Zr-catalyzed kinetic resolution of allylic ethers and mo-catalyzed chromene formation in synthesis. Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol

Article abstract of DOI:10.1021/ja981378o

The first enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol (3) is described. The synthesis includes the efficient (EBTHI)Zr-catalyzed kinetic resolutions of cycloheptenyl styrenyl ethers 8 and 16, which are subsequently t

Full text of DOI:10.1021/ja981378o

8340
J. Am. Chem. Soc. 1998, 120, 8340-8347
Zr-Catalyzed Kinetic Resolution of Allylic Ethers and Mo-Catalyzed
Chromene Formation in Synthesis. Enantioselective Total Synthesis
of the Antihypertensive Agent (S,R,R,R)-Nebivolol
Charles W. Johannes, Michael S. Visser, Gabriel S. Weatherhead, and Amir H. Hoveyda*
Contribution from the Merkert Chemistry Center, Department of Chemistry, Boston College,
Chestnut Hill, Massachusetts 02467
ReceiVed April 22, 1998
Abstract: The first enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-nebivolol (3) is
described. The synthesis includes the efficient (EBTHI)Zr-catalyzed kinetic resolutions of cycloheptenyl styrenyl
ethers 8 and 16, which are subsequently treated with 4 mol % Mo(CHCMe2Ph)(N(2,6-(i-Pr)2C6H3))(OCMe-
(CF3)2)2 to afford chiral nonracemic 2-substituted chromenes (R,R)-9 and (S,R)-17. Since the present
retrosynthetic analysis dissects the molecule into two chromene fragments, both the (R) and (S) antipodes of
(EBTHI)Zr catalyst are required. Accordingly, Buchwald’s efficient resolution process is used to resolve
rac-(EBTHI)ZrCl2 (from catalytic hydrogenation of commercially available rac-(EBI)ZrCl2), such that the
two requisite transition metal chiral catalysts are obtained by a single process. Other noteworthy features of
the synthesis include a highly efficient, regio- and stereoselective Pd-catalyzed opening of cyclic allylic epoxide
7 with diaryloxystannane 15 and a photochemical modification of the C2 chromane side chain (e.g., 10 f 11).
Introduction
Scheme 1
An important aspect of research at the interface of inorganic
and organic chemistry is the development of metal-catalyzed
transformations that allow for the efficient and enantioselective
preparation of organic molecules. In this context, we recently
reported the total synthesis of the antifungal agent Sch 38516
(fluvirucin B1),1 where a number of metal-catalyzed processes
were used to control the regio- and stereochemical outcome of
key bond forming events. The Zr-catalyzed asymmetric alkyl-
ation of an unsaturated heterocycle (promoted by 1)2 and the
Mo-catalyzed formation of a 14-membered lactam (promoted
by 2)3 were two of the noteworthy reactions. These catalytic
operations transpired efficiently and stereoselectively and
contributed significantly to the brevity of the synthesis route.
After the above studies, the medicinal significance of chromane
systems4 and the inability of our Zr-catalyzed protocol to resolve
2-substituted chromenes efficiently led us to initiate the study
of a number of additional metal-catalyzed transformations.5
(S,R,R,R)-Nebivolol (3, Scheme 1) is one of a multitude of
therapeutically important agents that bear a chromane unit.6 In
1990, researchers at the Janssen Research Foundation and R.
W. Johnson Pharmaceutical Research Institute reported the
(1) (a) Houri, A. F.; Xu, Z.; Cogan, D. A.; Hoveyda, A. H. J. Am. Chem.
Soc. 1995, 117, 2943-2944. (b) Xu, Z.; Johannes, C. W.; Salman, S. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 1996, 118, 10926-10927. (c) Xu, Z.;
Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302-10316.
(2) (a) Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. J. Am. Chem. Soc.
1993, 115, 6697-6698. (b) Didiuk, M. T.; Johannes, C. W.; Morken, J. P.;
Hoveyda, A. H. J. Am. Chem. Soc. 1995, 117, 7097-7104. (c) For a recent
review, see: Hoveyda, A. H.; Morken, J. P. Angew. Chem., Int. Ed. Engl.
1996, 35, 1262-1284.
(3) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446-452. (b) Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1833-
1836. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036-2056. (d) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371-388. (e) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
(4) For a Mn-catalyzed kinetic resolution of 2,2-disubstituted chromenes,
see: Vander Velde, S. L.; Jacobsen, E. N. J. Org. Chem. 1995, 60, 5380-
5381.
(5) (a) Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda, A. H.
J. Am. Chem. Soc. 1997, 119, 1488-1489. (b) Harrity, J. P. A.; La, D. S.;
Cefalo, D. R.; Visser, M. S. J. Am. Chem. Soc. 1998, 120, 2343-2351.
S0002-7863(98)01378-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/06/1998

EnantioselectiVe Synthesis of (S,R,R,R)-NebiVolol
J. Am. Chem. Soc., Vol. 120, No. 33, 1998 8341
structure and pharmacological properties of this â1-adrenergic
antagonist, which was first prepared in the racemic form.
Various enantiomers were subsequently obtained optically pure
through separation procedures involving chiral HPLC.6b In
clinical studies with hypertensive patients, (S,R,R,R)- or d-
nebivolol has proved to be a potent â1-adrenergic receptor
blocker that has caused reduction of heart rate and blood
pressure and improved left ventricle function.7 Although one
of the other enantiomeric forms, (R,S,S,S)- or l-nebivolol, is
inactive, it has a significant synergistic effect on the antihy-
pertensive efficiency of the (S,R,R,R) isomer.8 In addition,
l-nebivolol has a positive influence on the antihypertensive
properties of related â1-blockers propanolol, atenolol, and
metoprolol.9
Herein, we disclose the first enantioselective total synthesis
of (S,R,R,R)-nebivolol (3). Zr-catalyzed kinetic resolution of
cyclic allylic styrenyl ethers10 and their Mo-catalyzed ring-
opening and ring-closing metathesis5 play a pivotal role in this
convergent total synthesis. The present study for the first time
challenges and demonstrates the synthetic utility of the above
two classes of catalytic reactions.
Scheme 2
derived ketone to obtain (S,R)-Wiii; a regioselective Baeyer-
Villiger oxidation12 would then give (S,S)-ix. A related pathway
would involve cycloheptenyl W (n ) 3) as the starting material.
As such, we intended to examine the utility of the Norrish type
II cleavage process (f(S,R)-x),13 a transformation that has
scarcely been used in synthesis.
It is worthy of note that, although the general plan presented
in Scheme 2 necessitates at least two steps in order to truncate
the C2 side chain, we judged that this approach remained
optimal, since (i) the requisite carbocyclic starting materials
would be readily prepared from commercially available cyclic
dienes (see below), and (ii) the relative stereochemistry could
be efficiently controlled at the early stages of the total synthesis
by taking advantage of the rigid framework of the cyclic starting
materials. An important feature of the proposed route is that,
while catalytic resolution of one segment ((R,R)-i) would require
the use of the (R)-(EBTHI)Zr system, the S complex could be
used to reach (S,S)-ii.4 We found this attribute of the synthesis
plan economically attractive, since we could use Chin and
Buchwald’s recently reported procedure14 to obtain both chiral
metallocene antipodes upon the resolution of rac-(EBTHI)ZrCl2,
which is easily accessed by catalytic hydrogenation of the
commercially available rac-(EBI)ZrCl2.15
Enantioselective Synthesis of the (R,R)-Chromane Frag-
ment (i). We began our studies by examining the Zr-catalyzed
kinetic resolution of cyclopentenyl styrenyl ethers. As shown
in eq 1, these substrates can be readily prepared by the regio-
and stereoselective nucleophilic opening of allylic epoxide 4
(obtained from oxidation of cyclopentadiene) with styrenyl-
phenol 516 to afford the parent alcohol 6a. We established that,
whereas 6a and triethylsilyl (TES) ether 6b undergo 20-30%
uncatalyzed alkylation within 2 h, there is <2% background
reaction for tert-butyldimethylsilyl ether 6c and tert-butyldi-
phenylsilyl ether 6d when these substrates (Table 1) are treated
with EtMgCl (5 equiv in THF, 70 °C). Despite the promising
initial results obtained for 6c and 6d, these substrates, as well
as those that undergo uncatalyzed reaction (6a and 6b), resolved
with inferior levels of enantioselectivity (krel e 4).17
Synthesis Plan
The general retrosynthetic analysis that was adopted is
illustrated in Scheme 1. According to this plan, fragments i
and ii would be joined through a reductive amination. The
requisite chiral chromanes would be derived from nonracemic
chromenes (R,R)-iii and (S,R)-iW, which would, in turn, be
obtained from the metal-catalyzed ring-opening and ring-closing
transformations of optically pure (R,R)-W and (S,R)-Wi. We
would access enantiomerically pure styrenyl ethers W and Wi
through Zr-catalyzed kinetic resolution.10 Such a strategy thus
requires efficient and selective catalytic resolution of cyclic
styrenyl ethers. It would be therefore imperative that the alkenyl
side chain in (R,R)-iii and (S,R)-iW be amenable to functional-
ization necessary to readily reach (R,R)-i and (S,S)-ii.
As illustrated in Scheme 2, we were particularly interested
in utilizing cyclopentenyl and cycloheptenyl substrates Wi (n )
1 and 3). With the smaller ring system (n ) 1), we planned to
modify the side chain of the derived chromene Wii by the
regioselective catalytic oxidation of the terminal olefin by a
Wacker-type process,11 followed by hydrogenation of the
(6) (a) For receptor binding and activity of various stereoisomers of
nebivolol, see: Pauwells, P. J.; Gommeren, W.; Van Lommen, G.; Janssen,
P. A. J.; Leysen, J. E. Mol. Pharm. 1988, 34, 843-851. (b) Synthesis and
pharmacological properties: Van Lommen, G.; De Bruyn, M.; Schroven,
M. J. Pharm. Belg. 1990, 45, 355-360. (c) Crystal structure: Peeters, O.
M.; Blaton, N. M.; De Ranter, C. J. Acta Crystallogr. 1993, C49, 2154-
2157. (d) For related synthetic studies, see: Zheng, H.-C.; Costanzo, M.
J.; Maryanoff, B. E. Tetrahedron Lett. 1994, 35, 4891-4894.
(7) (a) De Cree, J.; Geukens, H.; Leempoels, J.; Verhaegen, H. Drug
DeV. Res. 1986, 8, 109-117. (b) De Cree, J.; Geukens, H.; Cobo, C.;
Verhaegen, H. Angiology 1987, 38, 440-448. (c) Van de Water, A.;
Janssens, W.; Van Nueten, J.; Xhonneux, R.; De Cree, J.; Verhaegen, H.;
Reneman, R. S.; Janssen, P. A. J. J. CardioVasc. Pharmacol. 1988, 11,
552-563.
(12) For a review of the Baeyer-Villiger oxidation, see: Krow, G. R.
In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 7, pp 671-688.
(13) (a) Wagner, P. J. Acc. Chem. Res. 1971, 4, 168-177. (b) Encinas,
M. V.; Wagner, P. J.; Scaiano, J. C. J. Am. Chem. Soc. 1980, 102, 1357-
1360. (c) Scaiano, J. C. Acc. Chem. Res. 1982, 15, 252-255.
(14) Chin, B.; Buchwald, S. L. J. Org. Chem. 1996, 61, 5650-5651.
(15) Waymouth, R. M.; Pino, P. J. Am. Chem. Soc. 1990, 112, 4911-
4914.
(16) Phenol 5 was prepared on the basis of procedures reported by Corey
and Christensen. (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40,
231-237. (b) Christensen, H. Synth. Commun. 1975, 5, 65-78.
(17) The value for krel is calculated by the equation reported by Kagan
and Fiaud. See: Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 53,
708-710. For a recent comprehensive review of metal-catalyzed kinetic
resolution, see: Hoveyda, A. H.; Didiuk, M. T. Curr. Org. Chem., in press.
(8) (a) DeCree, J.; Geukens, H.; Verhaegan, H. Eur. Heart J. 1990, 11
(Suppl.), Abstr 1865. (b) Midol-Monet, M.; Davy, M.; Heimburger, M.;
Beslot, F.; Cohen, Y. J. Pharm. Pharmacol. 1991, 43, 504. (c) Van de
Water, A.; Xhonneux, R. S.; Janssen, P. A. J. Eur. J. Pharm. 1988, 156,
95-103. (d) Xhonneux, R. S.; Wouters, L.; Renman, R. S.; Janssen, P. A.
J. Eur. J. Pharm. 1990, 181, 261-265. (e) Bowden, C. R.; Marchione, C.
S. J. Pharmacol. Exp. Ther. 1989, 251, 599-605.
(9) Howe, R.; McLoughlin, B. J.; Rao, B. S.; Smith, L. H.; Chodnekar,
M. S. J. Med. Chem. 1969, 12, 452-458.
(10) Visser, M. S.;. Harrity, J. P. A.; Hoveyda, A. H. J. Am. Chem. Soc.
1996, 118, 3779-3780.
(11) For a review of Wacker-type oxidations, see: Tsuji, J. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford,
1991; Vol. 7, pp 449-468.

8342 J. Am. Chem. Soc., Vol. 120, No. 33, 1998
Johannes et al.
Table 1. Zr-Catalyzed Kinetic Resolution of Cyclopentenyl
Scheme 4
Styrenyl Ethersa
b
substrate
R
krel
6a
6b
6c
6d
H
Et3Si
t-BuMe2Si
t-BuPh2Si
2.4
3.7
3.3
1.9
turned our attention to the adjustment of the length of the
chromane side chain by a photochemical Norrish type II
cleavage. We were aware of previous mechanistic studies
indicating that such transformations have higher quantum
efficiency21 and afford larger amounts of cleavage products
when more polar solvents are used. It has been suggested that,
with polar solvents, the corresponding 1,4-biradical intermediate
(13, Scheme 4) adopts a transoid conformation (anti-13) to favor
the generation of cleavage products. In contrast, in nonpolar
media, the cisoid orientation (gauche-13) is significantly
populated, leading to the formation of cyclobutenyl adducts.22
Indeed, our attempts to effect the conversion of (R,R)-10 to
(R,R)-11 in C6H6, Et2O, or THF (Vycor or Corex) resulted in
either low conversion (∼10% with C6H6) or substantial forma-
tion of unidentified byproducts, including diastereomeric cy-
clobutanols (14). Reaction efficiency improved noticeably upon
irradiation of (R,R)-10 for 2.5 h in MeOH at 22 °C (Vycor),
affording (R,R)-11 in 38% isolated yield. When photolysis was
performed at -10 °C, the desired product was obtained in 58%
yield, along with 36% of the recovered starting material after
chromatography (90% yield based on the recovered starting
material); longer reaction times led to lower yields due to
product decomposition.23 The addition of 1 mol % Et3N proved
to be necessary to avoid concomitant removal of the silyl
protecting group.
a Conditions: 10 mol % (R)-1, 5 equiv of EtMgCl, 70 °C, THF,
2-4 h. b Selectivities determined by chiral HPLC analysis (Chiralpak
AD) of the derived parent alcohols (6a).
Scheme 3a
a Conditions: (a) 1.0 equiv of 5, 1.5 equiv of K2CO3, acetone, 12 h,
80%. (b) 1.1 equiv of TBSOTf, 2 equiv of 2,6-lutidine, CH2Cl2, 4 h,
93%. (c) 10 mol % (R)-(EBTHI)Zr-binol, 5 equiv of EtMgCl, 70 °C,
THF, 3 h, 44%. (d) 4 mol % 2, 1 atm ethylene, C6H6, 24 h, 97%. (e)
25 mol % PdCl2, 25 mol % CuCl, 1 atm O2, DMF, H2O, 4 h, 87%. (f)
10% (by weight) Pd/C, 1 atm H2, 30 min, 98%. (g) hν, Vycor filter, 1
mol % Et3N, MeOH, 2.5 h, 58% (90% based on recovered starting
material). (h) O3, CH2Cl2/MeOH (5:1), 10 min, -78 °C; 3 equiv of
NaBH4, 22 °C, 1.5 h, 91%. (i) 1.5 equiv of ADDP, 1.5 equiv of Bu3P,
1.5 equiv of phthalimide, C6H6, 20 h, 85%. (j) H4N2, EtOH, 70 °C, 4
h, 68%.
Synthesis of the amine segment (R,R)-12 was effected in a
three-step process. An ozonolytic cleavage-reduction sequence
performed on the monosubstituted olefin of (R,R)-11 was
followed by conversion of the resulting primary alcohol to a
primary amine. The latter operation involved a modified
Mitsonobu procedure (85%)24 and a hydrazine-mediated depro-
tection to afford (R,R)-12 in 58% overall yield.
Enantioselective Synthesis of the (S,S)-Chromane Frag-
ment (ii). The (S,S)-chromene segment also called for the
opening of the oxirane ring in rac-7 with regio- and stereo-
chemical control (Scheme 5). In this case, however, cleavage
of the allylic epoxide with syn stereochemistry was required.
To address this issue, we took note of an elegant study by Trost
and Tengalia,25 regarding a directed26 Pd-catalyzed coupling of
allylic epoxides with various cyclic tin alkoxides; reactions were
reported to occur in a 1,2-syn fashion (vs 1,4-allylic substitu-
We therefore turned our attention to the possibility of utilizing
cycloheptenyl systems as the starting materials. As before (cf.
eq 1), and as shown in Scheme 3, the regio- and stereoselective
nucleophilic opening of allylic epoxide rac-7 with styrenyl-
phenol 5 proceeded smoothly (>98% regioselectivity, 80%).
Protection of the resulting secondary carbinol delivered rac-8
in 93% yield.18 Treatment of rac-8 with 5 equiv of EtMgCl
and 10 mol % (R)-(EBTHI)Zr-binol at 70 °C (THF) resulted in
the isolation of the recovered starting material (R,R)-8 in >98%
ee and 44% yield (krel g 25). In the presence of 4 mol %
Mo(CHCMe2Ph)(N(2,6-(i-Pr)2C6H3))(OCMe(CF3)2)2 (2)19 and
under an atmosphere of ethylene (C6H6, 22 °C, 24 h), (R,R)-8
was converted to unsaturated chromene (R,R)-9 in 97% yield
after silica gel chromatography.5
The two alkene sites in the relatively unstable 2-substituted
chromene20 were differentiated through an efficient Pd-catalyzed
“Wacker” oxidation of the terminal olefin (R,R)-9 to afford the
derived methyl ketone in 87% isolated yield; subsequent
catalytic hydrogenation delivered (R,R)-10 (98%). We next
(21) Wagner, P. J. J. Am. Chem. Soc. 1967, 89, 5898-5901.
(22) (a) Sciano, J. C. Tetrahedron 1982, 38, 819-824. (b) Reddy, G.
D.; Jayasree, B.; Ramamurthy, V. J. Org. Chem. 1987, 52, 3107-3113.
(23) Alternatively, the aldehyde derived from oxidation of the terminal
alkene in (R,R)-9 could be subjected to Norrish type II cleavage. However,
preliminary studies indicated that such photochemical processes are
significantly less efficient. This observation is consistent with the proposal
that the less substituted biradical intermediates derived from an aldehyde
are shorter lived than those derived from ketone substrates.
(18) Epoxide 7 was prepared by oxidation (peracetic acid) of the
commercially available cycloheptadiene. The overall yield for the three steps
(from cycloheptadiene to rac-8) is 72%.
(19) (a) Fox, H. H.; Yap, K. B.; Jennifer, R.; Cai, S.; Schrock, R. R.
Inorg. Chem. 1992, 31, 2287-2289. (b) Schrock, R. R.; Murdzek, J. S.;
Bazan, G. C.; Robbins, J.; DiMare, M.; Oregan, M. J. Am. Chem. Soc.
1990, 112, 3875-3886.
(20) 2-Substituted chromenes undergo significant decomposition at 22
°C within 24 h.
(24) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Tsunada, T.; Yamamiya,
Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639-1642.
(25) Trost, B. M.; Tengalia, A. Tetrahedron Lett. 1988, 29, 2931-2934.
(26) For a review of directed reactions, see: Hoveyda, A. H.; Evans, D.
A.; Fu, G. C. Chem. ReV. 1993, 93, 1307-1370.

EnantioselectiVe Synthesis of (S,R,R,R)-NebiVolol
J. Am. Chem. Soc., Vol. 120, No. 33, 1998 8343
Scheme 5a
Scheme 7a
a Conditions: (a) 2.5 mol % Pd(PPh3)4, 0.5 equiv of 15, 4-Å
molecular seives (powder), THF, 10 min, 84%. (b) 1.1 equiv of
TBSOTf, 2 equiv of 2,6-lutidine, CH2Cl2, 4 h, 93%. (c) 10 mol %
(S)-(EBTHI)Zr-biphen, 5 equiv of EtMgCl, 70 °C, THF, 3 h, 40%. (d)
4 mol % 2, 1 atm ethylene, C6H6, 24 h, 97%. (e) 25 mol % PdCl2, 25
mol % CuCl, 1 atm O2, DMF, H2O, 4 h, 87%. (f) 10% (by weight)
Pd/C, 1 atm H2, 30 min, 98%. (g) hν, Vycor filter, 1 mol % Et3N,
MeOH, 2.5 h, 58% (90% based on recovered starting material). (h)
O3, CH2Cl2/MeOH (5:1), -78 °C; Me2S, 22 °C, 10 min, 91%.
a Conditions: (a) 1.4 equiv of NaBH(OAc)3, 1,2-dichloroethane, 2
h, 91%. (b) 10% HCl, MeOH, 30 min, 97%.
antipode) proceeded with excellent selectivity (krel g 25). The
subsequent Mo-catalyzed chromene synthesis ((S,R)-16 f (S,R)-
17) transpired efficiently and in high yield.
Union of the Chromane Fragments and Completion of
the Synthesis. The total synthesis was completed by the two
reactions illustrated in Scheme 7. Coupling of (R,R)-12 and
(S,S)-19 by reductive amination (NaBH(OAc)3, f23, 91%),
followed by the removal of the silyl ether protecting groups
(10% HCl, MeOH), afforded (S,R,R,R)-nebivolol (HCl salt; 88%
yield for the two-step sequence).28 The synthetic material
tion). We argued that, under similar conditions, dialkylstan-
nylbis(phenoxide) 15 might add to rac-7 to afford rac-16.
However, the feasibility of this plan was less than certain, since
all the successful cases in the Trost report involved the use of
1 equiv of a cyclic dialkoxy stannane. Nonetheless, after
extensive experimentation, we established that treatment of rac-7
with 0.5 equiv of 15 (Scheme 5) in the presence of 2.5 mol %
Pd(PPh3)4 (THF, 10 min) leads to the formation of rac-7 with
>98% regio- and stereoselectivity in 84% yield after chroma-
tography.
1
proved identical with an authentic sample by H NMR, 13C
NMR, TLC, IR, and HRMS analysis, optical rotation, and
elemental analysis.
Conclusions
Origin of the Regio- and Stereoselective Pd-Catalyzed
Epoxide Opening. Although the exact reason for this highly
selective transfer is not clear at present, a plausible reaction
pathway can be put forward (Scheme 6). Directed transfer of
the first phenoxide unit may proceed via stannate xi, as proposed
initially.25 The group-selective transfer of the second phenoxy
unit (20 f 21 through xii) is noteworthy, however (<2%
transfer of the alkoxy group in xii is observed). Additional
experiments indicated that prolonged reaction times (2 h) lead
to the formation of the product derived from the alkoxy transfer
(22); when the reaction was quenched after 10 min, <2% 22
was detected.27 Presumably, under extended reaction times,
allylic phenoxide 21 reacts with the active Pd(0) catalyst to
regenerate xii, to result in the formation of the undesired bicyclic
ether.
In brief, we present an efficient and convergent enantiose-
lective total synthesis of (S,R,R,R)-nebivolol in the optically pure
form in 10.9% overall yield. The Zr-catalyzed kinetic resolution
of cyclic aryl ethers and their subsequent Mo-catalyzed conver-
sion to the 2-substituted chromenes serve a pivotal function.
The present work demonstrates that the resulting 2-alkenyl-
chromene can be functionalized to afford myriad chiral nonra-
cemic heterocycles. Resolution of rac-(EBTHI)ZrCl2 affords
the R and S enantiomers, which are both utilized in the
asymmetric synthesis of the two requisite subtargets; accord-
ingly, the overall plan is rendered more efficient and cost-
effective. However, future developments are required for the
identification of a more efficient chiral Zr catalyst, such that
lower levels of catalyst loading (<10 mol %) are required. In
addition to the Zr- and Mo-catalyzed transformations discussed
above, the efficient and selective Pd-catalyzed addition of
aryloxystannes to allylic epoxides further highlight the utility
of organometallic chemistry in the design and execution of
efficient and stereoselective synthesis routes to various biologi-
cally important target molecules.
As illustrated in Scheme 5, conversion of rac-16 to (S,S)-19
was carried out efficiently and in a fashion similar to that
adopted for the synthesis of (R,R)-12 (Scheme 3). Importantly,
the Zr-catalyzed resolution, with (S)-(EBTHI)Zr-biphen (ob-
tained from the same resolution operation that afforded the R
Scheme 6
Experimental Section
General Information. Infrared (IR) spectra were recorded on a
Perkin-Elmer 781 spectrophotometer, νmax in cm-1. Bands are char-
acterized as broad (br), strong (s), medium (m), and weak (w). 1H
NMR spectra were recorded on a Varian Unity 300 (300 MHz) or
Varian GN-400 (400 MHz). Chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard
(CHCl3, δ 7.26). Data are reported as follows: chemical shift,
integration, multiplicity (s ) singlet, d ) doublet, t ) triplet, q )
(27) For example, after 2 h, hydrolysis product derived from 22 is isolated
in 53% yield along with 11% of 21. These data suggest that, although 21
is the kinetically favored product, the thermodynamic selectivity is not as
high.
(28) Our attempts toward reductive coupling of benzylamine derived from
(S,S)-12 and (R,R)-19 under a variety of conditions resulted in the formation
of unidentified products. We therefore selected to carry out the coupling
with the unmasked primary amine.

8344 J. Am. Chem. Soc., Vol. 120, No. 33, 1998
Johannes et al.
quartet, br ) broad, m ) multiplet), coupling constants (Hz), and
assignment. 13C NMR spectra were recorded on a Varian Unity 300
(75 MHz) or Varian GN-400 (100 MHz) with complete proton
decoupling. Chemical shifts are reported in ppm from tetramethylsilane
with the solvent as the internal reference (CDCl3, δ 77.0 ppm).
Electronic spectra were collected on a Cary 1E UV/vis spectropho-
tometer. An Alltech Associates DB-1 capillary column (30 m × 0.32
mm) was used to determine conversions. Enantiomer ratios were
determined by chiral HPLC with either a Chiralcel OB/H column or a
Chiralpak AD column or by analysis of the derived (R)-MPTA ester.
Microanalyses were performed by Robertson Microlit Laboratories
(Madison, NJ). High-resolution mass spectrometry was performed by
University of Illinois Mass Spectrometry Laboratories. Photolyses were
carried out using a 450-W medium-pressure Hanovia lamp. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter.
All reactions were conducted in oven-dried (135 °C) and flame-
dried glassware under an inert atmosphere of dry argon. Tetrahydro-
furan was distilled from sodium metal/benzophenone ketyl, and
dichloromethane was distilled from calcium hydride. All Grignard
reagents were prepared from the appropriate alkyl halide purchased
from Aldrich and used without further purification. Mg turnings
(Strem) were washed with 5% HCl in MeOH, and then with Et2O and
THF, and were subsequently flame-dried. Mo(CHCMe2Ph)(N(2,6-(i-
Pr)2C6H3))(OCMe(CF3)2)2 was purchased from Strem and recrystallized
from pentanes prior to use or prepared by the method of Schrock et
al.19 1,1′-(Azodicarbonyl)dipiperidine (ADDP), diethyl azodicarboxyl-
ate (DEAD), 2-cyclohexen-1-ol, (ethyl)triphenyl phosphonium bromide,
2-bromo-4-fluorophenol, cycloheptadiene, 2,6-lutidine, and potassium
tert-butoxide were used as received from Aldrich. tert-Butyldimeth-
ylsilyl triflate was prepared by the method of Corey.29 Copper chloride,
palladium chloride, and tetrakis(triphenylphosphine)palladium were
used as received from Strem.
dropwise. The resulting solution was allowed to slowly warm to 22
°C, and stirring was allowed to continue for 14 h. At this point, the
reaction was quenched by dropwise addition of 50 mL of a saturated
solution of NH4Cl. The resulting mixture was diluted with 50 mL of
H2O and washed three times with 50 mL portions of Et2O; organic
layers were dried over anhydrous MgSO4. The solution containing the
unpurified reaction product was absorbed onto silica gel (∼25 g), and
the solvent was subsequently removed in vacuo to afford a pale yellow
silica gel-product mixture which was directly dry-packed on a
chromatography column and eluted with 20:1 mixture solution of
hexanes/EtOAc. Silica gel chromatography afforded 1.02 g (6.71 mmol,
94%) of a yellow oil as a 9:1 mixture of Z:E olefin isomers (as
determined by analysis of the 400-MHz 1H NMR spectrum) (Rf ) 0.53
in 3:1 hexanes/EtOAc). IR (KBr): 3446 (br), 3031 (m), 2943 (w),
2917 (w), 1495 (s), 1187 (s), 771 (m). 1H NMR: δ 6.85 (3H, m,
aromatic CH), 6.73 (2H, m, aromatic CH), 6.34 (1H, dd, J ) 11.2,
1.6, vinylic CH), 4.96 (1H, s, ArOH), 1.73 (3H, dd, J ) 6.96, 1.83,
CH3). 13C NMR: δ 157.7, 155.4, 148.7 (d, J ) 2.3), 131.9, 123.3 (d,
J ) 1.5), 115.9 (d, J ) 29.6), 115.8, 114.9 (d, J ) 22.7), 158.4, 156.1,
148.2, 129.3, 124.5 (d, J ) 2.3), 116.5 (d, J ) 8.3), 114.2 (d, J )
23.5), 113.2 (d, J ) 22.7), 18.8.
1,2-Epoxy-3-cycloheptene (rac-7). Cycloheptadiene (5.0 g, 55
mmol) and Na2CO3 (23.4 g, 220 mmol) were suspended in 90 mL of
CH2Cl2, and the resulting mixture was cooled to 0 °C and charged in
a dropwise fashion with 11.3 mL of peracetic acid (54 mmol) dissolved
in 20 mL of CH2Cl2. The mixture was allowed to warm to 22 °C and
stirred for 14 h, after which filtration was carried out to remove Na2-
CO3. The resulting solution was diluted with 100 mL of a saturated
solution of Na2S2O3 and washed three times with 75-mL portions of
CH2Cl2; organic layers were subsequently dried over anhydrous MgSO4.
Removal of solvent in vacuo afforded 5.9 g (53 mmol, 97%) of a
colorless oil. IR (KBr): 3024 (w), 2936 (s), 2873 (w), 2841 (w), 1444
(s), 935 (s), 733 (m). 1H NMR: δ 5.89 (1H, m, vinylic CH), 5.78
(1H, m, vinylic CH), 3.42 (1H, m, allylic CHOCH), 3.22 (1H, dd, J )
4.7, 4.4, CHOCH), 2.24 (2H, m, allylic CH), 1.98 (2H, m, aliphatic
CH), 1.60 (2H, m, aliphatic CH). 13C NMR: δ 138.5, 123.8, 60.7,
53.6, 31.4, 29.7, 22.1.
Fluorsalicylaldehyde. To 4-fluorophenol (30.0 g, 268 mmol) in
180 mL of H2O was added NaOH (70.7 g, 1.77 mol). The reaction
was heated to 55 °C, after which CHCl3 (46.8 mL, 589 mmol) was
slowly added dropwise. The reaction was subsequently heated to 70
°C for 1 h. The mixture was cooled to 22 °C, diluted with 50 mL of
H2O, and acidified with concentrated HCl (20 mL). The resulting
solution was washed three times with 50-mL portions of CH2Cl2, and
the organic layers were dried over anhydrous MgSO4. Removal of
solvent in vacuo afforded a red oil, which was purified by silica gel
chromatography (100:1 hexanes/EtOAc) to afford 8.3 g (59 mmol, 22%)
of a white solid (mp 82-84 °C; Rf ) 0.67 in 3:1 hexanes/EtOAc). IR
(KBr): 3055 (w), 2892 (w), 1665 (m), 1488 (s), 1281 (s), 1149 (s),
anti-2-(2-(1′-Propenyl)-4-fluorophenoxy)-3-cyclohepten-1-ol. Sty-
renylphenol 5 (0.50 g, 3.3 mmol) was dissolved in 2.75 mL of acetone,
and the resulting solution was treated with K2CO3 (0.76 g, 5.5 mmol)
and allowed to stir for 10 additional minutes. Cycloheptadiene oxide
(0.30 g, 2.7 mmol) was then added dropwise, and the mixture was
heated to 55 °C in an oil bath for 24 h. The reaction was allowed to
cool to 22 °C and filtered to remove excess K2CO3. Evaporation of
organic solvents in vacuo afforded a yellow oil, which was purified by
silica gel chromatography (40:1 hexanes/EtOAc) to afford 0.47 g of
the desired styrenyl ether (1.8 mmol, 80%) (Rf ) 0.19 in 10:1 hexanes/
EtOAc). IR (KBr): 3478 (br), 3031 (m), 2943 (s), 2861 (s), 1596
877 (m) cm-1 1H NMR: δ 10.79 (1H, s, CHO), 9.85 (1H, s, OH),
.
7.27 (1H, m, aromatic CH), 6.97 (1H, m, aromatic CH). 13C NMR: δ
195.4, 157.9, 156.8, 154.5, 124.8 (d, J ) 23.5), 119.2 (d, J ) 6.8),
118.1 (d, J ) 22.7).
(m), 1426 (m), 1243 (s), 1035 (m), 809 (m) cm-1 1H NMR: δ 6.99
.
Fluorsalicylaldehyde (Alternative and Higher Yielding Method).
2-Bromo-4-fluorophenol (5.0 g, 26 mmol) was dissolved in 400 mL
of THF, and the resulting solution was cooled to -60 °C. At this point,
the mixture was charged with n-BuLi (27.2 mL of a 2.5 M in hexanes,
68 mmol) in a dropwise fashion. The reaction temperature was
maintained at -60 °C for 1 h. Dimethylformamide (2.4 mL, 31 mmol)
was then added slowly in a dropwise manner (at -60 °C), after which
the mixture was stirred for an additional 5 min. The mixture was
subsequently allowed to warm to 22 °C, diluted with 50 mL of a
saturated solution of aqueous NH4Cl, and washed with 5 × 75 mL of
Et2O. The resulting organic layers were dried over anhydrous MgSO4.
Removal of organic solvents in vacuo afforded a red oil, which was
purified by silica gel chromatography (25:1 hexanes/EtOAc) to afford
2.97 g (21.2 mmol) of a white solid (81% yield).
2-Propenyl-4-fluorophenol (5). To ethyltriphenylphosphonium
bromide (5.83 g, 15.7 mmol) in 100 mL of toluene was added potassium
tert-butoxide (1.76 g, 15.7 mmol) in 24 mL of THF in a dropwise
manner. The resulting cloudy red solution was stirred at 22 °C for 4
h. The mixture was subsequently cooled to -78 °C, and the aromatic
aldehyde (1.00 g, 7.14 mmol), dissolved in 16 mL of toluene, was added
(1H, dd, J ) 9.2, 3.1, aromatic CH), 6.88-6.75 (2H, m, aromatic CH),
6.48 (1H, dd, J ) 11.5, 1.3, vinylic ArCHCH), 6.05-5.85 (2H, m,
vinylic CH), 5.58 (1H, dt, J ) 11.7, 2.7, vinylic CH), 4.66 (1H, d, J )
8.1, CHOAr), 3.72 (1H, dt, J ) 3.5, 9.5, CHOH), 2.98 (1H, s, OH),
2.95 (1H, s, OH), 2.28 (2H, m, allylic CH), 2.05 (2H, m, aliphatic
CH), 1.80 (3H, dd, J ) 8.9, 1.8, CH3), 1.78-1.39 (2H, m, aliphatic
CH). 13C NMR: δ 158.0, 155.7, 151.1, 132.9, 130.9, 128.7, 124.3,
116.7 (d, J ) 22.8), 114.6 (d, J ) 8.4), 113.8 (d, J ) 22.8), 83.1, 70.9,
36.0, 28.0, 14.6. HRMS calcd for C16H19FO2: 262.1369. Found:
262.1370. Anal. Calcd for C16H19FO: C, 73.26; H, 7.30. Found: C,
73.40; H, 7.53.
anti-2(R)-(2-(1′-Propenyl)-4-fluorophenoxy)-1(R)-tert-butyldi-
methylsiloxy-3-cycloheptene ((R,R)-8). Styrenyl alcohol, prepared
according to the procedure described above (0.85 g, 3.2 mmol), was
dissolved in 16 mL of CH2Cl2, and the resulting solution was treated
with 8.2 mL of 2,6-lutidine (7.1 mmol). The mixture was then cooled
to -78 °C and charged with 1.48 mL of TBSOTf (6.44 mmol) in a
dropwise manner; the reaction temperature was maintained at -78 °C
for 4 h. The reaction was quenched by the addition of ∼10 mL of a
saturated solution of NaHCO3; the resulting mixture was allowed to
warm to 22 °C, diluted with 50 mL of H2O, and washed three times
with 50-mL portions of Et2O. Organic layers were dried over anhydrous
(29) Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455-3458.

EnantioselectiVe Synthesis of (S,R,R,R)-NebiVolol
J. Am. Chem. Soc., Vol. 120, No. 33, 1998 8345
(s), 1252 (m), 836 (m) cm-1 1H NMR: δ 6.78-6.62 (3H, m, aromatic
MgSO4. Removal of volatiles in vacuo afforded a yellow oil, which
was purified by silica gel chromatography (200:1 hexanes/Et2O) to
afford 1.16 g of rac-8 (3.06 mmol, 95%) as a yellow oil. (Rf ) 0.53
in 10:1 hexanes/EtOAc). rac-8 (100 mg, 0.27 mmol) was dissolved
in 0.75 mL of THF, followed by the addition of 0.58 mL of a 2.29 M
solution of EtMgCl in THF. To the stirred solution was added 17.3
mg of (R)-(EBTHI)Zr-biphenol (0.03 mmol) in one portion, and the
reaction vessel was equipped with a reflux condenser and submerged
into a preheated 70 °C oil bath. The solution was allowed to stir at
this temperature for 3 h; the flask was then removed from the oil bath
and cooled to 0 °C. At this point, the solution was quenched by the
addition of 1 mL of wet ether, followed by 2 mL of H2O, and then 2
mL of a 2 M solution of HCl. The solution was washed three times
with 5-mL portions of Et2O, and the organic layers were dried over
anhydrous MgSO4. Removal of volatiles in vacuo afforded a yellow
oil, which was purified by silica gel chromatography (hexanes to obtain
product with Rf ) 0.37 in 20:1 hexanes/EtOAc, followed by 100:1
heaxanes/EtOAc to obtain unreacted starting material with Rf ) 0.26
in 20:1 hexanes/EtOAc) to afford 40.2 mg of (R,R)-8 (0.11 mmol) as
a clear oil (40%). Enantiomeric excess was determined by analysis of
the 1H NMR (400 MHz) spectrum of the derived (R)-MTPA ester. IR
(KBr): 2929 (s), 2886 (w), 2856 (m), 1486 (s), 1249 (m), 1197 (m),
.
CH), 6.36 (1H, dd, J ) 9.9, 1.8, vinyl CH), 5.82 (1H, dd, J ) 10.1,
2.2, vinyl CH), 4.85 (1H, m, ArOCH), 3.86 (1H, m, CHOTBS), 2.44
(2H, m, CH2C(O)CH3), 2.12 (3H, s, CH2C(O)CH3), 1.79-1.38 (4H,
m, aliphatic CH), 0.87 (9H, s, (CH3)3CSi), 0.08 (6H, s, CH3Si). 13C
NMR: δ 208.7, 158.6, 155.9, 149.5, 124.3, 123.8, 116.2 (d, J ) 8.4),
115.0 (d, J ) 31.9), 112.8 (d, J ) 23.5), 77.9, 73.2, 43.7, 31.9, 29.8,
25.8, 20.0, 18.0, -4.4, -4.7. HRMS calcd for C21H31FO3Si (M - H):
377.1947. Found: 377.1950. Anal. Calcd for C21H31FO3Si: C, 66.63;
H, 8.25; F, 5.02. Found: C, 66.82; H, 8.41; F, 5.09. [R]22
+180.79 (THF, c ) 0.1).
)
589
2(R)-(1(R)-tert-Butyldimethylsiloxy-5-oxohexyl)-6-fluoro-3,4-di-
hydro-2H-benzopyran ((R,R)-10). Chromene ketone, prepared ac-
cording to the procedure described above (0.20 g, 0.53 mmol), was
dissolved in 1.5 mL of EtOH, and 10 mg of Pd/C was added (5 wt %).
The reaction was allowed to stir under an atmosphere of H2 at 22 °C
for 30 min. Removal of the catalyst by filtration through a pad of
Celite, residue wash with (twice) 30-mL portions of Et2O, and removal
of the solvent in vacuo affored a colorless oil. When necessary,
purification was accomplished by silica gel chromatography with 20:1
hexanes/EtOAc to afford 0.18 g (0.46 mmol) of the desired ketone as
a colorless oil (98%) (Rf ) 0.36 in 10:1 hexanes/EtOAc). IR (KBr):
2954 (s), 2928 (s), 2883 (w), 2855 (m), 1718 (m), 1493 (s), 1219 (s),
1086 (m), 837 (m) cm-1 1H NMR: δ 6.98 (1H, d, J ) 9.0, aromatic
.
836 (m) cm-1 1H NMR: δ 6.74 (3H, m, aromatic CH), 3.86 (2H, m,
.
CH), 6.82 (2H, m, aromatic CH), 6.56 (1H, d, J ) 11.7, vinylic CH),
5.85 (2H, m, vinylic CH), 5.58 (1H, d, J ) 11.9, vinylic CH), 4.74
(1H, m, ArOCH), 3.89 (1H, m, CHOTBS), 2.12 (2H, m, allylic CH),
1.83 (3H, dd, J ) 6.6, 1.6, CH3), 1.78-1.44 (2H, m, aliphatic CH),
0.83 (9H, s, (CH3)3CSi), 0.07 (3H, s, CH3Si), -0.08 (3H, s, CH3Si).
13C NMR: δ 157.5, 155.1, 151.9 (d, J ) 2.3), 132.6, 130.4, 127.1,
116.5 (d, J ) 22.8), 114.8 (d, J ) 8.3), 113.5 (d, J ) 22.0), 81.3, 72.2,
36.9, 28.3, 25.8, 22.8, 18.1, 14.5, -4.7, -5.0. HRMS calcd for C22H33-
FO2Si (M - H): 375.2155. Found: 375.2156. Anal. Calcd for
C16H19FO: C, 70.17; H, 8.83; F, 5.04. Found: C, 70.01; H, 8.85; F,
ArOCH, CHOTBS), 2.46 (2H, m, CH2C(O)CH3), 2.18 (3H, s, CH2C-
(O)CH3), 2.02-1.38 (6H, m, aliphatic CH), 0.90 (9H, s, (CH3)3CSi),
0.1 (6H, s, CH3Si). 13C NMR: δ 208.8, 157.7, 155.4, 150.9, 117.4 (d,
J ) 7.5), 115.3 (d, J ) 22.0), 113.8 (d, J ) 22.7), 78.7, 73.5, 43.8,
31.5, 29.9, 25.9, 25.3, 21.8, 20.0, 18.2, -4.3, -4.6. UV-vis (Et2O,
λmax, nm): 278. HRMS calcd for C21H33FO3Si: 380.2183. Found:
380.2183. Anal. Calcd for C21H33FO3Si: C, 66.28; H, 8.74; F, 4.99.
Found: C, 66.12; H, 8.80; F, 5.17. [R]22589 ) -38.11 (THF, c ) 0.1).
2(R)-(1(R)-tert-Butyldimethylsiloxy-2-propenyl)-6-fluoro-3,4-di-
hydro-2H-benzopyran ((R,R)-11). Chromane ketone (R,R)-10 (0.06
g, 0.15 mmol) was dissolved in MeOH (3.7 mL, distilled over Mg and
degassed by three freeze-pump-thaw cycles) in a quartz test tube.
The mixture was cooled to 0 °C, after which 37 µL of Et3N (1 vol %)
was added. The mixture was irradiated through a Vycor filter with a
450-W medium-pressure mercury lamp for 2 h 20 min. Subsequent
removal of solvent in vacuo afforded a colorless oil. Purification by
silica gel chromatography with 50:1 hexanes/EtOAc afforded 0.03 g
of (R,R)-11 (0.09 mmol) as a colorless oil (58%) (Rf ) 0.59 in 10:1
hexanes/EtOAc). IR (KBr): 2968 (w), 2927 (s), 2854 (m), 1494 (s),
1218 (s), 777 (m) cm-1.1H NMR: δ 6.75 (3H, m, aromatic CH), 5.93
(1H, M, vinyl CH), 5.36 (1H, dt, J ) 17.2, 1.83, trans vinyl CHCH2),
5.22 (1H, dt, J ) 10.6, 1.6, cis vinyl CHCH2), 4.35 (1H, m, ArOCH),
3.89 (1H, ddd, J ) 10.8, 5.7, 2.2, CHOTBS), 2.75 (2H, m, benzylic
CH), 2.03-1.55 (2H, m, aliphatic CH), 0.93 (9H, s, (CH3)3CSi), 0.11
(3H, s, CH3Si), 0.08 (3H, s, CH3Si). 13C NMR: δ 157.8, 155.4, 150.8,
136.8 117.4 (d, J ) 7.5), 116.2, 115.3 (d, J ) 22.0), 78.9, 74.8, 25.8,
24.9, 22.0, 18.3, -4.7, -4.8. HRMS calcd for C18H27FO2Si (M + H):
4.95. [R]22 ) -6.32 (THF, c ) 0.1).
589
2(R)-(1(R)-tert-Butyldimethylsiloxy-5-hexenyl)-6-fluoro-2H-ben-
zopyran ((R,R)-9). Molybdenum alkylidene 2 (35.0 mg, 0.04 mmol)
was added to a solution of (R,R)-8 (0.34 g, 0.90 mmol) dissolved in 9
mL of benzene. The reaction vessel was fitted with a balloon of
ethylene and purged three times with ethylene, and the mixture was
allowed to stir at 22 °C for 20 h. Addition of ethyl vinyl ether or
MeOH to quench the alkylidene catalyst, followed by the removal of
volatile solvents in vacuo, afforded a black oil, which was purified by
silica gel chromatography (200:1 hexanes/EtOAc) to afford 0.32 g (0.88
mmol) of a colorless oil (97%) (Rf ) 0.75 in 10:1 hexanes/EtOAc). IR
(KBr): 2964 (m), 2928 (s), 2885 (w), 2856 (s), 1488 (s), 1251 (m),
1214 (m), 776 (m) cm-1 1H NMR: δ 6.78-6.63 (3H, m, aromatic
.
CH), 6.38 (1H, dd, J ) 10.1, 1.6, vinylic CH), 5.82 (1H, m, vinylic
CH), 5.00 (1H, dd, J ) 17.1, 1.5, trans vinylic CHCH2), 4.94 (1H, d,
J ) 10.3, cis vinylic CH), 4.84 (1H, m, ArOCH), 3.86 (1H, m,
CHOTBS), 2.05 (2H, m, allylic CH), 1.70-1.38 (4H, m, aliphatic CH),
0.87 (9H, s, (CH3)3CSi), 0.06 (6H, s, CH3Si). 13C NMR: δ 158.3,
156.0, 149.6, 138.7, 124.3, 123.9, 116.2 (d, J ) 8.4), 114.9 (d, J )
22.8), 114.5 (d, J ) 23.5), 78.0, 73.4, 33.8, 31.9, 25.8, 24.9, 18.0, -4.4,
-4.6. HRMS calcd for C21H31FO2Si (M - H): 361.1998. Found:
361.1996. Anal. Calcd for C21H31FO2Si: C, 69.57; H, 8.62; F, 5.24.
323.1843. Found: 323.1847. [R]22 ) -0.621 (THF, c ) 0.031).
589
2(R)-(1(R)-tert-Butyldimethylsiloxy-2-hydroxyethyl)-6-fluoro-3,4-
dihydro-2H-benzopyran. Allylic silyl ether (R,R)-11 (19 mg, 0.16
mmol) was placed in a 10-mL round-bottom flask and dissolved in 2
mL of a 4:1 CH2Cl2/MeOH solution mixture. The mixture was then
charged with NaHCO3 (3.5 mg, 0.25 equiv) and cooled to -78 °C. At
this point, O3 was introduced into the mixture (ozone is passed through
a plug of Drierite) for 10-15 min. Reaction progress was monitored
by TLC analysis (Rf product ) 0.42 in 3:1 hexanes/EtOAc). Upon
disappearance of the starting material, NaBH4 (10 mg, 0.18 mmol) was
added (at -78 °C), and the mixture was allowed to warm slowly to 23
°C over 1 h; stirring continued for an additional 1.5 h. The reaction
was quenched by the addition of 2 mL of a saturated solution of
NaHCO3 and washed three times with 5-mL portions of CH2Cl2.
Purification was accomplished by silica gel chromatography (6:1
hexanes/EtOAc) to provide 17.5 mg of the desired alcohol (0.054 mmol,
91%) as a colorless oil. IR (KBr): 3450 (w, br), 2967 (m), 2926 (m),
2892 (w), 2857 (m), 1511 (s), 1269 (m) 1217 (s), 1108 (m), 832 (m).
1H NMR: δ 6.70-6.81 (3H, m, aromatic CH), 3.98-4.04 (1H, ddd,
OCHCHOSi, J ) 11.17, 5.67, 2.01), 3.89-3.94 (1H, dd, J ) 10.1,
Found: C, 69.71; H, 8.71; F, 5.19. [R]22 ) +174.40 (THF, c )
589
0.1).
2(R)-(1(R)-tert-Butyldimethylsiloxy-5-oxohexyl)-6-fluoro-2H-ben-
zopyran. PdCl2 (37 mg, 0.21), CuCl (29 mg, 0.29 mmol), and H2O
(0.250 mL, 14.1 mmol) were added to 5 mL of DMF, and the resulting
mixture was stirred under an atmosphere of O2 for 1 h. Benzopyran
(R,R)-9 (0.30 g, 0.83 mmol) in 3.3 mL of DMF was added to the
mixture, and stirring was continued under an O2 atmosphere at 22 °C
for 12 h. The reaction was quenched by the dropwise addition of 50
mL of a saturated solution of NH4Cl. The mixture was subsequently
diluted with 25 mL of H2O and washed three times with 50-mL portions
of Et2O. The resulting solution was dried over anhydrous MgSO4.
Removal of solvent in vacuo afforded a yellow oil, which was purified
by silica gel chromatography (20:1 hexanes/EtOAc) to afford 0.22 g
(0.60 mmol) of a colorless oil (87%) (Rf ) 0.23 in 10:1 hexanes/EtOAc).
IR (KBr): 2954 (m), 2928 (m), 2895 (w), 2856 (m), 1717 (s), 1488

8346 J. Am. Chem. Soc., Vol. 120, No. 33, 1998
Johannes et al.
5.5, CHOSi), 3.74-3.80 (1H, dd, J ) 11.2, 4.2, CHHNH2), 3.66-
3.71 (1H, dd, J ) 11.3, 4.6, CHHNH2), 2.70-2.88 (2H, m, ArCH2-
CH2), 2.00-2.08 (1H, m, Ar CH2HH), 1.70-1.82 (1H, m, ArCH2CHH),
was then diluted with three 30-mL portions of 1.0 N HCl and washed
with 3 × 75 mL of Et2O. The resulting solution was dried over
anhydrous MgSO4. Removal of solvent in vacuo afforded a yellow
oil. Silica gel chromatography (13:1 hexanes/EtOAc) afforded 0.99 g
of the alcohol as a colorless oil (2.7 mmol, 83%).
0.92 (9H, s, t-BuSi), 0.6 (3H, s, CH3SiMe), 0.4 (3H, s, MeSiCH3). 13
C
NMR: δ 157.9, 153.0 (d, J ) 488.4), 123.1 (d, J ) 6.9), 117.4 (d, J
) 8.4), 115.2 (d, J ) 22.8), 113.8 (d, J ) 23.5), 77.6, 74.1, 63.4, 25.8,
25.0, 22.5, 18.2, -4.4, -4.7. HRMS calcd for C17H27FO3Si: 327.1792.
Alternative One-Pot Procedure for the Synthesis of syn-2-(2-(1′-
Propenyl)-4-fluorophenoxy)-3-cyclohepten-1-ol. Phenol 5 (217 mg,
1.42 mmol) was dissolved in 10 mL of THF, and n-Bu2Sn(OMe)2 was
subsequently added to this solution (214 mg, 0.720 mmol). At this
point, 100 mg of activated 4-Å molecular sieves (flame dried) was
added, and the mixture was allowed to stir under an Ar atmosphere
for 3 h. At this time, Pd(Ph3)4 (0.025 mmol) was added, resulting in
a red solution. The mixture was then immediately charged with a THF
solution of epoxide 7 (1.4 mmol in 5 mL of THF). Residual rac-7
was added with an additional wash with 1 mL of THF. After 10 min,
TLC analysis indicated complete consumption of the starting material.
The reaction was quenched with 5 mL of H2O, followed by 5 mL of
a 2 M solution of HCl. The insoluble salts were removed by filtration,
followed by wash with 5 mL of Et2O. The aqueous layer was washed
with three 5-mL portions of Et2O, and the organics were dried over
anhydrous MgSO4, which was removed by subsequent filtration.
Removal of solvents in vacuo afforded the desired phenyl ether as a
yellow oil. Purification was accomplished by silica gel chromatography
(13:1 hexanes/EtOAc) to afford 280 mg (1.07 mmol, 74%) of the
alcohol as a colorless oil. IR (KBr): 3421 (br), 3037 (w), 2936 (s),
Found: 327.1793. [R]22 ) -0.744 (THF, c ) 0.015).
589
2(R)-(1(R)-tert-Butyldimethylsiloxy-2-ethanphthalimidyl)-6-fluoro-
3,4-dihydro-2H-benzopyran. The silyl alcohol (25.4 mg, 0.080 mmol)
was weighed into a 5-mL round-bottom flask and dissolved in 0.26
mL of benzene; the mixture was cooled to 0 °C, and Bu3P (0.039 mL,
0.150 mmol) and phthalimide (23 mg, 0.16 mmol) were added
subsequently. The mixture was then charged with azadicarbonyldipi-
peridine (ADDP; recrystallized from benzene/hexanes; 34.9 mg, 0.156
mmol) in one portion to produce a yellow solution which turned clear
after 5 min. The mixture was allowed to warm to 23 °C and stirred
for 20 h. The reaction was quenched by adding ∼10 mL of hexanes,
at which point excess ADDP crashed out of solution and was removed
by filtration through a plug of Celite. After removal of hexanes in
vacuo, purification was accomplished by silica gel chromatography
(10:1 hexanes/EtOAc) to provide 30.4 mg of the desired phthalimide
(0.07 mmol, 85%) as a colorless oil (Rf ) 0.60 in 3:1 hexanes/EtOAc).
IR (KBr): 2962 (w), 2949 (w), 2869 (w), 1717(s), 1491 (w), 1408
(w), 1233 (w) cm-1 1H NMR: δ 7.80-7.77 (2H, dd, J ) 5.5, 3.1,
.
NCOCCH), 7.68-7.65 (2H, dd, J ) 5.5, 2.9, NCHOCCHCH), 6.75-
6.50 (3H, m, aromatic CH), 4.37-4.31 (1H, dt, J ) 7.7, 5.5, ArCOCH),
3.94-3.87 (2H, m, ArCOCHCHOTBS, CHHN), 3.83-3.76 (1H, m, J
) 13.5, 7.7, CHHN), 2.79-2.70 (2H, m, ArCH2), 2.11-2.05 (1H, m,
ArCH2CHH), 1.95-1.82 (1H, m, ArCH2CHH), 0.77 (9H, s, t-BuSi),
0.01 (3H, s, CH3SiCH3), -0.14 (3H, s, CH3SiCH3). 13C NMR: δ 168.3,
157.9, 153 (d, J ) 478), 133.9, 132.2, 123.2, 117.4 (d, J ) 8.3), 115.2
(d, J ) 22.0), 113.7 (d, J ) 22.8), 77.7, 69.8, 39.8, 25.6, 25.2, 21.4,
17.9, -4.7, -4.9. HRMS calcd for C25H30FNO4Si (M + H): 456.2007.
Found: 456.2008.
2873 (w), 1495 (s), 1262 (m), 1199 (s) 878 (m) cm-1 1H NMR: δ
.
6.98 (1H, dd, J ) 9.3, 2.9, aromatic CH), 6.89-6.70 (2H, m, aromatic
CH), 6.55 (1H, dd, J ) 11.7, 1.3, vinyl CH), 6.04 (1H, m, vinyl CH),
5.86, (1H, m, vinyl CH), 5.62 (1H, m, vinyl CH), 4.86 (1H, m, CHOAr),
4.08 (1H, m, CHOH), 2.34-2.02 (3H, m, aliphatic CH), 1.83 (3H, dd,
J ) 5.5, 1.8, CHCH3), 1.84-1.50 (3H, m, aliphatic CH). 13C NMR:
δ 158.0, 155.6, 151.0 (d, J ) 2.1), 134.1, 129.1, 128.1, 124.5, 116.8
(d, J ) 22.8), 115.4 (d, J ) 8.3), 113.8 (d, J ) 22.8), 81.3, 70.0, 34.4,
28.3, 20.9, 14.6. HRMS calcd for C16H19FO2: 262.1369. Found:
262.1372. Anal. Calcd for C16H19FO2: C, 73.26; H, 7.30; F, 7.24.
Found: C, 72.90; H, 7.65; F, 6.99.
2(R)-(2-tert-Butyldimethylsiloxy-3-aminopropyl)-6-fluoro-4(R)-di-
hydrobenzopyran ((R,R)-12). The protected amine-phthalimide,
prepared as described above (30.0 mg, 0.066 mmol), was weighed into
a reaction flask equipped with a coldfinger and dissolved in 0.66 mL
of EtOH; the solution was then charged with H2NNH2 (7 µL, 0.1 mmol).
The reaction tube was submerged into a preheated 75 °C oil bath and
left to stir for 6 h. The solvent was removed in vacuo to obtain a
white solid, which was passed through a plug of Celite eluted with
CH2Cl2. Purification of the clear oil residue was accomplished by silica
gel chromatography (10:1 CH2Cl2/MeOH) to provide 16 mg (0.05
mmol, 74%) of a colorless oil (Rf ) 0.39 in 10:1 CH2Cl2/MeOH). IR
(KBr): 3408 (w), 2974 (w), 2942 (w), 2873 (w), 1501 (w), 1262 (w),
syn-2(S)-(2-(1′-Propenyl)-4-fluorophenoxy)-1(R)-tert-butyldimeth-
ylsiloxy-3-cycloheptene ((S,R)-16). Racemic phenyl ether 16 (101 mg,
0.27 mmol) was dissolved in 0.2 mL of THF, followed by the addition
of 1.14 mL of a 1.18 M solution of EtMgCl in THF. The mixture was
subsequently charged with (S)-(EBTHI)Zr-binol (17.1 mg, 0.027 mmol),
and the reaction vessel was equipped with a reflux condenser and
submerged into a preheated 70 °C oil bath. The solution was stirred
at this temperature for 1.5 h, removed from the oil bath, and cooled to
0 °C. At this point, the reaction was quenched by the addition of 1
mL of wet ether, followed by 2 mL of H2O, and then 2 mL of a 2 M
solution of HCl. The solution was then washed three times with 5-mL
portions of Et2O, and the organic layers were dried over anhydrous
MgSO4. Removal of volatiles in vacuo afforded a yellow oil, which
was purified by silica gel chromatography (pretreated with 10 wt %
AgNO3; hexanes; Rf ) 0.48 (20:1 hexanes/EtOAc)), and the solvent
was removed in vacuo to afford 44.3 mg optically pure ((S,R)-16) (0.12
mmol, 44%) of a clear oil. Enantiomeric excess was determined by
1224 (w), 1117 (w) cm-1 1H NMR: δ 6.70 (3H, m, aromatic CH),
.
3.98 (1H, dd, J ) 11.2, 5.5, 3.8, SiOCH) (1H, dt, J ) 10.8, 5.7,
OCHCOSi), 2.96 (1H, dd, J ) 13.2, 3.6, ArCHHCH2), 2.70-2.85 (3H,
m, ArCHHCH2, H2NCH2), 1.96-2.04 (1H, m, ArCH2CHH), 1.60-
1.78 (3H, m, ArCH2CHH, CH2NH2), 0.92 (9H, s, t-BuSi), 0.14 (3H, s,
CH3SiMe), 0.12 (3H, s, MeSiCH3). 13C NMR: δ 157.8, 153 (d, J )
461.0), 123.1, 117.4 (d, J ) 8.4), 115.2 (d, J ) 22.7), 113.8 (d, J )
23.5), 78.0, 75.5, 44.0, 25.9, 25.2, 22.4, 18.2, -4.3, -4.5. HRMS calcd
1
analysis of the H NMR (400 MHz) spectrum of the derived MTPA
ester. IR (KBr): 3034 (m), 2930 (s), 2855 (s), 1483 (s), 1250 (s),
for C17H28FNO2Si (M + H): 326.1952. Found: 326.1950. [R]22
) -0.468 (THF, c ) 0.010).
1193 (s), 841 (m) cm-1 1H NMR: δ 6.98 (1H, dd, J ) 9.3, 3.1,
.
589
aromatic CH), 6.85-6.67 (2H, m, aromatic CH), 6.59 (1H, d, J ) 11.7,
vinylic CH), 5.92 (1H, m, vinylic CH), 5.80 (1H, m, vinyl CH), 5.36
(1H, d, J ) 11.2, vinylic CH), 4.78 (1H, m, ArOCH), 4.2 (1H, d, 5.7,
CHOTBS), 4.16 (1H, d, J ) 5.7, CHOTBS), 2.31-2.03 (2H, m, allylic
CH) 1.83 (3H, dd, J ) 6.9, 1.8, CH3), 1.80-1.45 (2H, m, aliphatic
CH), 0.88 (9H, s, (CH3)3CSi), 0.07 (3H, s, CH3Si), 0.04 (3H, s, CH3-
Si). 13C NMR: δ 157.5, 155.2, 151.9, 131.3, 131.1, 127.1, 125.3, 116.7
(d, J ) 23.5), 114.0 (d, J ) 8.3), 113.4 (d, J ) 22.7), 81.4, 70.6, 36.2,
28.3, 25.8, 20.6, 14.6, -4.7, -4.8. HRMS calcd for C22H33FO2Si (M
- H): 375.2155. Found: 375.2156. Anal. Calcd for C22H33FO2Si:
syn-2-(2-(1′-Propenyl)-4-fluorophenoxy)-3-cyclohepten-1-ol. Phe-
nol 5 (1.0 g, 6.6 mmol) was dissolved in 50 mL of benzene containing
800 mg of 4-Å molecular sieves. To this mixture was added n-Bu2-
Sn(OMe)2 (0.75 mL, 3.3 mmol) in a dropwise fashion. The reaction
was stirred for 14 h at 22 °C. Filtration through a Schlenck tube to
remove molecluar sieves and removal of solvent in vacuo afforded the
purported phenoxystannane as a yellow oil which was used without
further purification. n-Bu2Sn(OAr)2 was then dissolved in 10 mL of
THF, and to this solution was added PPh3 (0.17 g, 0.66 mmol) and
Pd2(dba)3 (0.15 g, 0.16 mmol). In a separate flask, rac-7 (0.74 g, 6.6
mmol) was dissolved in 24 mL of THF; the latter solution was added
to the Pd-containing original mixture, cooled to 0 °C, in a dropwise
manner over a period of 1.5 h. TLC analysis indicated that the reaction
was complete immediately after addition of rac-7. The reaction mixture
C, 70.17; H, 8.83; F, 5.04. Found: C, 70.22; H, 8.66; F, 5.34. [R]22
) +18.27 (THF, c ) 0.1).
589
2(S)-(2′-tert-Butyldimethylsiloxy-5-hexenyl)-6-fluoro-2H-benzopy-
ran ((S,R)-17). IR (KBr): 2961 (m), 2936 (m), 2854 (m), 1501 (s),
1262 (m), 1224 (m), 840 (m) cm-1 1H NMR δ 6.80-6.65 (3H, m,
.

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
Supporting Information Available: Spectral data for all
reaction products (39 pages). See any current masthead page
for ordering information and Web access instructions.
JA981378O