A novel linking-protecting group strategy for solid-phase organic chemistry with configurationally stable α-[N-(phenylfluorenyl)]amino carbonyl compounds: Synthesis of enantiopure norephedrines on solid support

Article abstract of DOI:10.1021/jo982413c

A novel linking strategy has been developed for synthesizing configurationally stable α-amino aldehyde on polymeric supports. Alkylation of L-alanine methyl ester with 9-bromo-9-p-bromophenylfluorenene, followed by ester hydrolysis and coupling to isoxazolidine, provided N-(9-p- bromophenylfluoren-9-yl)alanine isoxazolidide (5), which was transformed into its corresponding boronate 2 by a palladium-catalyzed cross-coupling reaction with diboron pinacol ester. Boronate 2 was anchored to four different polymeric aryl halides 6-9 in 70-99% yields. Polymer-bound alaninal 1b was then synthesized on non-cross-linked polystyrene by hydride reduction of isoxazolidide 10b. Treatment of alaninal 1b with phenylmagnesium bromide, cleavage of the resulting amino alcohol in a 1:2:2 TFA/CH₂Cl₂/anisole cocktail, and acylation with di-tert-butyl dicarbonate furnished N- (BOC)norephedrines 14 that were demonstrated to be enantiopure by conversion to diastereomeric thioureas 15 and analysis by HPLC. In summary, we have developed a process by which the 9-phenylfluoren-9-yl protecting group has been converted into a new linker for the solid-phase synthesis and manipulation of α-amino carbonyl compounds.

Full text of DOI:10.1021/jo982413c

2486
J . Org. Chem. 1999, 64, 2486-2493
A Novel Lin k in g-P r otectin g Gr ou p Str a tegy for Solid -P h a se
Or ga n ic Ch em istr y w ith Con figu r a tion a lly Sta ble
r-[N-(P h en ylflu or en yl)]a m in o Ca r bon yl Com p ou n d s: Syn th esis of
En a n tiop u r e Nor ep h ed r in es on Solid Su p p or t
Francis Gosselin, J o Van Betsbrugge, Mostafa Hatam, and William D. Lubell*
De´partement de chimie, Universite´ de Montre´al, C. P. 6128, Succursale Centre Ville,
Montre´al, Que´bec H3C 3J 7, Canada
Received December 10, 1998
A novel linking strategy has been developed for synthesizing configurationally stable R-amino
aldehyde on polymeric supports. Alkylation of L-alanine methyl ester with 9-bromo-9-p-bromo-
phenylfluorenene, followed by ester hydrolysis and coupling to isoxazolidine, provided N-(9-p-
bromophenylfluoren-9-yl)alanine isoxazolidide (5), which was transformed into its corresponding
boronate 2 by a palladium-catalyzed cross-coupling reaction with diboron pinacol ester. Boronate
2 was anchored to four different polymeric aryl halides 6-9 in 70-99% yields. Polymer-bound
alaninal 1b was then synthesized on non-cross-linked polystyrene by hydride reduction of
isoxazolidide 10b. Treatment of alaninal 1b with phenylmagnesium bromide, cleavage of the
resulting amino alcohol in a 1:2:2 TFA/CH2Cl2/anisole cocktail, and acylation with di-tert-butyl
dicarbonate furnished N-(BOC)norephedrines 14 that were demonstrated to be enantiopure by
conversion to diastereomeric thioureas 15 and analysis by HPLC. In summary, we have developed
a process by which the 9-phenylfluoren-9-yl protecting group has been converted into a new linker
for the solid-phase synthesis and manipulation of R-amino carbonyl compounds.
In tr od u ction
sary prior to steps for generating molecular diversity.
Solution-phase amine protection that converts into a
solid-phase amine linker anytime during synthesis may
offer advantages over conventional support-bound pro-
tecting groups because penultimate intermediates could
be initially synthesized in solution on large scale and then
attached to supports for transformation via molecular
diversification chemistry.
The development of novel strategies for effectively
linking organic compounds to solid supports has become
essential as solid-phase chemistry and combinatorial
technology have evolved into fundamental tools for drug
discovery.1 In principle, the ideal linker should provide
effective loading onto the support, stability under a
diverse variety of reaction conditions, and easy product
removal without contamination from the linker.2 Al-
though several strategies have emerged for attaching
amines to solid supports,3-5 many of these linkers are
not stable under strong base, strong acid, or organo-
metallic reaction conditions. Furthermore, because such
linkers often require amine attachment to the support
early in the synthesis, multiple reactions may be neces-
The 9-phenylfluoren-9-yl (PhF) amine protecting group
has ensured configurational stability in the preparation
and manipulation of R-amino carbonyl compounds during
solution-phase syntheses of enantiopure alkaloids,6,7
heterocycles,8 and amino acids.9,10 The PhF group pre-
vents the racemization of R-amino carbonyl compounds
by sterically shielding the R-proton and by positioning
the R-proton and carbonyl in a planar geometry in which
deprotonation is stereoelectronically disfavored.10,11 Rela-
tive to the trityl group,5,12 the PhF group is also signifi-
cantly more stable to solvolysis in acid because of the
(1) Recently reviewed: Brown, R. C. D. J . Chem. Soc., Perkin Trans.
1 1998, 3293 and refs 1-27 therein.
(2) Examples include the following. Germanium- and silicon-based
traceless linkers: (a) Plunkett, M. J .; Ellman, J . A. J . Org. Chem. 1997,
62, 2885. Safety-catch linkers: (b) Backes, B. J .; Ellman, J . A. J . Am.
Chem. Soc. 1994, 116, 11171. For additional examples see ref 1.
(3) Urethane linkers that comprise the elements of their solution-
phase counterparts include the following. BOC linker: (a) Herna´ndez,
A. S.; Hodges, J . C. J . Org. Chem. 1997, 62, 3153. Fmoc linker: (b)
Rabanal, F.; Giralt, E.; Albericio, F. Tetrahedron Lett. 1992, 33, 1775.
Cbz linker: (c) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W.
Tetrahedron Lett. 1996, 37, 937. (d) Hauske, J . R.; Dorff, P. Tetrahedron
Lett. 1995, 36, 1589.
(6) Christie, B. D.; Rapoport, H. J . Org. Chem. 1985, 50, 1239.
(7) Examples include (a) (+)-vincamine [Gmeiner, P.; Feldman, P.
L.; Chu-Moyer, M. Y.; Rapoport, H. J . Org. Chem. 1990, 55, 3068] and
(b) (+)-castanospermine and (+)-6-epicastanospermine: Gerspacher,
M.; Rapoport, H. J . Org. Chem. 1991, 56, 3700.
(8) Blanco, M.-J .; Sardina, F. J . J . Org. Chem. 1996, 61, 4748.
(9) Examples include: (a) Lubell, W. D.; J amison, T. F.; Rapoport,
H. J . Org. Chem. 1990, 55, 3511. (b) Beausoleil, E.; L’Archeveˆque, B.;
Be´lec, L.; Atfani, M.; Lubell, W. D. J . Org. Chem. 1996, 61, 9447. (c)
Gosselin, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 7463. (d) Polyak,
F.; Lubell, W. D. J . Org. Chem. 1998, 63, 5937. (e) Koskinen, A. M. P.;
Schwerdtfeger, J .; Edmonds, M. Tetrahedron Lett. 1997, 38, 5399.
(10) (a) Humphrey, J . M.; Bridges, R. J .; Hart, J . A.; Chamberlin,
A. R. J . Org. Chem. 1994, 59, 2467. (b) Atfani, M.; Lubell, W. D. J .
Org. Chem. 1995, 60, 3184.
(4) Dimethoxybenzylamine linker: (a) J ensen, K. J .; Songster, M.
F.; Va´gner, J .; Alsina, J .; Albericio, F.; Barany, G. In Peptides:
Chemistry, Structure and Biology; Kaumaya, P. T. P., Hodges, R. S.,
Eds.; ESCOM Sci. Pub. B.V.: Leiden, The Netherlands, 1996; p 30.
(b) Sharma, S. K.; Songster, M. F.; Colpitts, T. L.; Hegyes, P.; Barany,
G.; Castellino, F. J . J . Org. Chem. 1993, 58, 4993. ADCC linker: (c)
Bannwarth, W.; Huebscher, J .; Barner, R. Bioorg. Med. Chem. Lett.
1996, 6, 1525.
(5) Trityl linkers: (a) Barlos, K.; Gatos, D.; Kallitsis, I.; Papaioan-
nou, D.; Sotiriou, P. Liebigs Ann. Chem. 1988, 1079. (b) Zikos, C. C.;
Ferderigos, N. G. Tetrahedron Lett. 1994, 35, 1767. (c) Bidaine, A.;
Berens, C.; Sonveaux, E. Bioorg. Med. Chem. Lett. 1996, 6, 1167.
(11) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1987, 109, 236.
(12) The acid lability of the trityl group is described: Sieber, P.;
Riniker, B. In Peptides: Chemistry and Biology, Proceedings of the
Tenth Am. Peptide Symposium; Marshall, G. R., Ed.; ESCOM Sci. Pub.
B. V.: Leiden, The Netherlands, 1988; pp. 270-272.
10.1021/jo982413c CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/17/1999

Synthesis of Enantiopure Norephedrines on Solid Support
J . Org. Chem., Vol. 64, No. 7, 1999 2487
Sch em e 1. Syn th esis of
9-Br om o-9-p-br om op h en ylflu or en e (Br P h F Br )
F igu r e 1. Resino N-(PhF)-R-amino aldehyde 1 and norephe-
drine.
to the support by an ether bond proved cumbersome due
to difficulties in synthesizing PhF groups possessing
protected ethers.
antiaromatic character of the fluorenyl cation.13 Because
of these attributes, we began to study the conversion of
the PhF protecting group into a new linker for the solid-
phase synthesis and manipulation of R-amino carbonyl
compounds.
Transition metal catalyzed cross-coupling chemistry
was examined for linking the PhF group and support,
because these reactions are usually high yielding both
in solution and on solid phase.19,20 Mild conditions for
converting aryl bromides into their respective aryl bor-
onates had recently been reported and appeared compat-
ible with a broad spectrum of functional groups.21 We
perceived that amino acids could be protected with
9-bromo-9-p-bromophenylfluorene in solution and that
palladium-catalyzed cross-coupling reactions could then
be used to link the N-(BrPhF)amino acid derivative to
the solid support (BrPhF ) 9-(9-p-bromophenylfluor-
enyl)).
This concept has now been validated by the solution-
phase synthesis of N-(BrPhF)alanine isoxazolidide and
its conversion into polymer-bound R-amino aldehyde 1
(Figure 1, R ) CH3). Alaninal 1 was examined because
R-amino aldehydes have been previously shown to be
susceptible to racemization from various reactions in
solution.11,22 By employing polymer-bound R-amino al-
dehyde 1 in the synthesis of enantiopure norephedrines,
we have demonstrated that the PhF protecting-linking
group approach can provide configurational stability
during the synthesis and modification of support-bound
R-amino carbonyl compounds.
Initially, we synthesized 9-bromo-9-phenylfluorenyl
cross-linked polystyrene by lithiation of cross-linked
polystyrene,14,15 followed by addition of fluorenone and
treatment of the tertiary alcohol with acetyl bromide in
benzene.15,16 L-Alanine methyl ester hydrochloride was
anchored to the polymer using Et3N in 1:1 CH2Cl2/CH3-
CN, as indicated by a strong band for the ester carbonyl
at 1736 cm-1 in the PA-FTIR spectrum.16,17 During the
course of our investigation, papers appeared describing
the preparation of 9-chloro-9-phenylfluorenyl cross-linked
polystyrene resin and a phenylfluorenyl acetic acid linker,
as well as their employment in peptide chemistry and
manipulations of achiral amines, which demonstrated the
greater acid stability of the PhF supports relative to trityl
resins.18 Focusing our attention on the synthesis and
configurational stability of resino R-amino carbonyl
compounds such as R-amino aldehyde 1 (Figure 1), we
realized that a limitation of the phenylfluorenyl cross-
linked polystyrene resins was the requirement to employ
several steps on the solid phase in order to convert the
starting resino ester into the desired R-amino aldehyde.
Since such reactions could be more effectively accom-
plished on large scale in solution,11 we discontinued our
studies on the PhF-resin; instead, we chose to develop a
PhF linker for synthesizing the penultimate intermediate
prior to resin attachment.
In developing a PhF linker, we pursued a protecting-
linking group that was synthesized in few steps from
inexpensive starting materials, compatible with solution-
and solid-phase chemistry, and attachable to an assort-
ment of different solid supports. The employment of
esters for joining the PhF group to the resin was judged
inadequate due to their reactivity with organometallic
reagents. Similarly, the phenylfluorenyl acetic acid linker18
was deemed unsuitable because the amide used to link
the PhF group to the resin was also expected to react
competitively with organometallic reagents during trans-
formations of the resino R-amino carbonyl compounds.
Furthermore, initial attempts to attach the PhF group
Resu lts
9-Bromo-9-p-bromophenylfluorene (BrPhFBr) was first
synthesized in two steps and 89% overall yield from
fluorenone by a procedure that was patterned closely
after the preparation of 9-bromo-9-phenylfluorene pub-
lished originally by Christie and Rapoport (Scheme 1).6,23
Metal-halogen exchange on 1,4-dibromobenzene with
n-butyllithium in THF at -78 °C gave p-bromophenyl-
lithium,24 which was treated with fluorenone to furnish
9-p-bromophenylfluoren-9-ol. The crude alcohol was sub-
(19) Reviewed in: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457.
(20) Illustrative transition metal-catalyzed cross-coupling examples
on solid-phase include: (a) Frenette, R.; Friesen, R. W. Tetrahedron
Lett. 1994, 35, 9177. (b) Koh, J . S.; Ellman, J . A. J . Org. Chem. 1996,
61, 4494. (c) Brown, S. D.; Armstrong, R. W. J . Org. Chem. 1997, 62,
7076. (d) Deshpande, M. S. Tetrahedron Lett. 1994, 35, 5613. (e)
Plunkett, M. J .; Ellman, J . A. J . Am. Chem. Soc. 1995, 117, 3306. (f)
J ones, L. I.; Schumm, J . S.; Tour, J . M. J . Org. Chem. 1997, 62, 1388.
(21) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995,
60, 7508. (b) Giroux, A.; Han, Y.; Prasit, P. Tetrahedron Lett. 1997,
38, 3841.
(22) Epimerization of R-heterosubstituted aldehydes is discussed in
refs 1 and 2 in: Lubell, W.; Rapoport, H. J . Org. Chem. 1989, 54, 3824.
(23) J amison, T. F.; Lubell, W. D.; Dener, J . M.; Krische´, M. J .;
Rapoport, H. Org. Synth. 1992, 71, 220.
(13) The solvolysis of TrCl is 6000 times faster than PhFCl: Bolton,
R.; Chapman, N. B.; Shorter, J . J . Chem. Soc. 1964, 1895.
(14) Farrall, M. J .; Fre´chet, J . M. J . J . Org. Chem. 1976, 41, 3877.
(15) Fyles, T. M.; Leznoff, C. C. Can J . Chem. 1976, 54, 935.
(16) Preliminary results were presented in part: Gosselin F.; Lubell,
W. D. 2nd Canadian Conference on Combinatorial Chemistry, Oct 6-7,
1997, Montre´al, Que´bec, Canada.
(17) Gosselin, F.; Di Renzo, M.; Ellis, T.; Lubell, W. D. J . Org. Chem.
1996, 61, 7980.
(18) (a) Bleicher, K. H.; Wareing, J . R. Tetrahedron Lett. 1998, 39,
4587. (b) Bleicher, K. H.; Wareing, J . R. Tetrahedron Lett. 1998, 39,
4591. A related 9-(4-carboxyphenyl)fluorenyl linker is presented: (c)
Henkel, B.; Bayer, E. Tetrahedron Lett. 1998, 39, 9401.
(24) (a) Ravindar, V.; Hemling, H.; Schumann, H., Blum, J . Synth.
Commun. 1992, 22, 841. In our hands, the Grignard reagent from 1,4-
dibromobenzene could not be prepared: (b) Pink, H. S. J . Chem Soc.
1923, 123, 3418.

2488 J . Org. Chem., Vol. 64, No. 7, 1999
Gosselin et al.
resin (Wang resin)31 were linked to N-(phenylfluorenyl)-
amino acid analogues because of the importance of these
supports in solid-phase organic synthesis.
Sch em e 2. Syn th esis of N-(Br P h F )a la n in e
Isoxa zolid id e 5
Aryl halide terminals were attached to the four differ-
ent supports (Scheme 4). For example, MeO-PEG-5000-
p-bromobenzyl ether 6 was synthesized by alkylation of
MeO-PEG-5000 using p-bromobenzyl bromide in THF in
the presence of NaI and 18-crown-6.28 Non-cross-linked
polystyrene (NCPS) m-iodophenyl ether 7 was prepared
by anionic polymerization of styrene using n-butyllithium
as initiator in toluene,32 chloromethylation using chlo-
romethyl methyl ether in the presence of ZnCl2,33 and
ether formation with m-iodophenol, NaI, and NaH in a
solution of 1:1 DMA/THF. Proton NMR spectroscopy was
used to determine the yield of the ether-forming reactions
to synthesize 6 and 7. Measurement of the methylene
proton signals of the benzylic ethers showed that MeO-
PEG-5000-p-bromobenzyl ether 6 and NCPS-m-iodo-
phenyl ether 7, were both prepared in >96% yield.
Treatment of Merrifield resin under similar conditions
as described for the synthesis of NCPS-m-iodophenyl
ether 7 gave Merrifield resin m-iodophenyl ether 8 in 82%
yield as ascertained by the increase in polymer weight.
Alkylation of Wang resin using KN(SiMe3)2 and p-
bromobenzyl bromide in THF at room temperature
furnished Wang resin p-bromobenzyl ether 9 in 78% yield
as determined by the increase in polymer weight.
Boronate 2 was coupled to polymer supports 6-9 using
[PdCl2(dppf)] as catalyst and Na2CO3 as base in DMF at
80 °C (Scheme 3).21 In the case of soluble polymer
supports 6 and 7, conversions were estimated by compar-
ing the integrations of the resino benzylic protons and
sequently agitated vigorously with aqueous HBr in
toluene to afford the desired bromide after crystallization
from isooctane.
L-N-[p-(Pinacolboronato)phenylfluorenyl]alanine isox-
azolidide (2), the polymer-bound aldehyde precursor, was
synthesized in four steps and 74% overall yield using
solution-phase chemistry (Schemes 2 and 3). Initially,
L-N-(BrPhF)alanine methyl ester 3 was synthesized in
92% yield from L-alanine methyl ester hydrochloride and
9-bromo-9-p-bromophenylfluorene using the literature
procedure for phenylfluorenation of R-amino esters.25
Hydrolysis of the methyl ester with aqueous LiOH in
dioxane furnished N-(BrPhF)alanine 4 in 97% yield.
N-(BrPhF)alanine isoxazolidide 5 was isolated as a white
crystalline solid in 91% yield from coupling alanine 4 and
isoxazolidine hydrochloride with N,N-diisopropylcarbo-
diimide and Et(i-Pr)2N in dichloromethane.11 Conversion
of p-bromophenylfluorenyl-protected amide 5 into its
corresponding boronate 2 was accomplished in 92% yield
after chromatography by treatment of isoxazolidide 5
with diboron pinacol ester, potassium acetate, and [PdCl2-
(dppf)]26 in DMSO at 80 °C for 20 h (Scheme 3).21
Different supports were examined in the palladium-
catalyzed cross-coupling reaction with boronate 2. For
example, boronate 2 was reacted with two soluble poly-
mer supports.27 Poly(ethylene glycol) monomethyl ether
(MeO-PEG-5000)28 and non-cross-linked-polystyrene
(NCPS)29 were used to anchor N-(phenylfluorenyl)amino
acid analogues because reaction conversions could be
1
the alanine methyl doublet in the H NMR spectra. The
cross-coupling of boronate 2 and MeO-PEG-5000-p-bro-
mobenzyl ether 6 gave a 50-60% conversion to resino
isoxazolidide 10a . Cross-coupling of NCPS-iodophenyl
ether 7 with boronate 2 gave NCPS-supported isoxazo-
lidide 10b in >98% conversion. Merrifield resin 8 reacted
with 2 to provide resino isoxazolidide 10c in 78% conver-
sion based on proton MAS NMR spectroscopic analysis
and comparison of the integrations for the alanine methyl
doublet and benzyl methylene protons.34 Finally, cross-
coupling of 2 to Wang resin 9 gave a 70% conversion to
resino isoxazolidide 10d as determined by weighing the
cleavage product, (p-hydroxymethylphenyl-PhF)alanine
isoxazolidide,35 obtained from exposing the polymer to a
1:1 TFA/CH2Cl2 solution.
1
monitored by H NMR spectroscopy of these supports in
At present, we have focused our attention on the use
of the soluble polymer-supported isoxazolidides 10a and
10b because reactions on these materials were effectively
monitored using solution-phase NMR spectroscopy. Alan-
inals 1a and 1b were respectively synthesized by reduc-
tion of polymer-bound isoxazolidides 10a and 10b with
solution. Boronate 2 was also cross-coupled with two
nonsoluble supports. Chloromethyl cross-linked polysty-
rene (Merrifield resin)30 and p-benzyloxybenzyl alcohol
(25) J amison, T. F.; Rapoport, H. Org. Synth. 1992, 71, 226.
(26) [PdCl2(dppf)] was prepared according to: Hayashi, T.; Konishi,
M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J . Am. Chem.
Soc. 1984, 106, 158. The dppf ligand was prepared according to:
Bishop, J . J .; Davison, A.; Katcher, M. L.; Lichtenberg, D. W.; Merrill,
R. E.; Smart, J . C. J . Organomet. Chem. 1971, 27, 241.
(27) Gravert, D. J .; J anda, K. D. Chem. Rev. 1997, 97, 489.
(28) The use of MeO-PEG-5000 has been reviewed in ref 27. Ether
formation with MeO-PEG-5000 was conducted as described in: (a)
Douglas, S. P.; Whitfield, D. M.; Krepinsky, J . J . J . Am. Chem. Soc.
1995, 117, 2116. (b) Douglas, S. P.; Whitfield, D. M.; Krepinsky, J . J .
J . Am. Chem. Soc. 1991, 113, 5095.
(29) Examples of the employment of NCPS-polymer include: (a)
Cramer, F. Helbig, R.; Hettler, H.; Scheit, K. H.; Seliger, H. Angew.
Chem., Int. Ed. Engl. 1966, 5, 601. (b) Green, B.; Garson, L. R. J . Chem.
Soc. C 1969, 401. (c) Guthrie, R. D.; J enkins, A. D.; Stehl´ıcek, J . J .
Chem. Soc. C 1971, 2690. (d) Narita, M. Bull. Chem. Soc. J pn. 1978,
51, 1477. (e) Chen, S.; J anda, K. D. J . Am. Chem. Soc. 1997, 119, 8724
and references cited in ref 27.
1
LiAlH4 in THF and identified by H NMR spectroscopy,
which showed an aldehyde peak at 9.1-9.2 ppm (Scheme
5).11 In the case of MeO-PEG-5000-supported alaninal 1a ,
(31) Wang, S.-S. J . Am. Chem. Soc. 1973, 95, 1328.
(32) Van Beylen, M.; Bywater, S.; Smets, G.; Szwarc, M.; Worsfold,
D. J . Adv. Polym. Sci. 1988, 86, 87.
(33) Andreatta, R. H.; Rink, H. Helv. Chim. Acta 1973, 56, 1205.
(34) The use of MAS NMR spectroscopy for monitoring solid-phase
chemistry is described: (a) Pop, I. E.; Dhalluin, C. F.; De´prez, B. P.;
Melnyk, P. C.; Lippens, G. M.; Tartar, A. L. Tetrahedron 1996, 52,
12209. (b) Sarkar, S. K.; Garigipati, R. S.; Adams, J . L.; Keifer, P. A.
J . Am. Chem. Soc. 1996, 118, 2305 and references therein.
(35) 1H NMR (CD3OD) δ 8.0-7.05 (m, 16 H), 5.4 (s, 1 H), 5.3 (s, 1
H), 4.25 (m, 1 H), 4.12 (m, 1 H), 4.02 (m, 1 H), 3.83 (m, 1 H), 3.56 (m,
1 H), 2.37 (m, 1 H) 2.10-1.98 (m, 1 H), 1.45 (d, 3 H, J ) 7.0 Hz).
(30) Merrifield, R. B. J . Am. Chem. Soc. 1963, 85, 2149.

Synthesis of Enantiopure Norephedrines on Solid Support
J . Org. Chem., Vol. 64, No. 7, 1999 2489
Sch em e 3. Atta ch m en t of N-(Br P h F )a la n in e Isoxa zolid id e 5 to P olym er ic Su p p or ts via Ar ylbr or on a te 2
Sch em e 4. P r ep a r a tion of Resin o Ar yl Ha lid es
Sch em e 5. Syn th esis a n d Con ver sion of
P olym er -bou n d Ala n in a l 1 in to En a n tiop u r e
Nor ep h ed r in es 14
6-9
stored overnight at room temperature without noticeable
decomposition. Polymer-bound norephedrines 11b were
synthesized by addition of a THF solution of phenylmag-
nesium bromide to a -78 °C solution of NCPS-supported
R-amino aldehyde 1b in THF. Parallel experiments were
conducted in solution to transform N-[BrPhF]alanine
isoxazolidide 5 into a 1:1 mixture of diastereomeric
N-(BrPhF)norephedrines 12 in 92% overall yield as
described in the Experimental Section. Comparison of the
proton NMR spectrum of NCPS-supported norephedrines
11b with that of N-(BrPhF)norephedrines 12 verified the
formation of the desired product from addition of phen-
ylmagnesium bromide to polymer-bound aldehyde 1b.
Cleavage of the amino alcohol product from the NCPS
support was initially studied using solutions containing
TFA in CH2Cl2 at room temperature; however, the
polymer became insoluble under these conditions, pre-
sumably due to cross-linking of polystyrene in acid,29b and
norephedrine could not be isolated. In examinations of
the cleavage conditions using both NCPS-supported
norephedrines 11b and N-(BrPhF)norephedrines 12, we
found that the polymer remained soluble in solutions of
TFA in CH2Cl2 containing anisole as cosolvent. Anisole
was introduced to trap carbocations formed during the
the reaction was conducted at room temperature because
the polymer had poor solubility in THF at lower temper-
atures. The polymer was isolated by precipitation in
1
diethyl ether and filtration. Although H NMR spectros-
copy indicated that MeO-PEG-5000-supported alaninal
1a was obtained in 66% yield, aldehyde 1a was not stable
and decomposed within 24 h at -20 °C. An attempt to
immediately react aldehyde 1a with excess phenylmag-
nesium bromide in THF at room temperature failed to
provide polymer displaying amino alcohol signals in the
1H NMR spectrum. These experiments indicated that
MeO-PEG-5000-polymer was not suitable for R-amino
aldehyde chemistry. In our hands, the breadth of chemi-
cal transformations performed with the MeO-PEG-5000-
polymer was greatly limited due to low solubility in
CH2Cl2, THF, and toluene below room temperature.
The NCPS-supported R-amino aldehyde, alaninal 1b,
was prepared by LiAlH4 reduction in THF at 0 °C and

2490 J . Org. Chem., Vol. 64, No. 7, 1999
Gosselin et al.
acid-induced cleavage.36 The reaction of the NCPS-
polymer and anisole was indicated by the presence of a
new peak at 3.74 ppm for the anisole methoxy group in
first example of a configurationally stable polymer-bound
R-amino aldehyde that has been used in the synthesis of
enantiopure norephedrines 14.
1
the H NMR spectrum of the polymer after the cleavage
Toward the development of an ideal linker, we have
demonstrated that the phenyflourenyl linking/protecting
group strategy is effective for loading advanced interme-
diates onto both soluble and insoluble supports. Alanine
isoxazolidide 2 was successfully anchored to polymer-
bound aryl halides by palladium-catalyzed cross-cou-
plings in 70-99% yields. Linker stability was demon-
strated both in the lithium aluminum hydride reduction
of support-bound isoxazolidide 10b and in the addition
of phenylmagnesium bromide to R-amino aldehyde 1b;
both organometallic reactions proceeded without linker
degradation. Final product removal was effected with
TFA in CH2Cl2 containing anisole as cosolvent, which
gave crude material of >75% purity after a simple
aqueous extraction and evaporation.
Because this method may be extended to other amino
acids and organometallic reagents, the potential exists
to apply polymer-bound R-amino aldehydes in syntheses
of amino alcohol libraries.39,40 However, the present
design has its limitations, and we are currently exploring
modifications to make this approach more amenable to
combinatorial chemistry. For example, to link the PhF
group to the resin, we are now examining alternative
transition metal-catalyzed cross-coupling procedures that
do not involve the employment of the relatively expensive
diboron pinacol ester.21 We are also investigating similar
chemistry with resino carbonyl compounds such as isox-
azolidides 10c and 10d , because we believe that insoluble
resins may be easier to manage in library syntheses
relative to their soluble polymer counterparts. Consider-
ing the numerous biologically active compounds that
possess amino alcohol components, this PhF protecting-
linking group strategy may find significant use in com-
binatorial science for drug discovery.
In summary, we have developed a novel strategy for
linking protected amino carbonyl compounds to solid
supports that employs transition metal catalyzed cross-
coupling chemistry. By employing this strategy to anchor
PhF-protected amines to soluble polymers, we found that
non-cross-linked polystyrene (NCPS) was better suited
for the synthesis of configurationally stable polymer-
bound alaninal 1 than the MeO-PEG-5000-polymer. The
addition of an organometallic reagent to R-amino alde-
hyde 1, polymer cleavage, and isolation via N-acylation
provided enantiopure N-(BOC)norephedrines 14. The
application of this strategy to the synthesis of different
configurationally stable polymer-bound R-amino carbonyl
compounds is presently under investigation to furnish a
variety of enantiomerically pure amine-bearing products.
reaction. Treatment of polymer 11b in a 1:2:2 TFA/CH2-
Cl2/anisole solution for 48 h at room temperature pro-
vided norephedrines that were conveniently isolated as
their N-BOC-derivatives. After an aqueous extraction
and evaporation of the aqueous phase, the purity of the
crude norephedrine was estimated to be >75% by com-
parison of the integration of the methyl doublets for the
product with that of other doublets in the same spectral
region. Treatment of the crude product with di-tert-butyl
dicarbonate and Et3N in MeOH followed by column
chromatography on silica gel provided a 3:1 mixture of
diastereomeric N-(BOC)-norephedrines 14 in 60% yield
from NCPS-supported ephedrines 11b. For comparison,
we note that a 1:1 mixture of diastereomeric N-(BOC)-
norephedrines 14 was obtained in 66% yield from the
solution-phase solvolysis of N-(BrPhF)norephedrines 12
and protection with di-tert-butyl dicarbonate. In sum-
mary, N-(BOC)-norephedrines 14 were produced in 46%
overall yield from L-N-[p-(pinacolboronato)phenylfluor-
enyl]alanine isoxazolidide 2.
The enantiomeric purity of norephedrines 14, which
were synthesized from support-bound alaninal 1b, was
determined by HPLC analysis of their 2,3,4,6-tetra-O-
acetyl-â-D-glucopyranosyl thioureas 15. Diastereomeric
N-(BOC)amino alcohols 14 were treated with trifluoro-
acetic acid in CH2Cl2 to remove the BOC group, and the
crude trifluoroacetates were acylated using 2,3,4,6-tetra-
O-acetyl-â-D-glucopyranosyl isothiocyanate (GITC) and
triethylamine in CH2Cl2.37 Thioureas 15, prepared from
material cleaved from the NCPS-polymer, were then
analyzed by reversed-phase HPLC using conditions that
resolved all four diastereomers.37 Comparison of the
magnitudes of the major peak for the (1R,2S)-thiourea
15 and the peak that coeluted with a sample of (1S,2R)-
thiourea 15 synthesized from authentic (1S,2R)-norephe-
drine indicated a 99:1 diastereomeric ratio of (1R,2S)- and
(1S,2R)-thioureas 15. Hence, amino alcohols 14 and
polymer-bound R-amino aldehyde 1b all are presumed
to be of a 99:1 enantiomeric ratio.
Discu ssion
The solid-phase synthesis of enantiopure product has
traditionally been addressed in peptide chemistry where
a wide milieu of reagents, protecting groups, and linkers
have been used to circumvent racemization.38 The current
renaissance of interest in solid-phase methods for syn-
thesizing different organic structures in enantiopure form
has created the necessity for new tools to manipulate
intermediates that may be configurationally labile on
polymeric supports.1 Toward the development of a new
linker for anchoring R-amino carbonyl compounds onto
polymer, we selected to adapt the PhF protecting group
to solid-phase chemistry because of its proven effective-
ness in providing enantiomerically pure amine-bearing
products in solution.6-11 Our studies have provided the
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all reactions
were run under argon atmosphere and distilled solvents were
transferred by syringe. THF was distilled from sodium/
benzophenone immediately before use; CH2Cl2 and CH3CN
were distilled from CaH2; CHCl3 was distilled from P2O5;
(36) Svanholm, U.; Parker, V. D. J . Chem. Soc., Perkin Trans. 1
1973, 562.
(37) Noggle, F. T., J r.; Clark, C. R.; De Ruiter, J . J . Liquid
Chromatogr. 1991, 14, 29.
(39) Alternative strategies for synthesizing amino alcohols on solid
supports include: (a) Kobayashi, S.; Moriwaki, M. Tetrahedron Lett.
1997, 38, 4251. (b) Kobayashi, S.; Moriwaki, M. Akiyama, R.; Suzuki,
S.; Hachiya, I. Tetrahedron Lett. 1996, 37, 7783.
(38) reviewed in: Solid-Phase Peptide Synthesis. Methods in En-
zymology; Fields, G. B., Ed.; Academic Press: New York, 1997; Vol.
289, Section I.
(40) For a solution-phase synthesis of amino alcohols via N-(PhF)-
amino ketones see: Paleo, M. R.; Calaza, M. I.; Sardina, F. J . J . Org.
Chem. 1997, 62, 6862.

Synthesis of Enantiopure Norephedrines on Solid Support
J . Org. Chem., Vol. 64, No. 7, 1999 2491
MeOH was distilled from Mg. DMSO and DMF were distilled
and stored over 4 Å molecular sieves. Potassium acetate was
recrystallized from 1:1 EtOH/H2O and dried at >100 °C under
vacuum before use. For reactions involving palladium cataly-
sis, the solutions were degassed for 10-15 min by bubbling
argon through the solution before addition of the catalyst.
Final reaction mixture solutions were dried over Na2SO4.
Chromatography was performed on 230-400 mesh silica gel,
TLC on aluminum-backed silica plates. Melting points are
uncorrected. Mass spectral data, HRMS, were obtained by the
DMAP (45 mg, 10 mol %), cooled to 0 °C for 15 min, and treated
with N,N-diisopropylcarbodiimide (1.15 mL, 200 mol %). The
mixture was stirred for 3 h at 0 °C, warmed to room
temperature, and evaporated to dryness. The residue was
purified by chromatography using 20-30% EtOAc in hexanes
as eluant to yield isoxazolidide 5 as a white solid. Recrystal-
lization from Et2O in hexanes gave white needles (1.54 g,
91%): mp 143-144 °C; [R]20D -140.5 (c ) 1, MeOH); Rf ) 0.41
(1:1 EtOAc/hexanes); 1H NMR δ 7.66-7.17 (m, 12 H), 3.56 (bm,
3 H), 3.13-3.01 (bm, 2 H), 2.64 (bs, 1 H), 1.97 (bm, 1 H), 1.80
(bm, 1 H), 1.12 (d, 3 H, J ) 7.0); 13C NMR δ 176.7, 73.1, 68.4,
48.6, 42.9, 27.0, 22.5; HRMS calcd for C25H24N2O279Br [MH+]
463.1021, found 463.1010. Anal. Calcd for C25H23N2O279Br: C,
64.80; H, 5.00; N, 6.05. Found: C, 64.92; H, 5.12; N, 6.12.
(2S)-N-[p -(P in a colb or on a t o)p h en ylflu or en yl]a la n in e
Isoxa zolid id e (2). A solution of isoxazolidide 5 (247 mg, 0.53
mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane
(diboron pinacol ester, 137 mg, 0.53 mmol, 100 mol %), and
KOAc (157 mg, 1.59 mmol, 300 mol %) in DMSO (5 mL) was
degassed for 10-15 min and treated with [PdCl2(dppf)] (10
mg, 3 mol %). The mixture was heated at 80 °C overnight.
Isoxazolidides 2 and 5 had the same Rf values in a variety of
eluants; however, staining with a ceric ammonium molybdate
solution showed a pink color for bromide 5 and a deep-blue
color for boronate 2. After complete disappearance of the pink
staining bromide was observed by TLC, the reaction was cooled
to room temperature and diluted with Et2O (10 mL) and H2O
(10 mL). The layers were separated, and the aqueous layer
was extracted with Et2O until TLC of the organic layer showed
no UV-active material. The combined organic layers were
washed with brine (10 mL), dried, and evaporated to a residue
that was chromatographed using 20-30% EtOAc in hexanes
as eluant. Evaporation of the collected fractions gave boronate
2 (251 mg, 92%) as a colorless solid: mp >230 °C; [R]20D -164.4
1
Universite´ de Montre´al Mass Spectrometry facility. H NMR
(400 MHz) and 13C NMR (75 MHz) spectra were recorded in
CDCl3. Chemical shifts are reported in ppm (δ units) downfield
of internal TMS and coupling constants are reported in Hz.
Aromatic carbons of compounds having PhF groups are not
reported.
9-p-Br om op h en ylflu or en -9-yl Br om id e (Br P h F Br ). A
solution of 1,4-dibromobenzene (5.0 g, 21 mmol) in THF (120
mL) at -78 °C was treated dropwise with n-butyllithium (7.98
mL, 19.95 mmol, 95 mol %, 2.5 M in hexanes), stirred for 20-
25 min at -78 °C, and treated dropwise with a solution of
fluorenone (3.60 g, 20 mmol, 95 mol %) in THF (30 mL). The
mixture was stirred for 5 min at -78 °C, warmed to room
temperature over 60 min, and quenched with H2O (20 mL).
The layers were separated, and the aqueous layer was
extracted with Et2O (2 × 100 mL). The combined organic layers
were washed with brine (20 mL), dried, and evaporated. The
crude residue was immediately dissolved in toluene (70 mL),
treated with HBr (60 mL, 48% aqueous solution), and stirred
vigorously, protected from light, for 24 h at room temperature.
The layers were separated, and the aqueous layer was
extracted with toluene (2 × 20 mL). The combined organic
layers were washed with brine (25 mL), dried, and evaporated
to yield Br P h F Br as an oil. Crystallization from isooctane
gave 7.14 g of colorless needles (89%): mp 112-113 °C; 1H
NMR δ 7.78-7.76 (m, 2 H), 7.62-7.60 (m, 2 H), 7.57-7.54 (m,
2 H), 7.50-7.43 (m, 4 H), 7.40-7.36 (m, 2 H); 13C NMR δ 149.0,
140.3, 137.9, 131.3, 129.3, 129.13, 129.11, 129.0, 128.8, 128.7,
128.6, 125.8, 122.2, 120.4, 66.4. Anal. Calcd for C19H12Br2: C,
57.04; H, 3.02. Found: C, 57.48; H, 3.00.
1
(c ) 0.23, CHCl3); Rf ) 0.41 (1:1 EtOAc/hexanes); H NMR δ
7.65-7.64 (m, 4 H), 7.41-7.15 (m, 8 H), 3.64-3.5*6 (bm, 3
H), 3.03-2.98 (bm, 2 H), 2.63 (bs, 1 H), 1.95-1.94 (bm, 1 H),
1.84-1.79 (bm, 1 H), 1.28 (s, 12 H), 1.80 (d, 3 H, J ) 7.0); 13
C
NMR δ 176.9, 83.7, 73.5, 68.3, 48.5, 42.9, 27.0, 24.9, 22.6;
HRMS calcd for C31H36N2O4B [MH+] 511.2768, found 511.2753.
Anal. Calcd for C31H35N2O4B: C, 72.95; H, 6.91; N, 5.49.
Found: C, 72.88; H, 7.06; N, 5.47.
(2S)-N-(Br P h F )a la n in e Meth yl Ester (3). A suspension
of L-alanine methyl ester hydrochloride (3.66 g, 26.25 mmol,
150 mol %) in CH3CN (70 mL) was treated with K3PO4 (11.70
g, 55.13 mmol, 210 mol %), Pb(NO3)2 (7.40 g, 22.31 mmol, 85
mol %), and BrPhFBr (7.0 g, 17.5 mmol), stirred for 36 h at
room temperature, and treated with MeOH (7.10 mL, 175
mmol). After being stirred for 30 min, the mixture was filtered
through a plug of Celite. The filter cake was thoroughly
washed with CHCl3 until the filtrate contained no UV-active
material. Evaporation of the volatiles and chromatography of
the residue using 5% EtOAc in hexanes as eluant gave ester
3 (7.31 g, 92%) as an oil that solidified on standing: mp 71-
MeO-P EG-5000 p-Br om oben zyl Eth er 6. To a suspension
of KH (574 mg, 5 mmol, 500 mol %, 35wt % in mineral oil)
prewashed with hexanes and 18-crown-6 (1,4,7,10,13,16-
hexaoxacyclooctadecane, 10 mg) in THF (50 mL) at room
temperature was added MeO-PEG-5000 (5 g, 1 mmol, 0.2
mmol/g, dried at room temperature overnight under vacuum
in the presence of P2O5). After the mixture was stirred for 10
min, p-bromobenzyl bromide (1.25 g, 5 mmol, 500 mol %) was
added to the mixture, which was stirred for 24 h at room
temperature and filtered on Celite. The filter cake was washed
with CH2Cl2 (15 mL) and evaporated to a volume of 15-20
mL of solvent. Diethyl ether was added to precipitate the
polymer, which was then filtered and washed with ether. The
polymer was recrystallized from EtOH in Et2O in the freezer,
filtered, and dried under vacuum to give 6 (4.4 g, 85%) as a
white powder: 1H NMR δ 7.45 (d, 2 H, J ) 8.4), 7.22 (d, 2 H,
J ) 8.6), 4.51 (s, 2 H).
Non -Cr oss-Lin k ed P olyst yr en e m -Iod op h en yl E t h er
(NCP S-m -iod op h en yl Eth er ) 7. A solution of m-iodophenol
(1.32 g, 6 mmol) in THF (50 mL) was treated with NaH (720
mg, 18 mmol, 60% in mineral oil), stirred for 30 min, and
treated with a solution of chloromethylated polystyrene (2 g,
2 mmol, 1 mmol/g, molecular weight ) 38634, molecular
weight distribution ) 1.56) and NaI (300 mg, 2 mmol) in N,N-
dimethylacetamide (25 mL). The mixture was heated at 60 °C
for 24 h and poured slowly into MeOH (200 mL) with vigorous
agitation. The precipitated polymer was collected, dissolved
in a minimal amount of THF, and reprecipitated on addition
of MeOH. The polymer was dried under vacuum to give NCPS-
m-iodophenyl ether 7 (2.1 g, 97%) as a powder: 1H NMR δ
7.35-6.25 (m, 40 H), 4.89 (bs, 2 H), 2.25-1.15 (m, 22 H).
Mer r ifield Resin m -Iod op h en yl Eth er 8. A suspension
of m-iodophenol (6.05 g, 27.5 mmol, 250 mol %) in THF (50
73 °C; Rf ) 0.25 (1:9 EtOAc in hexanes); [R]20 -173.0 (c ) 1,
D
1
CHCl3); H NMR δ 7.69-7.67 (m, 2 H), 7.37-7.16 (m, 10 H),
3.29 (s, 3 H), 2.93 (bs, 1 H), 2.76 (q, 1 H, J ) 7.0), 1.11 (d, 3 H,
J ) 7.0); HRMS calcd for C23H21NO279Br [MH+] 422.0756,
found 422.0747.
(2S)-N-(Br P h F )a la n in e (4). A solution of (2S)-N-(BrPhF)-
alanine methyl ester (3, 3 g, 7.10 mmol) in dioxane (30 mL)
was treated with a 2 M aqueous solution of LiOH (17.75 mL,
500 mol %), heated at a reflux for 3 h, cooled to room
temperature, and acidified with concentrated H3PO4 to pH
5-6. The mixture was then saturated with solid NaCl and
extracted with EtOAc until TLC of the organic layer contained
no UV-active material. The combined organic layers were
washed with brine (15 mL), dried and evaporated to give 4
(2.80 g, 97%) as a white foam: 1H NMR δ 7.76-7.69 (m, 2H),
7.23 (m, 10 H), 2.70 (q, 1H, J ) 7.2), 1.16 (d, 3H, J ) 7.2). 13C
NMR (CDCl3) δ 176.1, 72.9, 52.8, 19.3; HRMS calcd for C22H19
-
NO279Br [MH+] 408.0599, found 408.0617.
(2S)-N-(Br P h F )a la n in e Isoxa zolid id e (5). A stirred mix-
ture of N-(BrPhF)alanine (4, 1.50 g, 3.68 mmol), hydroxy-
benzotriazole (596 mg, 4.41 mmol, 120 mol %), and isoxazoli-
dine hydrochloride (806 mg, 7.36 mmol, 200 mol %) in CH2Cl2
(36 mL) was treated with Et(i-Pr)2N (1.92 mL, 300 mol %) and

2492 J . Org. Chem., Vol. 64, No. 7, 1999
Gosselin et al.
mL) and N,N-dimethylacetamide (50 mL) was treated with
NaH (1.32 g, 33 mmol, 300 mol %, 60% in mineral oil), stirred
for 15 min, and treated with chloromethylated cross-linked
polystyrene (Merrifield resin, 2% cross-linked, 10 g, 11 mmol,
1.1 mmol/g) and NaI (300 mg, 2 mmol). The mixture was
heated at 70 °C for 48 h, cooled to room temperature, filtered,
and washed sequentially with 15 mL/g resin of the following
solvents: dioxane, THF, water, acetone, MeOH, and Et2O. The
polymer was then dried under vacuum to give 11.7 g of ether
8 (82% yield by weight increase).
Wa n g Resin p-Br om oben zyl Eth er 9. A suspension of
Wang resin (1.0 g, 0.92 mmol, 0.92 mmol/g) in THF (15 mL)
at room temperature was treated with KN(SiMe3)2 (3.68 mL,
1.84 mmol, 200 mol %, 0.5 M in toluene), stirred for 30 min,
and treated with p-bromobenzyl bromide (460 mg, 1.84 mmol,
200 mol %). After being stirred overnight, the reaction mixture
was quenched with excess water, filtered, and washed sequen-
tially with 15 mL/g resin of the following solvents: dioxane,
THF, water, acetone, MeOH, and Et2O. The resin was dried
under vacuum to give 1.12 g of ether 9 (78%).
MeO-P EG-5000-su p p or ted isoxa zolid id e 10a was pre-
pared using the reaction conditions described below for 10b
in the general protocol, precipitated from cold diethyl ether,
filtered, and washed with cold diethyl ether. The polymer was
then dried under vacuum. Proton NMR spectroscopic analysis
of the polymer 10a showed a conversion of 50-60% by
integration of the methyl doublet of alanine isoxazolidide
relative to the benzylic methylene protons of the polymer: 1H
NMR δ 7.50-7.21 (m, 16 H), 4.58 (bs, 2 H), 3.15 (bs, 1 H),
3.05 (bs, 1 H), 2.60 (bs, 1 H), 1.95 (bm, 1 H), 1.80 (bm, 1 H),
1.15 (bd, 3 H).
Gen er a l P r oced u r e for Cr oss-Cou p lin g to P olym er ic
Ar yl Ha lid es: Syn th esis of NCP S-Su p p or ted Isoxa zoli-
d id e 10b. A solution of polymer 7 (350 mg, 0.35 mmol) and
boronate 2 (241 mg, 0.47 mmol, 134 mol %) in DMF (10 mL)
containing aqueous 2 M Na2CO3 (588 µL, 1.18 mmol, 250 mol
%) was degassed for 10-15 min, treated with [PdCl2(dppf)]
(14 mg, 5 mol %), heated at 80 °C overnight, and then cooled
to room temperature. The polymer was precipitated by addi-
tion of excess MeOH and collected by decanting the solvent
away from the solid after placing the mixture in a centrifuge
for 3-5 min. The collected polymer was dissolved in a minimal
amount of CHCl3, precipitated with MeOH, and recollected
using a centrifuge as described. This process was repeated
three times, and the recovered polymer was dried under
vacuum, which provided 411 mg, (93%) of isoxazolidide 10b:
1H NMR δ 4.94 (bs, 2 H), 3.64 (bs, 1 H), 3.59 (bs, 2 H), 3.15
(bs, 1 H), 3.07 (bs, 1 H), 2.62 (bs, 1 H), 1.16 (bd, 3 H, J ) 6.2).
Mer r ifield r esin o isoxa zolid id e 10c was prepared using
the reaction conditions described for 10b, filtered, and washed
sequentially with 15 mL/g resin of the following solvents:
DMF, water, acetone, THF, MeOH, and Et2O. The resin was
dried under vacuum to give 10c, which was shown by 1H MAS
NMR spectroscopic analysis to be of 78% conversion by
integration of the methyl doublet of alanine isoxazolidide
relative to the benzylic methylene protons of the polymer: 1H
MAS NMR (300 MHz with nanoprobe) δ 4.90 (bs, 2 H), 3.60
(bm, 3 H), 3.15-3.00 (bm, 2 H), 2.60 (bs, 1 H), 1.15 (bs, 3 H).
Wa n g r esin o isoxa zolid id e 10d was prepared using the
reaction conditions described for 10b, isolated by filtration,
and washed sequentially with 15 mL/g resin of the following
solvents: DMF, water, acetone, THF, MeOH, and Et2O. The
resin was dried under vacuum to give 10d , which was
estimated to be of 70% conversion by cleavage of a 60 mg
sample (0.04 mmol, 0.72 mmol/g) using TFA (2 mL) in CH2Cl2
(2 mL), which gave 15 mg of N-(p-hydroxymethylphenyl-PhF)-
alanine isoxazolidide.35
filtrate was washed with brine, dried, and evaporated to
furnish polymer-bound aldehyde 1b (50 mg, 96%): 1H NMR δ
9.25 (bs, 1 H), 4.93 (bs, 2 H), 2.65 (bs, 1 H), 0.98 (bs, 3 H).
NCP S-Su p p or ted (1RS,2S)-1-P h en yl-2-N-(P h F )a m in o-
1-p r op a n ol 11b. A solution of alaninal 1b (106 mg, 0.11
mmol) in THF (6 mL) was cooled to -78 °C and treated with
a 1 M solution of PhMgBr (450 µL, 400 mol %) in THF. The
stirred clear solution was allowed to warm to -10 °C over 3 h
and quenched with MeOH (5 mL). The polymer was precipi-
tated by addition of excess MeOH and collected by decanting
the solvent away from the solid after placing the mixture in a
centrifuge for 3-5 min. The collected polymer was dissolved
in a minimal amount of CHCl3, precipitated with MeOH, and
recollected using a centrifuge as described. This process was
repeated three times, and the recovered polymer was dried
under vacuum, which provided amino alcohol 11b (111 mg,
85% yield): 1H NMR δ 4.93 (bs, 2 H), 4.11 (bs, 1 H), 2.41 (bs,
0.5 H), 2.28 (bs, 0.5 H), 0.57 (1.5 H), 0.44 (bs, 1.5 H).
(1RS, 2S)-N-(BOC)n or ep h ed r in es 14. A solution of poly-
mer 11b (100 mg, 0.08 mmol) in dichloromethane (2 mL) and
anisole (2 mL) was treated dropwise with TFA (950 µL), stirred
for 48 h at room temperature, and treated with H2O (5 mL).
The layers were separated, and the aqueous layer was
evaporated to a crude amino alcohol that was treated with
(BOC)2O (120 mol %) and Et3N (200 mol %) in dichloromethane
(1 mL). After being stirred for 20 h at room temperature, the
solution was evaporated to a residue that was chromato-
graphed using a gradient of 0-50% EtOAc in hexanes as
eluant. Evaporation of the collected fractions gave 12 mg of
N-protected norephedrine 14 (60%) as a 3:1 mixture of dia-
stereomers: 1H NMR δ 7.35-7.26 (m, 5 H), 4.86 (d, 0.3 H, J
) 2.9), 4.64 (bm, 0.5 H), 4.56 (d, 0.7 H, J ) 6.1), 4.03 (bm, 0.4
H), 3.88 (bm, 0.1 H), 1.47 (s, 6 H), 1.41 (s, 3 H), 1.08 (d, 0.8 H,
J ) 6.9), 1.00 (d, 2.2 H, J ) 6.9); HRMS calcd for C14H22NO3
[MH+] 252.1600, found 252.1607.
En a n tiom er ic P u r ity of Am in o Alcoh ols 14. A solution
of 14 (2 mg) in dichloromethane (500 µL) was treated with
TFA (500 µL) for 1 h at room temperature. The volatiles were
removed under vacuum, and the residue was treated with
GITC (3.7 mg, 120 mol %) and Et3N (1.3 µL, 120 mol %) in
dichloromethane (500 µL) at room temperature for 20 min. The
volatiles were removed under vacuum, and the ureas 15 were
dissolved in HPLC-grade methanol (1 mg/mL) and examined
by reversed-phase HPLC using H2O/MeOH/AcOH (51:48:1) as
eluant on a C18 column with a flow rate of 1.0 mL/min.37 The
limits of detection were determined by measuring the relative
integrations of the peaks for diastereomeric thioureas 15 from
the (1R,2S)- and (1S,2R)-norephedrines. Less than 1% of the
1S,2R isomer was detected in the HPLC trace of (1R,2S)-
thiourea 15.
9-Br om o-9-p h en ylflu or en yl P olystyr en e Resin . A sus-
pension of polystyrene (2.8 g, 27 mequiv, washed according to
the procedure described in ref 14) in cyclohexane (20 mL) was
treated with N,N,N′,N′-tetramethylethylenediamine (4 mL)
and stirred for 20 min at room temperature. A 2.5 M solution
of n-butyllithium (13.5 mL, 33.8 mmol) in hexanes was added,
and the mixture was heated at 65 °C for 4.5 h. After cooling
to room temperature, removal of the solvents by cannula, and
washing of the resin with cyclohexane (2 × 10 mL), the resin
was swollen in THF (15 mL) at 0 °C and treated with a solution
of fluorenone (2.02 g, 11.2 mmol, 200 mol %) in THF (10 mL).
After 10 min, the cooling bath was removed, and the suspen-
sion was left to stir at room temperature overnight, quenched
with water (10 mL), and stirred for 5 min. The resin was
filtered and washed with 15 mL/g of the following solutions:
MeOH, THF, acetone, 2:1 THF/H2O, Et2O, H2O, THF, MeOH,
and Et2O. The resin was dried overnight under vacuum at 55
NCP S-Su p p or ted (2S)-N-(P h F )a la n in a l 1b. A solution
of polymer-supported isoxazolidide 10b (60 mg, 0.05 mmol) in
THF (6 mL) was cooled to 0 °C and treated with a 1.5 M
solution of LiAlH4 (50 µL, 0.075 mmol, 150 mol %) in THF.
The clear solution was stirred for 25 min at 0 °C, quenched
by the addition of EtOAc (2 mL) followed by water (1 mL),
and filtered through a plug of sodium bicarbonate on Celite.
The filter cake was washed thoroughly with EtOAc, and the
°C to provide 3.54 g of a yellow resin (PA-FTIR: 3548 cm-1
)
containing 1.15 mmol of alcohol per gram of resin as deter-
mined by mass increase. A suspension of resin (1.0 g, 1.15
mmol) in benzene (15 mL) was treated with acetyl bromide
(444 µL, 6 mmol, 522 mol %) and heated at a reflux overnight.
The solution was cooled, and the resin was filtered, washed
thoroughly with Et2O, and dried overnight under vacuum at
55 °C to furnish 1.08 g of a yellow resin with a loading of 1

Synthesis of Enantiopure Norephedrines on Solid Support
J . Org. Chem., Vol. 64, No. 7, 1999 2493
mmol/g resin as ascertained by mass increase. Spectroscopic
analysis by PA-FTIR indicated complete disappearance of the
diluted with water (5 mL). The layers were separated, and the
aqueous layer was evaporated to a residue. A solution of the
residue in MeOH (1.2 mL) was treated with Et3N (13 µL) and
(BOC)2O (12 mg, 120 mol %), stirred overnight at room
temperature, and evaporated to a residue that was chromato-
graphed using a 0-50% gradient of EtOAc in hexanes.
Evaporation of the collected fractions gave 14 (15 mg, 66%)
as a 1:1 diastereomeric mixture that exhibited the same
characteristics as material prepared on the NCPS-polymer.
alcohol band at 3548 cm-1
.
Solu tion -P h a se Syn th esis of N-(BOC)-n or ep h ed r in es.
A solution of (2S)-N-(BrPhF)alanine isoxazolidide (5, 463 mg,
1 mmol) in THF (10 mL) at 0 °C was treated with a solution
of LiAlH4 (730 µL, 1.1 mmol, 110 mol %, 1.5 M in THF), stirred
for 20 min at 0 °C, quenched with EtOAc (2 mL) and water (2
mL), and filtered through a plug of sodium bicarbonate on
Celite. The filtrate was diluted with EtOAc (10 mL), washed
with brine (5 mL), dried, and evaporated to a solid that was
dissolved in THF (10 mL), cooled to -78 °C, and treated with
a 1 M solution of phenylmagnesium bromide (5 mL, 500 mol
%) in THF, stirred for 1.5 h at -78 °C, warmed to room
temperature over 30 min, quenched with water (2 mL), and
diluted with EtOAc (15 mL). The organic layer was washed
with brine (5 mL), dried, and evaporated to a residue that was
chromatographed using a gradient of 0-30% EtOAc in hexanes
as eluant. Evaporation of the collected fractions gave a 1:1
diastereomeric mixture of N-(BrPhF)norephedrines 12 (448
mg, 95% from isoxazolidide 5) as an oil: 1H NMR δ 7.75-6.86
(m, 17 H), 4.21 (d, 0.5 H, J ) 3.3), 4.13 (d, 0.5 H, J ) 8.4),
3.37 (bs, 1 H), 2.40 (m, 0.5 H, J ) 3.3, 6.7), 2.30 (dq, 0.5 H, J
) 1.9, 6.4), 0.56 (d, 1.5 H, J ) 6.7), 0.44 (d, 1.5 H, J ) 6.4);
HRMS calcd for C28H25NO79Br 470.1119, found 470.1132.
A solution of N-(BrPhF)norephedrines 12 (42.3 mg, 0.1
mmol) in CH2Cl2 (1 mL) and anisole (1 mL) was treated with
TFA (900 µL), stirred at room temperature overnight, and
Ack n ow led gm en t. This research was supported in
part by the Natural Sciences and Engineering Research
Council (NSERC) of Canada and the Ministe`re de
l’EÄ ducation du Que´bec. F.G. thanks NSERC for a PGSB
Scholarship (1997-99) and FCAR for a M.Sc. Scholar-
ship (1996-97). The authors thank Professor Todd
Marder at the University of Durham, as well as Merck
Frosst Canada and Sigma-Aldrich Chemicals, for gener-
ous gifts of diboron pinacol ester.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
3, 4, 6, 7, 10a -c, 1b, 11b, and 14 and HPLC trace of thioureas
15. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O982413C