A Soluble Polymer Approach to the "Fishing Out" Principle: Synthesis and Purification of β-Amino Alcohols

Full text of DOI:10.1021/jo971732l

J . Org. Chem. 1998, 63, 889-894
889
displaying the classic â-amino alcohol pharmacophore.6
The methodology provides a simple route to the high
through-put solution synthesis of novel potential adren-
ergic agents.
A Solu ble P olym er Ap p r oa ch to th e
“F ish in g Ou t” P r in cip le: Syn th esis a n d
P u r ifica tion of â-Am in o Alcoh ols
Manabu Hori Kim D. J anda*
Resu lts a n d Discu ssion
Department of Chemistry, The Scripps Research Institute,
and The Skaggs Institute for Chemical Biology, 10550
North Torrey Pines Road, La J olla, California 92037
“Fishing out” is a technique involving polymer-sup-
ported reactions or reagents. In this scenario, the desired
product is formed as a component in a complex mixture
and the polymer is, in effect, used to extract the desired
component from a mixture. Thus, the mixture containing
the compound of interest is treated with an appropriate
polymer-supported reagent to selectively extract the
desired product. The other components of the mixture
are removed, and the desired compound is released from
the polymer. To investigate the “fishing out” technique
in a liquid-phase format, we turned to the soluble
polymer support poly(ethylene glycol).7 We have previ-
ously shown how this homopolymer can by applied in a
number of settings from combinatorial synthesis to ligand
accelerated catalysis.8 The exemplary reaction sequence
that we undertook involved the synthesis of propranolol
(1) (Scheme 1), a well-known â-adrenergic blocking agent
containing a â-amino alcohol core structure.6,9 The
reaction sequence shown in Scheme 1 generates propra-
nolol in a 40% yield. The impurities from this route
besides starting reagents include the bis-naphthol 4. It
was our contention that by utilizing a polymer-supported
reagent, propranolol could be synthesized and then
“fished out” from a sequential homogeneous reaction
sequence that required no column-supported purification
of intermediate 2, byproduct 4, or any of the starting
materials. Demonstration of this reaction sequence, we
hoped, could then be generalized for the synthesis and
purification of a variety of molecules containing the
â-amino alcohol moiety.10
Received September 16, 1997
In tr od u ction
High through-put organic synthesis has become a
paradigm for the production of small-molecule libraries.1
Countless examples now exist on the solid-phase syn-
thesis of these libraries, but relatively few examples of
libraries generated by solution syntheses have been
published.2 Reasons for such trends have been mainly
due to the difficulties in driving these reactions to
completion and/or isolating pure products, yet solution-
phase synthesis is the foundation upon which synthetic
chemists are trained and in which synthetic methodology
is developed.
Recently, several groups have developed strategies that
allow solution-phase synthesis to be conducted in a
library format. Techniques termed covalent scavenger
and polymer-supported quench have been applied for the
removal of unreacted starting materials, excess reagents,
and unwanted byproducts.3 Resin capture, on the other
hand, initiates library synthesis in solution followed by
material transfer to a solid support for further transfor-
mation.4 Described herein is a method for library
synthesis in solution and subsequent purification of the
desired products via a soluble polymer-supported reagent.
The strategy is based on the “fishing out” principle5 and
offers an alternative to solid-phase synthesis and resin
capture/scavenger techniques. Using the “fishing out”
technique, we have synthesized a set of structures
It has been reported that boranes can react with
structures displaying the â-amino alcohol subunit to
generate 1,3,2-oxazaborolidines.11 Such compounds can
then be reversibly decomposed to give a â-amino alcohol
in the presence of acid. On the basis of these studies,
we set out to find suitable boranes for attachment to poly-
(ethylene glycol). Scheme 2 shows a select series of
* To whom correspondence should be addressed.
(1) (a) Chaiken, I. M., J anda, K. D., Eds. Molecular Diversity and
Combinatorial Chemistry Libraries and Drug Discovery; American
Chemical Society: Washington, DC, 1996. (b) Wilson, S. R., Czarnik,
A. W., Eds. Combinatorial Chemistry Synthesis and Application; J ohn
Wiley & Sons: New York, 1997. (c) Thompson, L. A.; Ellman, J . A.
Chem. Rev. (Washington, D.C.) 1996, 96, 555. (d) Armstrong, R. W.;
Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. M. Acc. Chem.
Res. 1996, 20, 123. (e) Balkenhohl, F.; Vondem Bussche-Hunnefeld,
C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2289.
(2) (a) Smith, P. W.; Lai, J . Y. Q.; Whittington, A. R.; Cox, B.;
Houston, J . G.; Stylli, C. H.; Banks, M. N.; Tiller, P. R. Bioorg. Med.
Chem. Lett. 1994, 4, 2821. (b) Carell, T.; Winter, E. A.; Sutherland,
A.; Rebek, J .; Dunayevskiy, Y. M.; Vouros, P. Chem. Biol. 1995, 2, 171.
(c) Pirrung, M. C.; Chen, J . J . Am. Chem. Soc. 1995, 117, 1240. (d)
Chen, S.; Commer, D. D.; Williams, J . P.; Myers, P. L.; Boger, D. L. J .
Am. Chem. Soc. 1996, 118, 2567. (e) Chen, S.; Tarby, C. M.; Commer,
D. D.; Williams, J . P.; Caporale, L. H.; Myers, P. L.; Boger, D. L. Bioorg.
Med. Chem. 1996, 4, 727. (f) Boger, D. L.; Ozer, R. S.; Anderson, C.-M.
Bioorg. Med. Chem. 1997, 7, 1903.
(5) (a) Hodge, P. In Synthesis and Separations Using Functional
Polymers; Sherrington, D. C., Hodge, D., Eds.; Wiley: New York, 1988;
pp 43-123. (b) Hodge, P.; Waterhouse, J . J . Chem. Soc., Perkin Trans.
1 1983, 2319. (c) Seymour, E.; Frechet, J . M. S. Tetrahedron Lett. 1976,
17, 3699. (d) Cheminat, A.; Benezra, C.; Farrall, M. J .; Frechet, J .
Tetrahedron Lett. 1980, 21, 617.
(6) Lednicer, D.; Mitscher, L. A. The Organic Chemistry of Drug
Synthesis; Wiley: New York, 1984; Vol. 3, pp 19-37.
(7) Harris, M. J ., Ed. Poly(Ethylene Glycol) Chemistry Biotechnical
and Biomedical Applications; Plenum: New York, 1992.
(8) (a) Han, H.; Wolfe, M. M.; Brenner, S.; J anda, K. D. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 6419. (b) Han, H.; J anda, K. D. J . Am.
Chem. Soc. 1996, 118, 2539. (c) Han, H.; J anda, K. D. J . Am. Chem.
Soc. 1996, 118, 7632. (d) Zhao, X.-Y.; J ung, K. W.; J anda, K. D.
Tetrahedron Lett. 1997, 38, 977. (e) Han, H.; J anda, K. D. Tetrahedron
Lett. 1997, 38, 1527. (f) J ung, K. W.; Zhao, X.-Y.; J anda, K. D.
Tetrahedron 1997, 53, 6645. (g) Gravert, D. J .; J anda, K. D. Chem.
Rev. 1997, 97, 489.
(3) (a) Kaldor, S. W.; Siegel, M. G.; Fritz, J . E.; Dressman, B. A.;
Hahn, P. J . Tetrahedron Lett. 1996, 37, 7193. (b) Kaldor, S. W.; Fritz,
J . E.; Tang, J .; McKinney, E. R. Bioorg. Med. Chem. Lett. 1996, 6, 3041.
(c) Gayo, L. M.; Suto, M. J . Tetrahedron Lett. 1997, 38, 513. (d) Flynn,
D. L.; Crich, J . Z.; Devraj, R. V.; Hockerman, S. L.; Parlow, J . J .; South,
M. S.; Woodard, S. J . Am. Chem. Soc. 1997, 119, 4874. (e) Booth, R.
J .; Hodges, J . C. J . Am. Chem. Soc. 1997, 119, 4882.
(9) Crowther, A. F.; Smith, L. H. J . Med. Chem. 1968, 11, 1009.
(10) Recently a â-amino alcohol library has been reported: Chng,
B.-L.; Ganesan, A. Bioorg. Med. Chem. Lett. 1997, 7, 1511.
(4) Keating, T. A.; Armstrong, R. W. J . Am. Chem. Soc. 1996, 118,
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S0022-3263(97)01732-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

890 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
Sch em e 1. Syn th etic Rou te to P r op r a n olol a n d
Im p u r ities Gen er a ted d u r in g Rea ction Sequ en ce
Sch em e 3. Syn th etic Rou te to th e Dia lk ylbor a n e
“F ish in g Ou t” Rea gen t 12
Sch em e 2. Rea ctivity of P r op r a n olol a n d Selected
Bor a n e Rea gen ts
ing from 3-(4-hydroxphenyl)propionic acid (5), 12 was
rapidly obtained in seven steps. The key transformations
in this sequence were (1) reaction of phenol 10 with
monomethyl ether poly(ethyene glycol) mesylate12 provid-
ing 11 and (2) addition of borane-methyl sulfide to 11
yielding the borane “fishing out” reagent 12. The borane
polymer 12 could be isolated as a solid; however, this
borane was found to be moisture-sensitive, and hence it
was found to be more convenient not to isolate this
material but rather to utilize it as a toluene solution.13
Our hope then was that this PEG-bound dialkylborane
would display similar chemical reactivity to propranolol
and other â-amino alcohols as was observed with the
small molecule disiamylborane (vide supra). We antici-
pated that the disubstituted poly(ethylene glycol) “label”
would ensure that all materials complexed to it would
exhibit similar physical properties to that of the ho-
mopolymer poly(ethylene glycol), this latter point being
of utmost importance if selective separation of the desired
â-amino alcohol from unwanted starting materials and
byproducts was to occur.
Application of 12 for the “fishing out” of propranolol
was performed in the following manner (Scheme 4). In
the first step a mixture of 1-naphthol (1.0 equiv), ep-
ichlorohydrin (1.2 equiv), and sodium hydride was re-
acted in DMF overnight at 50 °C. This was followed by
an extraction/concentration to remove excess base and
the reaction solvent N,N-dimethylformamide (concentra-
tion percentage by HPLC: 2, 46%; 3, 37%; 4, 10%). This
resultant mixture of the desired epoxide 2 and unwanted
compounds that were examined in the presence of pro-
pranolol. The most promising results occurred when
2-methyl-2-butene or 2,3-dimethyl-2-butene was reacted
with borane dimethyl sulfide producing either disiamyl-
borane (Scheme 2, eq 4) or thexyborane (Scheme 2, eq
5). Both of these alkylboranes reacted with propranolol
generating the desired 1,3,2-oxazaborilidinone. However,
due to chromatographic instability these complexes could
only be qualitatively identified by NMR.
Keeping these findings in mind, we synthesized the
MeO-PEG-dialkylborane reagent 12 (Scheme 3). Start-
(11) (a) Masamune, S.; Kim, B.; Petersen, J . S.; Sato, T.; Veenstra,
S. J . J . Am. Chem. Soc. 1985, 107, 4549. (b) Masamune, S.; Short, R.
P. J . Am. Chem. Soc. 1989, 111, 1892. (c) Corey, E. J .; Bakshi, R. K.;
Shibata, S.; Chen, C.-P.; Singh, V. K. J . Am. Chem. Soc. 1987, 109,
7925. (d) Brown, H. C.; Racherla, U. S.; Pellechia, P. J . J . Org. Chem.
1990, 55, 1868. (e) Berenguer, R.; Garcia, J .; Vilarrasa, J . Tetrahedron
Asymmetry 1994, 5, 165. (f) Matteson, D. S. In Reactivity and Structure
Concept in Organic Chemistry; Hafner, K., Rees, C. W., Trost, B. M.,
Lehn, J .-M., Schleyer, P., Von Rague′, Zahradnik, R., Eds.; Springer:
Berlin; Vol. 32, pp 353-361.
(12) Zhao, X.-Y.; J anda, K. D. Tetrahedron Lett. 1997, 38, 5437.
(13) It should be noted that while this approach negates the
moisture-sensitivity problem in isolating the reagent 12, it can
compromise the yield of the desired product. This is due to the excess
borane-methyl sulfide complex that is needed in forming 12. Borane-
methyl sulfide can compete with 12 in the formation oxazaborolidines.

Notes
Sch em e 4. Sequ en ce Used To Syn th esize a n d
J . Org. Chem., Vol. 63, No. 3, 1998 891
between 25:75 and 35:65); flow rate, 1.0 mL; UV detection, 254
nm. 1H and 13C NMR were recorded at 300 and 75 MHz,
respectively, in CDCl3. High-resolution mass spectra (HRMS)
were performed in the analytical department of The Scripps
Research Institute.
P u r ify P r op r a n olol
3-(4-Hyd r oxyp h en yl)-1-p r op a n ol (6). This compound is
available from Aldrich (19,741-6); however, its quoted price (1 g
) $16.15) makes it more economical to synthesize the material
from 3-(4-hydroxphenyl)propionic acid, 5 (39,353-3, 10 g )
$13.80). Thus to a suspension of LiAlH4 (8.0 g, 210 mmol, 1.0
equiv) in THF (300 mL) was added a solution of 3-(4-hydroxy-
phenyl)propionic acid (25.0 g, 150 mmol, 1.0 equiv) in THF (200
mL) dropwise at rt, and the mixture was stirred at 60 °C for 2
h. The reaction mixture was acidified with 1 M HCl, diluted
with water, and extracted with AcOEt (ethyl acetate). The
extract was washed with water, saturated NaHCO3, and brine,
dried over MgSO4, and concentrated in vacuo to give 5 (20 g,
88%) as a colorless oil: 1H NMR δ 1.85 (2H, m), 2.26 (2H, t, J )
7.3 Hz), 3.66 (2H, t, J ) 6.4 Hz), 3.75 (1H), 5.15 (1H), 6.74 (2H,
d, J ) 8.5 Hz), 7.04 (2H, d, J ) 8.5 Hz).
3-[4-(Meth oxym eth oxy)p h en yl]-1-p r op a n ol (7). To a mix-
ture of compound 6 (15.0 g, 99 mmol, 1.0 equiv) and DMF (500
mL) was added NaH (60% dispersion, 4.0 g, 100 mmol, 1.0 equiv)
at rt, and the resulting mixture was stirred for 15 min.
Chloromethyl methyl ether (8.0 g, 99 mmol, 1.0 equiv) was added
dropwise to the mixture at rt, and the mixture was stirred for 2
h. The reaction mixture was diluted with water and extracted
with AcOEt. The extract was washed with water, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (hexane:AcOEt ) 2:1) to give 7 (11.5
g, 59%) as a colorless oil: 1H NMR δ 1.85 (2H, m), 2.65 (2H, t,
J ) 7.4 Hz), 3.47 (3H, s), 3.64 (2H, td, m), 5.14 (2H, s), 6.95
(2H, d, J ) 6.6 Hz), 7.11 (2H, d, J ) 6.6 Hz); 13C NMR δ 31.10,
34.25, 55.83, 62.02, 94.47, 116.17, 134.75, 192.25, 155.27; HRMS
calcd for 196.1099 C11H16O3 (M+), found 196.1093.
3-[4-(Meth oxym eth oxy)p h en yl]p r op ion a l (8). A solution
of compound 7 (23.0 g, 120 mmol, 1.0 equiv) in CH2Cl2 (50 mL)
was added to a mixture of pyridinium chlorochromate (38.0 g,
180 mmol, 1.5 equiv) in CH2Cl2 (1000 mL) at rt, and the mixture
was stirred for 3.5 h. The reaction mixture was washed with
hexane (400 mL) and filtered through silica gel (60 g). The silica
gel was eluted with a mixture of hexane and AcOEt (1:1, 250
mL). The collected filtrate was combined and concentrated in
vacuo. The residue was purified by column chromatography
(hexane:AcOEt ) 2:1) to give 8 (20.0 g, 88%) as a colorless oil:
1H NMR δ 2.74 (2H, td, J ) 7.3, 1.3 Hz), 2.90 (2H, t, J ) 7.3
Hz), 3.46 (3H, s), 5.14 (2H, s), 6.95 (2H, d, J ) 8.5 Hz), 7.10
(2H, d, J ) 8.5 Hz), 9.80 (1H, J ) 1.3 Hz); 13C NMR δ 27.17,
45.34, 55.80, 94.34, 116.28, 129.16, 133.58, 155.56, 201.63;
HRMS calcd for C11H16O3 194.0943 (M+), found 194.0936.
1-(Meth oxym eth oxy)-4-(4-m eth yl-3-pen ten yl)ben zen e (9).
To a mixture of isopropyltriphenylphosphonium iodide (75.0 g,
170 mmol, 1.8 equiv) and THF (800 mL) was added butyllithium
(2.5 M in hexane, 75 mL) at -70 °C dropwise, and the mixture
was stirred at rt for 20 min. To the mixture was added a solution
of compound 8 (18.0 g, 93 mmol, 1.0 equiv) in THF (80 mL)
dropwise at -70 °C, and the mixture was stirred at rt for 2 h.
The reaction mixture was diluted with hexane (500 mL) and
filtered through silica gel (60 g). The filtrate was concentrated
in vacuo, and the residue was purified by column chromatog-
raphy (hexane:AcOEt ) 20:1) to give 9 (16.0 g, 78%) as a
colorless oil: 1H NMR δ 1.56 (3H, s), 1.67 (3H, s), 2.28 (2H, m),
2.56 (2H, t, J ) 6.6 Hz), 3.47 (3H, s), 5.15 (2H, s), 5.12-5.18
(1H, pseudo-t), 6.94 (2H, d, J ) 6.6 Hz), 7.10 (2H, d, J ) 6.6
Hz); 13C NMR δ 17.64, 25.67, 30.21, 35.26, 55.86, 94.56, 116.08,
123.73, 129.31, 135.86, 155.27; HRMS calcd for 220.1463 C14H20O2
(M+), found 220.1468.
starting material/byproduct was reacted with isopropy-
lamine (0.8 equiv) at 70 °C for 1.5 h (concentration
percentage by HPLC: 1, 36%; 2, 24%; 4, 10%). Propra-
nolol was selectively “labeled” by the addition of the
polymer borane reagent 12 granting the polymer ox-
azaborolidine complex 13. Diethyl ether precipitation
allowed purification of 13 from all starting materials and
byproducts. Subsequent addition of HCl to a CH2Cl2/
MeOH solution of 13 provided propranolol after simple
precipitation of the spent polymer support in 58% yield,
this based on the ratio of isolated mass over theoretical
yield of compound 12 (see Table 1) and greater than 92%
purity (Scheme 4).
The scope of this procedure (vide supra) has been
expanded to the parallel synthesis (Scheme 5) of discrete
â-amino alcohols on a multimilligram scale (Table 1). The
building blocks were broken up into three categories: (1)
aromatic phenols or sulfonamides, (2) epichlorohydrin,
and (3) primary or secondary aliphatic or aromatic
amines. While we have only attempted the synthesis of
20 compounds, clearly the potential to construct libraries
of â-amino alcohols exists. All isolated â-amino alcohols
1
were characterized by H NMR, 13C NMR, HPLC, and
MS. The mass recovery and purity of these â-amino
alcohols was good to excellent in view of the simplicity
of our isolation procedure. The most problematic build-
ing block was p-anisidine; its poor nucleophilicity led to
low reactivity as seen in several of the cases shown in
Table 1. However, even when poor yields of the final
â-amino alcohols were observed, the purity of the desired
compound was still excellent.
In summary, a general reagent has been developed for
the selective “fishing out” of â-amino alcohols. The
â-amino alcohol moiety is a pharmacophore structure
found in â-adrenergic blockers that is of significant
interest to the pharmaceutical industry. The methodol-
ogy we have described supports at least a two-step
synthetic strategy and an isolation procedure less labori-
ous than column chromatography. The procedure could
undoubtedly be automated and adapted to create new
reagents for the “fishing out” of other classes of molecules
possessing interesting pharmacophores.
4-(4-Meth yl-3-p en ten yl)p h en ol (10). A mixture of 9 (16.0
g, 73 mmol, 1.0 equiv), 12 M HCl (30 mL), and THF (250 mL)
was stirred at rt for 2 h. The reaction mixture was diluted with
water and extracted with AcOEt. The extract was washed with
water, saturated NaHCO3, and brine, dried over MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography (hexane:AcOEt ) 6:1) to give 10 (12.0 g, 94%)
as a colorless oil: bp 110 °C (0.02 mmHg); 1H NMR δ 1.55 (3H,
s), 1.67 (3H, s), 2.28 (2H, m), 2.55 (2H, t, J ) 7.3 Hz), 4.67 (1H,
OH), 5.17-5.11 (1H, t-like), 6.74 (2H, d, J ) 8.4 Hz), 7.04 (2H,
Exp er im en ta l Section
All chemicals were obtained from commercial suppliers and
used without further purification. Analytical TLC (thin-layer
chromatography) was carried out on precoated plates (Merck
silica gel 60, F254). Column chromatography was performed with
silica gel (Merck, 70-230 mesh). HPLC analysis was performed
with a VYDAC reverse-phase C18 column (25 cm × 4.6 mm);
mobile phase, acetonitrile-water (contains 0.1% TFA, ratio

892 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
Ta ble 1. â-Am in o Alcoh ols

Notes
J . Org. Chem., Vol. 63, No. 3, 1998 893
Ta ble 1 (Con tin u ed )
a
The yield was calculated as the ratio of isolated mass over theoretical yield of compound 12 and is expressed as a percentage. bPurity
was determined by HPLC. c Compound 23 was not isolated due to low reactivity of p-anisole. Greater than 80% purity was confirmed
d
by 1H NMR spectrum.
Sch em e 5. P a r a llel Ap p r oa ch Used To Cr ea te â-Am in o Alcoh ols
d, J ) 8.4 Hz); 13C NMR δ 17.64, 25.67, 30.24, 35.17, 115.01,
115.07, 123.71, 129.48, 132.08, 134.62, 153.42; HRMS calcd for
176.1201 C12H16O (M+), found 176.1198.
Bis[5-[4-(MeO-P E G-oxy)p h en yl]-2-m et h ylp en t a n -3-yl]-
bor a n e (12). To a mixture of 11 (1.0 g, 0.2 mmol, 1.0 equiv)
and toluene (3 mL) was added BH3-SMe2 (1 M in CH2Cl2, 0.6
mL, 0.6 mmol, 3.0 equiv). This solution was stirred at 70 °C for
20 min (toluene solution of 12, see general procedure). The
reaction mixture was diluted with ether (80 mL), and the
resulting solid was collected by filtration to give 12 (970 mg,
97%) as a colorless powder (Note: this material is moisture-
sensitive): 1H NMR 0.7-0.9 (12H), 1.0-1.8 (8H), 2.2-2.7 (4H),
3.3-4.1 (MeO-PEG),6.7-6.8 (4H), 6.9-7.1 (4H); 13C NMR δ
58.94, 67.32, 69.69, 70.61, 71.60, 114.37, 129.18, 135.50, 156.75.
[[4-(4-Meth yl-3-p en ten yl)p h en yl]oxy]p oly(eth ylen e gly-
col) Meth yl Eth er (11). A mixture of MeO-PEG5000 mesylate12
(50.0 g, 10.0 mmol, 1.0 equiv), compound 10 (7.0 g, 40 mmol,
4.0 equiv), Cs2CO3 (13.0 g, 40 mmol, 4.0 equiv), and DMF (400
mL) was stirred at 80 °C overnight. To the reaction mixture
was added 1 M HCl-MeOH (60 mL), and the mixture was
concentrated in vacuo. The residue was suspended in CH2Cl2
(300 mL), and any insoluble material was removed via filtration.
The filtrate was concentrated to about half-volume and diluted
with ether (900 mL). The resulting solid was collected by
filtration to give 11 as a colorless powder (50 g, 98%): 1H NMR
δ 1.48 (3H, s), 1.59 (3H, s), 2.16 (2H, m), 2.51 (2H, t, J ) 4.5
Hz), 3.3-4.1 (MeO-PEG), 4.97-5.10 (1H, t-like), 6.78 (2H, d, J
) 7.5 Hz), 7.0 (2H, d, J ) 7.5 Hz); 13C NMR δ 17.31, 25.34, 29.88,
34.80, 58.65, 61.20, 67.03, 69.40, 70.18, 71.39, 114.00, 123.39,
128.88, 131.57, 134.25, 134.25, 156.49.
N-Isop r op yl-4-tolu en esu lfon a m id e (16). To a mixture of
p-toluenesulfonyl chloride (5.1 g, 27 mmol, 1.0 equiv) and CH2-
Cl2 (70 mL) was added isopropylamine (5.0 g, 85 mmol, 3.1 equiv)
at 0 °C, and the mixture was stirred at rt for 30 min. The
reaction mixture was washed with saturated NaHCO3 and brine,
dried over MgSO4, and concentrated in vacuo to give 16 (5.5 g,
96%) as a colorless oil: 1H NMR δ 1.05 (6H, d, J ) 6.5 Hz), 2.41
(3H, s), 3.39-3.47 (1H, m), 4.40 (1H, b), 7.28 (1H, d, J ) 8.0

894 J . Org. Chem., Vol. 63, No. 3, 1998
Notes
Hz), 7.75 (2H, d, J ) 8.0 Hz); 13C NMR δ 21.48, 23.65, 126.98,
129.60, 138.03, 143.14; HRMS calcd for 214.0902 C10H15NO2S
(M + H+), found 214.0897.
(3H, s), 2.59-2.62 (1H, m), 2.83-2.85 (1H, m), 3.05 (1H, dd, J
) 12.0, 5.2 Hz), 3.17-3.21 (1H, m), 3.47 (1H, dd, J ) 12.0, 4.6
Hz), 4.11 (1H, m), 7.27 (2H, d, J ) 8.3 Hz), 7.69 (2H, d, J ) 8.3
Hz); 13C NMR δ 19.99, 21.46, 21.60, 44.90, 46.96, 49.16, 51.98,
Gen er a l P r oced u r e for â-Am in o Alcoh ol Syn th esis a n d
P u r ifica tion . A mixture of NaH (60% dispersion, 33 mmol, 1.0
equiv) was washed with hexane (2 × 10 mL). This was added
to a flask containing the phenol or sulfonamide (33 mmol, 1.0
equiv), epichlorohydrin (40 mmol, 1.2 equiv), and DMF (60 mL)
which was stirred overnight at 50 °C. The reaction mixture was
diluted with water and extracted with AcOEt. The extract was
washed with water, dried over MgSO4, and concentrated in
vacuo. (The excess epichlorohydrin should be removed in this
procedure.) This impure reaction mixture was diluted with
toluene to make approximately a 0.5 M solution of the epoxide.
To 1 mL of this were added an amine (0.4 M in toluene, 1 mL)
and LiClO4 (40 mg, 38 mmol, 0.8 equiv), and the solution was
stirred overnight at 70 °C. Upon completion of the reaction all
soluble material was added to a toluene solution of 12 (vide
supra), and this was stirred at 70 °C for 1.5 h. This reaction
mixture was diluted with ether (80 mL), and the resulting solid
was collected by filtration followed by addition to CH2Cl2 (2 mL)/
MeOH (2 mL). The mixture was added to 1 M HCl-MeOH (0.5
mL), and this was stirred at rt for 10 min. To this solution was
added t-BuOK (200 mg, 1.8 mmol, 3.6 equiv), and the mixture
was stirred at rt for 10 min before dilution with ether (80 mL).
The resulting solid was filtered, and the filtrate was concen-
trated in vacuo. The residue was suspended in ether (10 mL),
and any insoluble material was removed by filtration. The
filtrate was concentrated in vacuo to give the â-amino alcohol.
1,2-Ep oxy-3-(1-n a p h th oxy)p r op a n e (2): see general pro-
126.94, 129.68, 137.68, 143.20; HRMS calcd for 270.1164 C13H19
-
NO3S (M+), found 270.1172.
MeO-P EG-bor a n e-P r op r a n olol Com p lex (13): see gen-
eral procedure up to addition of HCl-MeOH; 1H NMR δ 0.8-
1.0 (12H), 1.0-1.8 (10H), 2.2-3.2 (7H), 3.2-4.1 (MeO-PEG),
6.7-6.8 (5H), 6.9-7.0 (4H), 7.2-7.5 (4H), 7.1-7.1 (1H), 8.1-
8.2 (1H).
P r op r a n olol (1): see general procedure; 1H NMR δ 1.09 (6H,
d, J ) 6.2 Hz), 2.79-3.00 (3H), 4.10-4.19 (3H), 6.81 (1H, d, J )
7.4 Hz), 7.32-7.50 (3H), 7.78 (1H), 8.23 (1H); 13C NMR δ 22.88,
22.92, 48.87, 49.55, 68.39, 70.67, 104.79, 120.50, 121.77, 125.15,
125.44, 125.76, 126.34, 127.44, 134.39, 154.23; HRMS calcd for
260.1651 C16H21NO2 (M + H+), found 260.1643.
3-(2-Bip h e n ylyl)-2-h yd r oxy-1-(isop r op yla m in o)p r o-
1
p a n e (24): see general procedure; H NMR δ 0.83 (3H, d, J )
6.3 Hz), 0.84 (3H, d, J ) 6.3 Hz), 2.38-2.61 (3H), 3.71-3.83 (3H),
6.90-7.38 (9H); 13C NMR δ 22.87, 22.99, 48.72, 49.16, 68.39,
71.39, 112.96, 121.41, 126.93, 127.95, 128.64, 129.45, 130.84,
138.38, 155.44; HRMS calcd for 286.1807 C18H23NO2 (M + H+),
found 286.1800.
N-[2-Hyd r oxy-3-(isop r op yla m in o)p r op yl]-N-isop r op yl-4-
1
tolu en esu lfon yla m id e (31): see general procedure; H NMR
δ 0.96-1.05 (12H), 2.38 (3H, s), 2.59-2.80 (4H), 3.02-3.18 (2H),
3.84 (1H, m), 4.04 (1H, m), 7.26 (2H, d, J ) 8.0 Hz), 6.68 (2H, d,
J ) 8.0 Hz); 13C NMR δ 20.68, 21.11, 21.47, 23.01, 23.08, 46.99,
48.84, 49.92, 69.81, 127.11, 129.68, 137.16, 143.29; HRMS calcd
for 329.1899 C16H28N2O3S (M + H+), found 329.1908.
1
cedure up to addition of amine; H NMR δ 2.84-2.88 (1H, m),
2.95-3.00 (1H, m), 3.49-3.50 (1H, m), 4.11-4.17 (1H, m), 4.37-
4.39 (1H, m), 6.80 (1H, d, J ) 7.5 Hz), 7.25-7.50 (4H), 7.78-
7.81 (1H, m), 7.28-7.30 (1H, m); 13C NMR δ 44.68, 50.21, 69.15,
102.81, 104.96, 121.68, 121.94, 125.27, 125.66, 126.45, 127.40,
134.42, 154.03; HRMS calcd for 200.0837 C13H12O2 (M+), found
200.0843.
1,2-Ep oxy-3-(2-bip h en ylyloxy)p r op a n e (15): see general
procedure up to addition of amine; 1H NMR δ 2.65-2.68 (1H,
m), 2.75-2.82 (1H, m), 3.24-3.27 (1H, m), 3.94-4.00 (1H, m),
4.14-4.23 (1H, m), 6.96-7.56 (9H); 13C NMR δ 44.59, 50.23,
68.92, 113.10, 121.64, 126.91, 127.95, 128.59, 129.42, 129.51,
131.01, 138.26, 155.41; HRMS calcd for 226.0994 C15H14O2 (M+),
found 226.0988.
Ack n ow led gm en t. This work was supported by The
Skaggs Institute for Chemical Biology. We thank Dr.
P. Wentworth, J r., for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
1
terization data and copies of HPLC, H NMR, and 13C NMR
spectra for 1, 18-22, and 24-37; high-resolution mass spectra
for 18-22, 25-30, and 32-37; copies of 1H and 13C NMR
1
spectra for 7-12 and 15-17; and copies of H NMR spectra
for 2, 4, 5, and 13 (86 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
N -(2,3-E p o x y p r o p y l)-N -is o p r o p y l-4-t o lu e n e s u lfo n -
a m id e (17): see general procedure up to addition of amine; 1H
NMR δ 0.95 (3H, d, J ) 8.1 Hz), 1.14 (3H, d, J ) 8.1 Hz), 2.40
J O971732L