Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-Nebivolol

Article abstract of DOI:10.1016/S0040-4020(00)00572-X

The total synthesis of (S,R,R,R)-Nebivolol, a hypertensive agent, is reported. Claisen rearrangement and a one-pot Sharpless asymmetric epoxidation, intramolecular epoxide opening with internal phenoxide anion to generate the chiral chromane are the key s

Full text of DOI:10.1016/S0040-4020(00)00572-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6339±6344
Enantioselective Total Synthesis of the Antihypertensive Agent
(S,R,R,R)-Nebivololq
*
S. Chandrasekhar and M. Venkat Reddy
Indian Institute of Chemical Technology, Hyderabad 500-007, India
Received 6 April 2000; revised 30 May 2000; accepted 15 June 2000
AbstractÐThe total synthesis of (S,R,R,R)-Nebivolol, a hypertensive agent, is reported. Claisen rearrangement and a one-pot Sharpless
asymmetric epoxidation, intramolecular epoxide opening with internal phenoxide anion to generate the chiral chromane are the key steps.
q 2000 Elsevier Science Ltd. All rights reserved.
Nebivolol, 1, is a potent and selective b1-adrenergic blocker
with antihypertensive activity.1 The selectivity of 1 in b1-
adrenocepter antagonism was greater than that of clinically
used atenolol, pindolol and propranolol.2 (S,R,R,R)-Nebivo-
lol was reported to be the most active isomer by the Janssen
Research Foundation and the R. W. Johnson Pharmaceutical
Research Institute.3 The bene®cial hemodynamic pro®le of
racemic nebivolol has been mainly ascribed to the l-enan-
tiomer,3d which is devoid of b-adrenoceptor blocking
properties as therapeutic doses. It is interesting to note
that d-nebivolol carries b-adrenoceptor blocking properties
while in other b-adrenoceptor antagonists these properties
are carried by the l-enantiomer.3e Our own interest in the
total synthesis of clinically useful compounds, especially
those containing amino functionality,4 prompted us to take
up the synthesis of this molecule. In this paper we disclose a
stereo- and enantioselective total synthesis of (S,R,R,R)-
Nebivolol. The general retrosynthetic analysis that was
adopted is illustrated in Scheme 1.
According to this plan, the fragments 2 and 3 would be
joined through nucleophilic opening of epoxide 3 with
amine 2. The fragments 2 and 3 would be obtained from a
one-pot Sharpless asymmetric epoxidation (SAE), ring
closure of appropriate allylalcohol 9a. The allyl alcohol
was in turn prepared from Clasien rearrangement of the
requisite allylic ether 5. Our synthesis began from commer-
cially available p-¯uorophenol 4, which on treatment with
acetone, K2CO3 and allylbromide under re¯ux conditions
furnished O-allyl ether 5, the prerequisite for Claisen
Scheme 1.
q
IICT communication no. 4390.
Keywords: amine; chromanes; antihypertensive; epoxidation; coupling reaction.
* Corresponding author. Fax: 191-40-7170512; e-mail: srivaric@iict.ap.nic.in
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00572-X

6340
S. Chandrasekhar, M. Venkat Reddy / Tetrahedron 56 (2000) 6339±6344
Scheme 2. (a) Allylbromide, K2CO3 (83%); (b) (i) heating, 2108C (76%), (ii) TBDMSCl, imidazole (84%); (c) BH3´Me2S, H2O2, OH2 (75%); (d) Dess±Martin
periodinane, followed by PPh3vCH-COOEt (72%); (e) (i) DIBAL (78%), (ii) TBAF in THF (80%); (f) (2)-DET, Ti(isopropoxide)4, TBHP, 2208C, NaOH
(65%); (g) TsCl, Py. (82%); (h) NaN3, DMF (77%); (i) Pd/C in EtOH (81%).
rearrangement5 (Scheme 2). Thermal rearrangement of
O-allyl ether 5 generated 2-allyl-4-¯uoro phenol 5a. Protec-
tion of the phenol group 6 was achieved with TBDMS-Cl
and imidazole. Hydroboration of 6 (BH3´Me2S, followed by
H2O2) furnished primary alcohol 7, which upon one pot
oxidation with Dess±Martin periodinane and Wittig ole®-
nation with ethyltriphenylphosporane furnished a,b-unsatu-
rated ester6 8. DIBAL-H reduction of ester 8 produced the
corresponding alcohol followed by desilylation (TBAF) to
yield the allyl alcohol 9a setting the stage for Sharpless
asymmetric epoxidation. The two requisite chromanes 10
and 13 were obtained from 9a in `one pot' on treatment
with (2)-DET and (1)-DET, respectively, followed by
sodium hydroxide workup.7 Chromane 10 on treatment
with tosylchloride followed by NaN3 in DMF gave the
azido alcohol 12 (Scheme 2). Reduction of the azide to its
corresponding amine 2 completed the synthesis of the left
fragment of Nebivolol.
Similarly under Mitsunobu conditions (p-NO2C6H4COOH,
TPP and DEAD) chromane 13 furnished benzoate deriva-
tive8 14 with inversion at C2. Standard deprotection of
di-PNB ester 14 (NaOMe, MeOH) to diol 15, monotosyl-
ation to 16 and base (NaOMe, CH2Cl2) to form epoxide 3
(Scheme 3). The total synthesis of 1 was completed by
coupling the two fragments involving nucleophilic opening
of epoxide 3 with hydroxy amine 2 followed by derivatizing
the product as the hydrochloride salt (Scheme 4). The spec-
tral data of 1 are in total agreement with the reported9
values.
In conclusion, we present an ef®cient and convergent synthesis
Scheme 3. (a) (1)-DET, Ti (isopropoxide)4, TBHP, 2208C, NaOH (65%); (b) p-NO2C6H4COOH, DEAD, TPP (61%); (c) NaOMe (72%); (d) TsCl, Py.
(75%); (e) NaOMe, in DCM (62%).
Scheme 4.

S. Chandrasekhar, M. Venkat Reddy / Tetrahedron 56 (2000) 6339±6344
6341
of (S,R,R,R)-Nebivolol in optically pure form. The com-
mercial availability of Sharpless asymmetric epoxidation
reagents and easy preparation of allylalcohols makes this
approach most attractive for the synthesis of other possible
isomers and analogues. The utilization of `one-pot' reac-
tions makes the synthesis quite ef®cient overall.
2-Allyl-(1-tert-butyldimethylsilyloxy)-4-¯uoro-benzene
(6). To a solution of 5a (18 g, 118 mmol) and imidazole
(12 g, 177 mmol) in dry CH2Cl2 (150 mL) was slowly
added t-butyldimethylsilyl chloride (19.5 g, 130 mmol) in
CH2Cl2 (25 mL) at 08C. The reaction mixture was stirred
for 10 h at room temperature after which it was diluted with
CH2Cl2 (100 mL). The organic layer was washed with water
(2£100 mL), brine (100 mL) and dried over Na2SO4. The
volatiles were removed under reduced pressure. The crude
product was puri®ed by column chromatography (hexane)
to afford silyl ether 6 (26.5 g, 84%) as a colorless oil. Rf (5%
ethyl acetate/hexane) 0.75; IR (neat): 3045, 3020, 2990,
Experimental
General methods
;
1650, 1580, 1200, 650 cm21 1H NMR (200 MHz,
CDCl3): d 6.85±6.65 (m, 3H, C6H3±F), 6.05±5.85 (m,
1H, CH2±CHvCH2), 5.15 (d, 1H, Jˆ1.5 Hz, CH2vCH),
5.05 (dd, 1H, Jˆ9.5, 1.5 Hz, CH2vCH), 3.35 (d, 2H,
Jˆ8.5 Hz, CH2±CHvCH), 1.05 (s, 9H, C(CH3)3), 0.2 (s,
6H, Si±2£CH3); EI MS m/z 152 (M12115), 73, 57 41 Anal
Calcd for C15H23OFSi: C, 67.62; H, 8.7. Found C, 67.75; H,
8.65.
Crude products were puri®ed by column chromatography on
silica gel (60±120 mesh). 1H NMR spectra were obtained in
CDCl3 at 200 MHz. Chemical shifts are given in ppm, with
respect to internal TMS, J values are quoted in Hz. Infrared
spectra were obtained neat, only the most signi®cant absorp-
tions in cm21 are indicated. DMSO, triethylamine and
CH2Cl2 were distilled from CaH2 and stored over molecular
sieves. Benzene and THF were dried over sodium and
benzophenone. All reactions were carried out under
nitrogen atmosphere using dry glassware.
3-(2-tert-Butyldimethylsilyloxy-5-¯uoro-phenyl)-1-pro-
panol (7). To a cold solution of 6 (15 g, 52.8 mmol) in THF
(100 mL) was added BH3´DMS (26.4 mmol, 1 M solution in
THF) and stirred for 1.5 h at 108C and monitored by TLC till
the starting material is consumed completely. The reaction
mixture was cooled to 08C, the excess boron reagent was
quenched with 1 M NaOH (8 mL) and stirred for 30 min
maintaining at 08C. 30% H2O2 (92.4 mmol) was added at
08C and stirred for 2 h. The reaction mixture was diluted
with water (100 mL), and extracted with ethyl acetate
(200 mL), the organic layers were combined and washed
with brine (150 mL). The organic layer is separated,
volatiles were removed under vacuum and the crude product
thus obtained was puri®ed by column chromatography (9:1
hexane/ethyl acetate) to afford 7 (12 g, 75%) as a colorless
oil. Rf (15% ethyl acetate/hexane) 0.5; IR (neat): 3550,
1-Allyloxy-4-¯uoro-benzene (5). To a solution of p-¯uoro-
phenol 4 (30 g, 267 mmol) in acetone (250 mL) were added
anhydrous K2CO3 (64.6 g, 468 mmol) and allyl bromide
(38.8 g, 321 mmol). The resulting mixture was re¯uxed
for 8 h, cooled to room temperature and poured into cold
water (500 mL). The aqueous layer was extracted with three
portions of ether (3£200 mL) and the combined organic
layers is washed with 2 M sodium hydroxide solution
(100 mL) and dried over anhydrous K2CO3. The solvents
were removed under vacuum to afford allyl phenyl ether 5
(34 g, 83%) as a colorless oil. Rf (10% ethyl acetate/hexane)
0.95; IR (neat): 3100, 3045, 1650, 1500, 980 650 cm21; 1H
NMR (200 MHz, CDCl3): d 7.05±6.80 (m, 4H, C6H4F),
6.15±5.95 (m, 1H, CH2±CHvCH), 5.45 (dd, 1H, Jˆ
14.0, 2.0 Hz, CH2±CHvCH), 5.3 (dd, 1H, Jˆ9.0,
1.0 Hz, CHvCH±CH2), 4.5 (d, 2H, Jˆ4.5 Hz, CH2±
CHvCH); EI MS m/z, 111 (M1241), 73, 57, 41; Anal
Calcd for C9H9OF: C, 71.04; H, 5.96. Found C, 71.10; H,
6.05.
3045, 2990, 1580, 1220, 1050, 650 cm21
;
1H NMR
(200 MHz, CDCl3): d 6.85±6.65 (m, 3H, C6H3±F) 3.60 (t,
2H, Jˆ5.9 Hz, CH2±OH) 2.65 (t, 2H, Jˆ5.9 Hz, CH2±
C6H3±F) 1.80±1.75 (m, 2H, CH2±CH2±C6H3±F) 1.02 (s,
9H, C(CH3)3) 0.22 (s, 6H, Si±2£CH3); EI MS m/z 266
[M1218], 97, 71, 57; Anal Calcd for C15H25O2FSi: C,
63.34; H, 8.86. Found C, 63.50; H, 8.62.
2-Allyl-4-¯uoro-phenol (5a). Compound 5 (25 g, 164
mmol) was heated at 2108C for 6 h. After monitoring by
TLC the reaction was cooled to room temperature and
was then dissolved in 100 mL of 5 M NaOH solution and
extracted with two portions (2£100 mL) of light petroleum
ether (60±808C) to remove small amounts of 2-methyl dihy-
drobenzofuran which forms as a by-product. The aqueous
alkaline solution was carefully acidi®ed with 2N hydrochloric
acid under cooling. The aqueous layer was extracted with
ether (300 mL) and dried over Na2SO4. The volatiles were
removed under reduced pressure to afford 2-allyl phenol
5a (19 g, 76%) as a colorless oil. Rf (15% ethyl acetate/
hexane) 0.75; IR (neat): 3345, 3045, 1650, 1360, 1200,
Ethyl-5-(2-tert-butyldimethylsilyloxy-5-¯uoro-phenyl)-
2-pentenoate (8). To a stirred solution of 7 (5 g, 17.6 mmol)
and benzoic acid (8.5 g, 70.4 mmol) in a mixture of dry
CH2Cl2 (100 mL) and dry DMSO (20 mL), Dess±Martin
periodinane (17.9 g, 42.2 mmol) was added. The reaction
mixture turned to orange-brown color within seconds and
started boiling. It was subsequently stirred for 30 min during
which time it attained room temperature. At this tempera-
ture was added ethyltriphenylphosphorane (7 g, 21 mmol)
and the reaction mixture was stirred for a further 10 h. It was
quenched with solid NaHCO3 (15 g). Ether (250 mL) was
added and stirred for 15 min. The mixture was ®ltered and
the organic layer was washed with water (100 mL) and brine
(100 mL) to afford the crude product which was puri®ed by
column chromatography (hexane/ethyl acetate 95:5) to
afford 8 (4.4 g, 72%) as a pale yellow oil. Rf (20% ethyl
acetate/hexane) 0.7; IR (neat): 3030, 2990, 1720, 1600,
1
685 cm21; H NMR (200 MHz, CDCl3): d 6.85±6.65 (m,
3H, C6H3±F), 6.10±5.90 (m, 1H, CH2±CHvCH2), 5.15 (dt,
2H, Jˆ8.6, 2.0 Hz CH2vCH), 3.35 (d, 2H, Jˆ7.5 Hz CH2±
CHvCH2); EI MS m/z 111(M1241), 72, 57, 41; Anal
Calcd for C9H9OF: C, 71. 04; H, 5.96. Found C, 71.10; H,
6.05.
1
1580, 1220, 685 cm21; H NMR (200 MHz, CDCl3): d

6342
S. Chandrasekhar, M. Venkat Reddy / Tetrahedron 56 (2000) 6339±6344
7.10±6.65 (m, 4H, C6H3±F1enone±H), 5.80 (d, 1H,
Jˆ17 Hz, CHvCH), 4.25 (q, 2H, Jˆ6.5 Hz, O±CH2),
2.75 (t, 2H, Jˆ7.8 Hz, CH2±C6H3±F), 2.45 (dt, 2H,
Jˆ7.5, 2.0 Hz, CH2±CHvCH), 1.35 (t, 3H, Jˆ6.5 Hz,
CH3±CH2), 1.05 (s, 9H, C(CH3)3), 0.25 (s, 6H, Si±
2£CH3); EI MS m/z 295 [M1257], 249, 221, 198, 167,
75, 57; Anal Calcd for C19H29O3FSi: C, 64.74; H, 8.29.
Found C, 64.85; H, 8.20.
ture for 4 h. The reaction mixture was subsequently allowed
to warm to 08C and poured into freshly prepared solution of
ferrous sulphate (3.2 g) and tartaric acid (1 g) in water
(20 mL) maintained at 08C. The two-phase mixture was
stirred for 30 min, the aqueous phase was separated and
extracted with CH2Cl2 (50 mL). The combined organic
phases were treated with a pre-cooled solution of 30%
NaOH in saturated brine (30 mL). The two-phase mixture
was stirred for 1 h at the same temperature. The aqueous
layer was separated and extracted with CH2Cl2 (2£50 mL).
The organic extracts were dried over Na2SO4 and concen-
trated to afford the crude product, which was puri®ed by
column chromatography (hexane/ethyl acetate 7:3) to afford
10 (1.4 g, 65%) as a semisolid. Rf (30% ethyl acetate/
hexane) 0.3; IR (neat): 3550, 3050, 2990, 1650, 1200,
1050, 960 cm21; [a]2D5ˆ171.8 (c 1 MeOH); 1H NMR
(200 MHz, CDCl3): d 6.82±6.65 (m, 3H, C6H3F), 4.0±
3.65 (m, 4H, OCH, CH±OH, CH2±OH), 2.90±2.70 (m,
2H, CH2±C6H3±F), 2.30±2.15 (m, 1H CH±CHO), 1.90±
1.75 (m, 1H, CH±CHO); EI MS m/z 212, 151, 125, 57
Anal Calcd for C11H13FO3: C, 62.26; H, 6.17. Found C,
62.30; H, 6.27.
5-(2-tert-Butyldimethylsilyloxy-5-¯uoro-phenyl)-(E)-2-
penten-1-ol (9). To a solution of 8 (7 g, 19.8 mmol) in dry
CH2Cl2 (75 mL) at 2108C under nitrogen atmosphere was
added DIBAL-H (49.7 mmol, 2 M solution in hexane). The
mixture was stirred at 08C for 30 min after which it was
allowed to attain room temperature and stirred for a further
2 h subsequently. The excess DIBAL-H was quenched with
methanol (2 mL) and poured into sodium potassium tarta-
rate solution (10 g in 100 mL water) with vigorous stirring
until the layers were separated. The aqueous layer was
extracted with ether and the combined organic extracts
were washed with brine (100 mL), dried over Na2SO4 and
concentrated. The crude product was puri®ed by column
chromatography (hexane/ethyl acetate 8:2) to afford 9
(4.8 g, 78%) as a colorless oil. Rf (20% ethyl acetate/
hexane) 0.65; IR (neat): 3500, 3045, 2990, 1600, 1550,
6-Fluoro-2-[1-hydroxy-2-(4-methylphenylsulfonyloxy)-
(1R)-ethyl]-(2S)-3H,4H-chromene (11). To a solution of
compound 10 (1.2 g, 5.6 mmol) in dry CH2Cl2 (15 mL)
containing dry pyridine (1 mL) at 08C under nitrogen atmo-
sphere was added tosyl chloride (1.2 g, 6.2 mmol) in CH2Cl2
(5 mL). The reaction mixture was stirred for 10 h at room
temperature. It was washed with saturated CuSO4 solution
(20 mL) and extracted with CH2Cl2 (50 mL). The organic
phase was dried over Na2SO4 and concentrated under
reduced pressure. The crude product was puri®ed by column
chromatography (hexane/ethyl acetate 1:9) to afford 11
(1.7 g, 82%) as a pale yellow solid. Mp (102±1048C); Rf
(30% ethyl acetate/hexane) 0.45; IR (KBr): 3500, 3045,
2990, 1650, 1500, 1160, 1050, 650 cm21; [a]D25ˆ154.4 (c
1
1200, 1050, 650 cm21. H NMR (200 MHz, CDCl3): d
6.85±6.50 (m, 3H, C6H3±F), 5.80±5.50 (m, 2H,
CHvCH), 4.05 (d, 2H, Jˆ4.6 Hz, CH2±OH), 2.65 (t, 2H,
Jˆ6.9 Hz, CH2±Ph), 2.30 (m, 2H, CH2±CHvCH), 1.0 (s,
9H, C(CH3)3), 0.20 (s, 6H, Si±2£CH3); EI MS m/z 310, 199,
75, 41; Anal Calcd for C17H27O2FSi: C, 65.75; H, 8.77.
Found C, 65.60; H, 8.84.
5-(5-Fluoro-2-hydroxy-phenyl)-E-2-penten-1-ol (9a). To
a stirred solution of 9 (5 g, 16 mmol) in THF (50 mL) at 08C
was added TBAF (8 mmol, 1 M solution in THF). The
reaction mixture was allowed to warm to room temperature
and stirred for a further 3 h. The excess TBAF was
quenched with saturated NH4Cl solution (50 mL) and the
reaction mixture was diluted with ethyl acetate (100 mL)
and washed with water (100 mL) and brine (50 mL). The
organic layer was dried over Na2SO4 and the volatiles were
removed under reduced pressure. The crude product thus
obtained was puri®ed by column chromatography
(hexane/ethyl acetate 7.5:2.5) to afford 9a (2.5 g, 80%) as
a colorless viscous oil. Rf (30% ethyl acetate/hexane) 0.35;
IR (neat): 3500, 3350, 3045, 2990, 1650, 1465, 1200,
1
1 CHCl3); H NMR (200 MHz, CDCl3): d 7.80 (d, 2H,
Jˆ8.0 Hz, C6H4±CH3), 7.35 (d, 2H, Jˆ8.0 Hz, C6H4±
CH3), 6.80±6.50 (m, 3H, C6H3±F) 4.35 (dd, 1H, Jˆ10.0,
2.0 Hz, CH±OTs), 4.20 (dd, 1H, Jˆ10.0, 4.2 Hz, CH±OTs),
3.95±3.80 (m, 2H, OCH, CH±OH), 2.85±2.70 (m, 2H,
CH2±C6H3±F), 2.48 (s, 3H CH3±C6H4), 2.25±2.15 (m,
1H, CH±CHO) 1.85±1.65 (m, 1H, CH±CHO); EI MS m/z
366, 151, 91; Anal Calcd for C18H19FO5S: C, 59.01; H, 5.23;
Found C, 58.94; H, 5.15.
1
650 cm21; H NMR (200 MHz, CDCl3): d 6.72±6.50 (m,
2-Azido-1-[6-¯uoro-(2S)-3H,4H-2-chromenyl]-(1R)-ethan-
1-ol (12). To a solution of 11 (1.25 g, 3.4 mmol) in dry DMF
(15 mL) was added sodium azide (1.05 g, 17 mmol) and
stirred for 10 h at 808C. The reaction mixture was cooled
to room temperature and diluted with water (20 mL), the
resulting mixture was extracted with ether (2£25 mL),
washed with water (25 mL) and brine (25 mL) and dried
with Na2SO4 and concentrated. The crude product was puri-
®ed by column chromatography (hexane/ethyl acetate 8:2)
to afford azide 12 (0.625 g, 77%) as a syrup. Rf (30% ethyl
acetate/hexane) 0.65; IR (neat): 3550, 3045, 2990, 2140
1650, 1180, 650 cm21; [a]D25ˆ150.2 (c 1 CHCl3); 1H
NMR (200 MHz, CDCl3): d 6.70±6.52 (m, 3H, C6H3±F),
3.85±3.65 (m, 2H, CH±O, CHOH), 3.45 (d, 2H, Jˆ4.5 Hz,
CH2±N3), 2.75±2.65 (m, 2H, CH2±C6H3±F), 2.25±2.0 (m,
1H, CH±CHO), 1.85±1.65 (m, 1H, CH±CHO); EI MS m/z
3H, C6H3±F), 5.70±5.45 (m, 2H, CHvCH), 3.95 (d, 2H,
Jˆ4.6 Hz, CH2±OH), 2.55 (t, 2H, Jˆ7.0 Hz, CH2±C6H3),
2.25 (m, 2H, CH2±CHvCH); EI MS m/z 195, 75, 41; Anal
Calcd for C11H13O2F: C, 67.33; H, 6.68; Found C, 67.45; H,
6.52.
1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-
1,2-ethanediol (10). To a stirred suspension of activated
Ê
powdered 4 A molecular sieves (5 g) in dry CH2Cl2
(50 mL) at 2208C under nitrogen atmosphere was added
(1)-DET (2.3 g, 11.2 mmol) in CH2Cl2 (15 mL), titanium
tetraisopropoxide (3.4 g, 12.3 mmol) and TBHP (40 mmol)
sequentially. After 20 min the resulting mixture was treated
with allyl alcohol 9a (2 g, 10.2 mmol) in CH2Cl2 (20 mL)
over a period of 20 min and maintained at the same tempera-

S. Chandrasekhar, M. Venkat Reddy / Tetrahedron 56 (2000) 6339±6344
6343
M1 237, 151, 125, 109, 57. Anal Calcd for C11H12FN3O2: C,
55.69; H, 5.10. Found C, 55.74; H, 5.05.
prepared NaOMe (0.62 g, 11.7 mmol) in methanol. The
reaction mixture was stirred for 3 h at room temperature.
The solvent was removed under vacuum. The reaction mass
was diluted with CH2Cl2 (25 mL) and quenched with satu-
rated NH4Cl solution (25 mL). The organic layer was
washed with water and brine, dried over Na2SO4 and the
volatiles were removed under vacuum to afford the crude
product which was puri®ed by column chromatography
(hexane/ethyl acetate 7:3) to afford 15 (0.6 g, 72%) as a
syrup. Rf (30% ethyl acetate/hexane) 0.3; IR (neat): 3500,
3045, 2990, 1650, 1500, 1200, 650 cm21; [a]D25ˆ65.80 (c 1
MeOH); 1H NMR (200 MHz, CDCl3): d 6.85±6.70 (m, 3H,
C6H3±F), 4.0±3.80 (m, 2H, CH±OH, CHO), 3.75 (dd, 1H,
Jˆ9.0, 3.0 Hz, CH±OH), 3.65 (dd, 1H, Jˆ9.0, 3.0 Hz, CH±
OH), 2.90±2.80 (m, 2H, CH2±C6H3±F), 2.35±2.20 (m, 1H,
CH±CHO), 1.95±1.8 (m, 1H, CH±CHO); EI MS m/z 212,
151, 125, 57; Anal Calcd for C11H13FO3: C, 62.26; H, 6.17.
Found C, 62.15; H, 6.25.
2-Amino-1-[6-¯uoro-(2S)-3H,4H-2-chromenyl]-(1R)-ethan-
1-ol (2). To a solution of 12 (0.250 mg, 1.05 mmol) in dry
methanol (5 mL) at room temperature was added 10% Pd±
charcoal (10 mg) and stirred under an atmosphere of hydro-
gen. After 8 h the reaction mixture was ®ltered through a
funnel and the ®ltrates were concentrated under vacuum to
afford 2 (0.180 g, 81%). The compound was dissolved in dry
ether and dry HCl gas was passed through the solution to
form the hydrochloride salt of compound 2 (0.155 g, 75%
yield); mp 60±638C; Rf (10% MeOH/CHCl3) 0.3; IR (KBr):
3550, 3500,3100, 3020, 2990, 1650, 1250, 650 cm21
;
1
[a]2D5ˆ10.40 (c 1 MeOH); H NMR (200 MHz, D2O): d
7.05±6.90 (m, 3H, C6H3±F), 4.25±4.05 (m, 2H, CH±OH,
CHO), 3.55 (dd, 1H, Jˆ12.3, 2.3 Hz, CH±NH2), 3.17 (dd,
1H, Jˆ12.3, 6.0 Hz, CH±NH2), 3.05±2.85 (t, 2H, Jˆ
7.0 Hz, CH2±C6H3±F), 2.35±2.20 (m, 1H, CH±CHO),
2.0±1.85 (m, 1H, CH±CHO); EI MS m/z M1 211, 194,
176, 151, 126, 60, 57; Anal Calcd for C11H14FNO2: C,
62.55; H, 6.68. Found C, 62.42; H, 6.50.
6-Fluoro-2-[1-hydroxy-2-(4-methylphenylsulfonyloxy)-
(1R)-ethyl]-(2R)-3H,4H-chromene (16). This compound
was prepared from 15 according to the procedure mentioned
in the preparation of compound 11 to afford 16 (75%) as a
pale yellow solid. Mp (102±1058C); Rf (30% ethyl acetate/
1-[6-Fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1S)-
1,2-ethanediol (13). This compound was prepared from 9a
according to the procedure mentioned in the preparation of
compound 10, where instead of (1)-DET, (2)-DET was
employed (65% yield). Rf (30% ethyl acetate/hexane) 0.3;
hexane) 0.45; IR (KBr): 3500, 2990, 1650, 1100, 960 cm21
;
[a]2D5ˆ152.40 (c 1 MeOH); 1H NMR (200 MHz, CDCl3): d
7.80 (d, 2H, Jˆ8.0 Hz, C6H4±CH3), 7.35 (d, 2H, Jˆ8.0 Hz,
C6H4±CH3), 6.75±6.55 (m, 3H, C6H3±F), 4.32 (dd, 1H,
Jˆ10.0, 2.0 Hz, CH±OTs), 4.20 (dd, 1H, Jˆ10.0, 3.2 Hz,
CH±OTs), 3.90±3.80 (m, 2H, OCH, CH±OH), 2.85±2.75
(m, 2H, CH2±C6H3±F), 2.45 (s, 3H, C6H4±CH3), 2.25±2.15
(m, 1H, CH±CHO), 1.85±1.70 (m, 1H, CH±CHO); EI MS
m/z M1 366, 151, 91; Anal Calcd for C18H19FO5S: C, 59.01;
H, 5.23; Found C, 58.85; H, 5.05.
IR (neat): 3550, 3045, 2990, 1650, 1100, 1050, 650 cm21
;
[a]2D5ˆ270.45 (c 1 MeOH); 1H NMR (200 MHz, CDCl3): d
6.85±6.65 (m, 3H, C6H3±F), 4.0±3.65 (m, 4H, CH±O, CH±
OH, CH2±OH), 2.85±2.70 (m, 2H, CH2±C6H3±F), 2.30±
2.15 (m, 1H, CH2±CHO), 1.90±1.70 (m, 1H, CH±CHO); EI
MS m/z 212, 151, 125, 57; Anal Calcd for C11H13FO3: C,
62.26; H, 6.17. Found C, 62.30; H, 6.15.
6-Fluoro-2-[(2R)-oxiran-2-yl]-(2R)-3H,4H-chromane (3).
To a cold solution of 16 (0.5 g, 1.36 mmol) in CH2Cl2
(20 mL) was added freshly prepared NaOMe (0.144 g,
2.7 mmol). The reaction mixture was stirred for 6 h at
room temperature. The reaction mixture was diluted with
CH2Cl2 (20 mL) and quenched with saturated NH4Cl solu-
tion (10 mL). The organic layer was washed with water and
brine, extracted with CH2Cl2 (50 mL), dried Na2SO4. The
volatiles were removed under reduced pressure. The crude
product was puri®ed by column chromatography (hexane/
ethyl acetate 95:5) to afford 3 (0.165 g, 62%) as a colorless
liquid. Rf (30% ethyl acetate/hexane) 0.75; IR (neat): 3045,
2990, 1650, 1160, 1050, 960, 650 cm21; [a]D25ˆ173.30 (c
2-(1,2-Di-(4-nitrophenylcarbonyloxy)-(1R)-ethyl-6-¯uoro-
(2R)-3H,4H-chromene (14). To a solution of diethyldiaza-
dicarboxylate (7.3 g, 42 mmol) in THF (50 mL) was added
triphenyl phosphine (11.5 g, 42 mmol) in THF (50 mL) at
2208C followed by addition of a solution of 13 (1.5 g,
7 mmol) in THF (20 mL) and p-nitro benzoic acid (7 g,
42 mmol) in THF (15 mL). The resulting solution was stir-
red for 5 h at 2208C and then allowed to warm to room
temperature while continuing the stirring for an additional
1 h. The solvent was removed under vacuum, ether was
added to the residue to precipitate the triphenylphosphine-
oxide, which was removed by ®ltration. The solvent from
the resulting ®ltrate was removed under vacuum, the crude
product was puri®ed by column chromatography (hexane/
ethyl acetate 95: 5) to afford 14 (2.2 g, 61%) as a syrup. Rf
(25% ethyl acetate/hexane) 0.55; IR (neat): 3050, 2990,
1720, 1650, 1425, 1100, 960 cm21; [a]D25ˆ245.80 (c 1
1
0.5 CHCl3); H NMR (200 MHz, CDCl3): 6.80±6.65 (m,
3H, C6H3±F), 3.80±3.65 (m, 1H, CH2±CHO), 3.10±3.02
(m, 1H, CHO), 2.90±2.70 (m, 4H, CH2±O, CH2±C6H3),
2.20±2.05 (m, 1H, CH±CHO), 2.0±1.80 (m, 1H, CH±
CHO); EI MS m/z 194, 151, 149, 96, 57; Anal Calcd for
C11H11FO2: C, 68.03; H, 5.71. Found C, 67.95; H, 6.62.
1
CHCl3); H NMR (200 MHz, CDCl3): 8.35±8.15 (2d, 4H,
2£NO2C6H4±CO), 6.80±6.70 (m, 3H, C6H3±F), 4.50±4.20
(m, 3H, CH2O, CH±OCO), 3.75±3.60 (m, 1H, CHO), 2.90±
2.70 (m, 2H, CH2±C6H3±F), 2.25±2.0 (m, 1H, CH±CHO),
1.95±1.80 (m, 1H, CH±CHO); Anal Calcd for
C25H19FN2O9: C, 58.83; H, 3.75 Found C, 58.65; H, 3.80.
(1)-(S,R,R,R)-a,a1-Imino-bis-(methylene)-bis-(6-¯uoro-
3,4-dihydro-2H,1-benzo-pyran-2-methanol)hydrochloride
(3´HCl) (1). Amine 2 (S,R) (65 mg, 0.3 mmol) was
dissolved in dry t-butanol (5 mL) and epoxide 3 (60 mg,
0.3 mmol), and catalytic amount of BF3´O(Et)2 were
added to the reaction mixture. The resulting mixture was
re¯uxed for 4 h. The solvent was removed under vacuum
and washed with water, brine and extracted with ethylacetate
1-[6-Fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-
1,2-ethanediol (15). To a cold solution of 14 (2 g,
3.9 mmol) in dry methanol (15 mL) was added freshly

6344
S. Chandrasekhar, M. Venkat Reddy / Tetrahedron 56 (2000) 6339±6344
Reneman, R. S.; Janssen, P. A. J. Eur. J. Pharm. 1990, 181, 261±
265. (c) Bowden, C. R.; Marchione, C. S. J. Pharmacol. Exp. Ther.
1989, 251, 599±605. (d) Rahn, K. H. Hemodynamic effects of the
optical isomers of betareceptor blocking agents, Eur. Heart J. 4
(Suppl. D) 27. (e) Van de Water, A.; Xhonneux, R. S.; Reneman,
R. S.; Janssen, P. A. J. Cardio vascular effects of d,l-nebivolol and
its enanatiomers a comparison with those atenolol, Eur. J. Pharm.
1988, 156, 95.
(20 mL) and dried over Na2SO4. The volatiles were concen-
trated to afford a yellowish oil. The crude product was
dissolved in dry DCM and dry HCl gas was passed through
the solution to form the hydrochloride salt of compound 1
(0.025 g, 20%) as a white solid. Rf (10:1 CH2Cl2/MeOH)
0.26; IR (KBr) 3350, 3173, 2950, 1495, 1450 cm21
.
[a]2D5ˆ10.038 (c 0.02 MeOH); lit. 10.040 (cˆ0.0027);
1H NMR (200 MHz, CDCl3): 6.84±6.72 (m, 6H, C6H3±F),
4.15±3.85 (m, 4H, CH±OH±CHO), 3.42±3.15 (m, 4H,
CH2±NH±), 2.95±2.72 (m, 4H, CH2±C6H3±F), 2.25±2.15
(m, 1H, CH±CHO), 2.20±1.80 (m, 2H, CH±CHO), 1.70±
1.68 (m, 1H, CH±CH2); HRMS calcd for C22H25F4NO4
(M11)ˆ406.1831, found 406.1833.
4. (a) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett. 1999,
40, 5071. (b) Chandrasekhar, S.; Mohapatra, S. Tetrahedron Lett.
1998, 39, 6415. (c) Chandrasekhar, S.; Mohapatra, S.; Yadav, J. S.
Tetrahedron 1999, 55, 4763.
5. (a) Adams, R. J. Am. Chem. Soc. 1919, 41, 648. (b) Lauer, L.
J. Am. Chem. Soc. 1939, 61, 1939. (c) Tarbell, D. S. Org. React.
1944, 2, 1±48.
Acknowledgements
6. Barrett, A. G. M.; Hamprecht, D.; Ohkubo, M. J. Org. Chem.
1997, 62, 9376±9378.
We thank Dr J. S. Yadav, Head, Organic DivisionÐI, IICT,
for helpful discussions and CSIR (New Delhi) for ®nancial
assistance to M. V. R.
7. (a) Hosokawa, T.; Kono, T.; Shinohara, T.; Murahashi. S. I.
J. Organomet. Chem. 1989, 370, C13. (b) Corey, E. J.; Ha, D. C.
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D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307. (d) Katsuki, T.;
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1
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