom
flask and dissolved in 1 mL of anhydrous 10% HCl in MeOH. After
5 min, a white precipitate formed. TLC analysis showed the reaction
to be complete after 12 h. The mixture was concentrated in vacuo to
afford a yellowish oil and a white solid, which was rinsed with CHCl3
and filtered through a microfilter to obtain 7 mg (0.05 mmol) of
nebivolol‚HCl salt as a white solid (0.05 mmol, 99%) (Rf ) 0.26 in
10:1 CH2Cl2/MeOH). IR (KBr): 3332 (br), 3181 (br), 2942 (w, br),
2848 (w), 1501 (m) 1438 (w), 1230 (m), 1149 (w), 1073 (w), 803 (w)
18.1, -4.5. [R]23 ) -6.770 (THF, c ) 0.0502). Anal. Calcd for
589
C21H31FO3Si: C, 66.63; H, 8.25; F, 5.02. Found: C, 66.39; H, 8.09;
F, 5.15.
2(S)-(1(R)-tert-Butyldimethylsiloxy-5-oxohexyl)-6-fluoro-3,4-di-
hydro-2(H)-benzopyran. IR (KBr): 2966 (m), 2937 (m), 2902 (w),
2856 (m), 1730 (m), 1497 (s), 1224 (m), 1097 (m), 836 (m), 783 (m)
cm-1 1H NMR: δ 6.80-6.67 (3H, m, aromatic CH), 3.91-3.80 (2H,
.
m, ArOCH, CHOTBS), 2.86-2.68 (2H, m, ArCH2), 2.46 (2H, t, J )
6.9, CH3COCH2), 2.15 (3H, s, CH3O), 1.98 (1H, m, ArCH2CHH),
1.42-1.83 (5H, m, ArCH2CHH, alkyl), 0.88 (9H, s, t-BuSi), 0.10 (3H,
s, CH3Si), 0.04 (3H, s, CH3Si). 13C NMR: δ 208.7, 157.7, 153.1 (d,
J ) 452), 123.2 (d, J ) 6.8), 117.3 (d, J ) 8.4), 115.1 (d, J ) 22.8),
113.7 (d, 23.5), 78.4, 73.5, 43.7, 33.1, 29.8, 25.9, 24.9, 21.5, 19.5,
18.2, -4.2, -4.6. [R]22589 ) +3.170 (THF, c ) 0.077). Anal. Calcd
for C21H33FO3Si: C, 66.28; H, 8.74; F, 4.99. Found: C, 66.23; H,
8.73; F, 5.01.
cm-1 1H NMR: δ 6.85-6.75 (6H, m, aromatic CH), 4.13-4.07 (1H,
.
m, OCHCHOH), 4.04-3.97 (2H, m, OCHCHOH), 3.94-3.89 (1H, m,
OCHCHOH), 3.53-3.20 (4H, m, CHOHCH2N), 2.96-2.77 (4H, m,
ArCH2), 2.28-2.20 (1H, m, ArCH2CHH), 2.22-1.86 (2H, m,
ArCH2CH2), 1.83-1.72 (1H, m, ArCH2CHH). 13C NMR: δ 158.5 (d,
J ) 235.6), 158.4 (d, J ) 235.6), 153.2 (d, J ) 61.1), 151.8 (d, J )
38.8), 125.0 (d, J ) 7.7), 124.8 (d, J ) 7.68), 118.8 (d, J ) 8.4),
118.7 (d, J ) 7.6), 116.5 (d, J ) 6.9), 116.3 (d, J ) 6.8), 115.0 (d, J
) 5.9), 114.8 (d, J ) 6.1), 79.1, 78.8, 69.5, 69.4, 51.6, 51.4, 25.9,
25.4, 24.6, 24.2. HRMS calcd for C22H25F4NO4 (M + H) ) 406.1831.
2(S)-(1(R)-tert-Butyldimethylsiloxy-2-propenyl)-6-fluoro-3,4-di-
hydro-2H-benzopyran ((S,R)-18). IR (KBr): 2955 (m), 2929 ((m),
2892 (w), 2856 (m), 1494 (m) 1255 (m), 1217 (m) 847 (m). 1H
NMR: δ 6.80-6.68 (3H, m, aromatic CH), 5.91 (1H, ddd, J ) 17.2,
10.6, 5.3, vinyl CH), 5.36 (1H, dt, J ) 17.2, 1.6, trans vinyl CH), 5.20
(1H, dt, J ) 10.6, 1.6, cis vinyl), 4.39 (1H, dd, J ) 4.9, 4.2, CHOTBS),
3.85 (1H, dq J ) 10.4, 4.2, ArOCH), 2.68-2.82 (2H, m, ArCH2), 2.20-
1.94 (1H, m, ArCH2CHH), 1.88-1.78 (1H, m, ArCH2CHH), 0.89 (9H,
s, t-BuSi), 0.08 (3H, s, CH3Si), 0.06 (3H, s, CH3Si). 13C NMR: δ
157.7, 155.3-150.9 (d, J ) 435.2), 137.8, 123.3, 117.2 (d, J ) 8.3),
113.7 (d, J ) 22.8), 78.9, 74.9, 29.7, 25.8, 24.7, 20.9, 18.3, -4.61,
-4.68. HRMS calcd for C18H27FO2 (M + H): 323.1843. Found:
Found: 406.1830. [R]22 ) +0.040 (MeOH, c ) 0.0027). Anal.
589
Calcd for C22H26ClF2NO4: C, 59.80; H, 5.93; N, 3.17; F, 8.60. Found:
C, 59.64; H, 5.82; N, 2.94; F, 8.36.
Acknowledgment. This work is fondly dedicated to Profes-
sor Thomas J. Katz (Columbia University) for his pioneering
and seminal contributions to the field of metal-catalyzed olefin
metathesis. Financial support from the National Institutes of
Health (GM-47480), the National Science Foundation (CHE-
9632278), and Johnson and Johnson is acknowledged. We are
grateful to Professor J. A. Berson (Yale University), Dr. B. E.
Maryanoff (Johnson and Johnson), Dr. J. P. A. Harrity, and Mr.
J. A. Tallarico (Boston College) for helpful discussions. We
are grateful to Dr. G. Van Lammen (Janssen Research Institute)
for samples of (S,R,R,R)-nebivolol and various related spectral
data. We thank Dr. John Birmingham (Boulder Scientific) for
a most generous gift of rac-(EBTHI)ZrCl2. Ms. Christine
DiBlasi provided invaluable experimental assistance.
323.1841. [R]22 ) +0.990 (THF, c ) 0.016).
589
2(S)-(1(S)-tert-Butyldimethylsiloxy-2-oxoethyl)-6-fluoro-3,4-dihy-
dro-2H-benzopyran ((S,S)-19). IR (KBr): 2961 (m), 2930 (m), 2886
(m), 2857 (m), 1737.90 (m), 1494 (m) 1258 (w), 1216 (m), 916 (w),
841 (w) cm-1 1H NMR: δ 9.78 (1H, s, CHO), 6.80-6.68 (3H, m,
.
aromatic CH), 4.28-4.22 (2H, m, CHOTBS, ArOCH), 2.89-2.70 (2H,
m, ArCH2), 1.99-1.87 (2H, m, ArCH2CH2), 0.92 (9H, s, t-BuSi), 0.14
(3H, s, SiCH3), 0.09 (3H, s, SiCH3). 13C NMR: δ 202.4, 158.0, 155.6-
150.3 (d, J ) 237.0), 122.7 (d, J ) 6.8), 117.4 (d, J ) 7.5), 115.2 (d,
J ) 22.8), 114.1 (d, J ) 22.8), 79.4, 76.3, 29.7, 25.7, 24.4, 22.1, -4.75,
-4.84. [R]22589 ) +0.398 (THF, c ) 0.0129). Anal. Calcd for C17H25-
FO2Si: C, 67.04; H, 8.44; F, 5.89. Found: C, 67.28; H, 8.56; F, 6.14.
(-)-[S,R,R,R]-r,r′-[Iminobis(methylene)bis[6-fluoro-3,4-dihydro-
2H,1-benzopyran-2-tert-butyldimethylsiloxymethyl] (23). Terminal
amine (R,R)-12 (9.0 mg, 0.03 mmol) was dissolved in 0.5 mL of freshly
distilled 1,2-dichloroethane. In a separate flask, aldehyde (S,S)-19 (12
mg, 0.04 mmol) was dissolved in 0.5 mL of THF, and the mixture
was transferred into the original flask by cannula (flask was rinsed
with 0.5 mL of solvent to ensure complete transfer). NaBH(OAc)3
(8.3 mg, 0.04 mmol) was added in one portion, and the reaction was
allowed to stir at 23 °C; TLC analysis after 3 h indicated that the
reaction was complete (Rf product ) 0.50 in 10:1 CH2Cl2/MeOH). At
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