A modular route to nonracemic cyclo-NOBINs. Preparation of the parent ligand for homo- and heterogeneous catalysis

Article abstract of DOI:10.1016/j.tet.2004.02.065

A sequence which combines a nonracemic tether, a naphthyl diol, and an aminonaphthol has been developed leading to the new ligand cyclo-NOBIN, which can easily be mounted onto polystyrene. Opportunities for extending the route to substituted cyclo-NOBINs are also discussed.

Full text of DOI:10.1016/j.tet.2004.02.065

Tetrahedron 60 (2004) 4443–4449
A modular route to nonracemic cyclo-NOBINs. Preparation of the
parent ligand for homo- and heterogeneous catalysis
*
Bruce H. Lipshutz, D. J. Buzard, Christina Olsson and Kevin Noson
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106-9510, USA
Received 22 January 2004; revised 17 February 2004; accepted 23 February 2004
Abstract—A sequence which combines a nonracemic tether, a naphthyl diol, and an aminonaphthol has been developed leading to the new
ligand cyclo-NOBIN, which can easily be mounted onto polystyrene. Opportunities for extending the route to substituted cyclo-NOBINs are
also discussed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Since its introduction by Kocovsky in 1991,1 the
binaphthylic ligand NOBIN (1) has found increasing
usage in synthesis.2 Replacement of an OH residue in
nonracemic BINOL with an NH2 group, along with the
inherent bias of the binaphthyl array, provide many
opportunities for designing new organometallic complexes,
in particular new catalysts for effecting selected asymmetric
transformations. As in the case of BINOL, it is likely that
substitution at the 3 and/or 30-sites may on occasion increase
significantly the level of steric discrimination and hence,
improve enantioselectivities.3 Although the basic NOBIN
skeleton is readily available in nonracemic form,4 such is
not the case for substituted analogues. Moreover, we are
unaware of any reports on the use of NOBIN in the context
Scheme 1. Anticipated coupling sequence with modules 4 and 5.
2. Results and discussion
From previous work on the preparation of cyclo-BINOLs,3,6
of heterogeneous catalysis, perhaps an obvious goal given
the increasing importance of such processes.5 In this
contribution, we describe our preparation of the novel
ligand cyclo-NOBIN 2 via a modular approach6 which
offers considerable flexibility for realizing both substituted
derivatives7 and a polymer-bound version.3
we anticipated that aminonaphthalene 4 could be attached
via base-induced substitution to nonracemic tether 3,
followed by Mitsunobu coupling with 5, thereby in two
steps arriving at fully joined modules (Scheme 1). Amine 4
was envisioned as deriving from naphthol 5 by Pd-catalyzed
amination of sulfonate 6 (Scheme 2).8 Thus, 5 was
Keywords: Binaphthyls; NOBINs; Ligands; Asymmetric catalysis; Heterogeneous catalysis.
*
Corresponding author. Tel.: þ1-805-893-2521; fax: þ1-805-893-8265; e-mail address: lipshutz@chem.ucsb.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.065

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B. H. Lipshutz et al. / Tetrahedron 60 (2004) 4443–4449
smoothly converted to its acetonide 8 (92%) prior to LAH
reduction of the diester to the corresponding primary diol
(95%). Monotosylation, as expected, was not selective
(43%) to tether 3, which nonetheless allows for recycling of
unconsumed diol setting the stage for subsequent attach-
ment of modules 4 and 5. The 4-step sequence from the
diester of 7 could be carried out without purification of
intermediates in an overall yield of 33%.
Scheme 2. Preparation of the amine-containing module 4.
Displacement of the tosylate in 3 with naphthol 5 gave the
initial adduct which was directly treated crude with tosyl
chloride in CH2Cl2/Et3N containing catalytic DMAP
(Scheme 4). Isolation afforded tosylate 9 after chromatog-
raphy. All attempts according to the sequence in Scheme 1
involving a Mitsunobu coupling were low-yielding and thus
were abandoned in favor of a second tosylate displacement.
Naphthol 4 was then used to couple with intermediate 9,
which took place in high yield to give 10. Simultaneous O
and N-debenzylation with H2 and Pd/C in warm (60 8C)
THF led to the cyclo-NOBIN seco dinaphthyl 11. Oxidation
of 11 with excess CuCl2 (4 equiv.) in MeOH at rt in the
presence of racemic a-methylbenzylamine gave a mixture
of diastereomers (5.9:1).1,3,6,9 The ratio of diastereomers
appeared to vary as a function of added amine in solution.
For example, benzylamine afforded a 2.3:1 mix of R/S
isomers (81% isolated). Ratios could be easily determined
by 400 MHz proton NMR, Other amines, such as t-BuNH2
and diphenylmethylamine were tested with CuCl2 in
alcoholic solvents and in mixtures of DMF and MeOH,
but ratios were not as high as those observed using racemic
a-methylbenzylamine in straight MeOH. Experiments
employing pure enantiomers of this amine did not affect
the de, nor yield, of the couplings. Similar results were
achieved when scaling up the reaction from the 0.05 to
1.00 mmol level. Pure diastereomers could be obtained
by traditional flash chromatography. The major isomer
was unequivocally established as (R)-cyclo-NOBIN
based on comparison of its CD spectrum with authentic
(R)-NOBIN.10
converted to nonaflate coupling partner 6 with perfluoro-
butanesulfonyl fluoride, NfF (NaH, THF, 0 8C; 55%), which
in the presence of benzylamine underwent smooth
Pd(0)-catalyzed coupling to give 4 in good overall yield
(75%) after treatment of the crude product with TBAF in
THF at room temperature.
A newly devised, streamlined route to gram quantities of
tether 3 was also developed (Scheme 3). Employing the
same trans-b-hydromuconic acid 7 as educt used pre-
viously, diesterification led to the olefinic diester (97%),
which was subjected to Sharpless asymmetric dihydroxyl-
ation with AD-mix-b at 0 8C under buffered conditions.
Selection of both the isopropyl esters as well as modified
dihydroxylation conditions was crucial for this sequence.
Use of methyl esters and unbuffered media encourages the
initial diol to react further, leading to undesired hydroxy-
butyryl lactone formation. The desired diol (78%), obtained
in virtually optically pure form (bis-Mosher ester) was
With ligands 12 in hand, attachment of 12a to polystyrene
(PS) was accomplished by initial hydrolysis of the acetonide
to afford diol 13. Direct acetalization of 13 with formylated
1% crosslinked polystyrene beads 143 led to polystyrene-
supported R-cyclo-NOBIN 15 (Scheme 5). Loadings in the
0.5–0.6 mmol/g range were typical.
Scheme 3. A new, highly efficient route to tether 3.
Scheme 4. A modular sequence to the parent cyclo-NOBINs 12.

B. H. Lipshutz et al. / Tetrahedron 60 (2004) 4443–4449
4445
Scheme 5. Mounting of the parent cyclo-NOBIN 12 onto polystyrene.
Scheme 6. A modular route to a 3-substituted cyclo-NOBIN 19.
Lastly, we have tested the potential for this sequence to
accommodate a substituted naphthyl module, ultimately
aiming for a new series of 3- and/or 30-mono- or
disubstituted cyclo-NOBINs. As a first representative case,
readily available naphthyl bromide 169 was manipulated in
the usual fashion to produce boronic acid 17, which
underwent Suzuki coupling with iodobenzene to give the
corresponding biaryl (Scheme 6). Exposure of the crude
product to TBAF gave naphthol 18 in 81% yield over the
three steps. Using this module in the sequence in place of
5 (cf. Scheme 4), the unsymmetrically substituted cyclo-
NOBIN 19 could be realized as a mix of diastereomers.
Several additional examples of these ligands bearing a
variety of substituents at the key sites ortho to oxygen (i.e.,
the 3-position) and/or nitrogen (i.e., the 30-position), as well
as selected examples for use in asymmetric catalysis (e.g.,
modified Carreira aldols)11 will be reported in due course.
4. Experimental
4.1. General
Reactions were performed in either oven-dried or flame-
dried glassware under an argon atmosphere with Teflon
coated stir bars and dry septa. THF, Et2O, and toluene were
freshly distilled from Na/benzophenone ketyl prior to use.
CH2Cl2 and DMF were freshly distilled from CaH2 prior
to use. All commercially available reagents were distilled
from CaH2, molecular sieves, or from themselves (under
reduced pressure) before use. Column chromatography was
performed using Davisil Grade 633 Type 60A silica gel.
All columns were prepared and run with the eluent ‘slurry’
loading method. Columns that were ‘doped’ with NEt3
were done so using 1-2% in the eluent ‘slurry’ and not
the eluting solvent. TLC analysis was performed on
commercial Kieselgel 60 F254 silica gel glass plates and
visualized with a UV lamp. p-Anisaldehyde (PA) or
ninhydrin were used to stain the plates and developed
using a hot plate.
3. Summary and conclusions
The first example of a modified nonracemic NOBIN ligand,
a cyclo-NOBIN, is reported. The route described is
particularly flexible in that it allows for introduction of
various substituents onto the individual modules at the key
(3- and 300-sites) that are to be built into the biaryl. The
potential for attachment to a solid support, such as
polystyrene has also been demonstrated for the parent
system.
NMR spectra were obtained on Varian Inova systems using
CDCl3, D2O, or deuterated acetone solvents with proton
and carbon resonance at 400 and 100 MHz, respectively.
All NMR spectra were referenced relative to TMS
(d 0.00) or the solvent used to obtain spectra (e.g.,
1
CDCl3: d 7.27 for H; d 77.23 for 13C) and are reported in
ppm.

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B. H. Lipshutz et al. / Tetrahedron 60 (2004) 4443–4449
1
FTIR spectra were obtained on an ATI Mattson Infinity
series spectrometer or a Jasco FT/IR-430 series spectro-
meter neat on NaCl plates or KBr pellets, and are reported in
cm21. Dr. James Pavlovich acquired low-resolution and
high-resolution mass spectral data on a VF Autospec, PE
Sciex QStar quadrapole/time-of-flight tandem mass spectro-
meter, or an analytical VG-70-250 HF instrument. A
Fisher–Johns melting point apparatus Model 2572A was
used to acquire all melting points that are all uncorrected.
Optical rotations were taken on a Perkin–Elmer 241MC
polarimeter (25 8C, 1 cm3 cell) or a Perkin–Elmer 341
polarimeter (25 8C, 1 cm3 cell cell). All reagents were
purchased from Aldrich, Alfa Aesar, Lancaster, Acros,
Fisher, or Strem and were purified prior to use where
applicable. All alkyllithium reagents were obtained from
Aldrich and titrated according to literature procedures prior
to use.12 All chromatography and general use solvents were
purchased from Fisher in 4 L bottles or 20 L drums and used
as received.
solid. H NMR (400 MHz, CDCl3) d 5.05 (sept, J¼6.4 Hz,
2H), 3.96 (m, 2H), 3.26 (d, J¼5.2 Hz, 2H), 2.65–2.51 (m,
4H), 1.26 (d, J¼6.4 Hz, 12H); 13C NMR (100 MHz, CDCl3)
d 172.4, 70.1, 68.6, 38.4, 22.0.
4.1.3. Diisopropyl (3R,4R)-3,4-isopropylidene-hexane-
1,6-dioate (8). To a flame dried 500 mL RBF was added
TsOH·H2O (309 mg, 1.62 mmol, 0.1 equiv.) as a solid
and then 2,2-dimethoxypropane (ca. 160 mL) was added
followed by addition of diisopropyl (3R,4R)-3,4-dihydroxy-
hexane-1,6-dioate (ca. 8.5 g, 32.4 mmol) as a solid. Hot
oven-dried molecular sieves (excess) were added and the
reaction was allowed to stand until all starting material was
consumed by TLC. The reaction was then filtered through
a pad of Celite and concentrated in vacuo yielding the
corresponding acetal (9.8 g, .99%) as a yellow oil.
Rf¼0.81 (60% EtOAc/hexanes, visualization with p-anisal-
dehyde stain).3 1H NMR (400 MHz, CDCl3) d 5.04 (sept,
J¼6.2 Hz, 2H), 4.16 (m, 2H), 2.62 (m, 4H), 1.40 (s, 6H),
1.25 (dd, J¼6.2, 2.9 Hz, 12H); 13C NMR (100 MHz,
CDCl3) d 170.2, 109.2, 76.9, 68.3, 38.5, 27.3, 22.0. IR
(neat): 3451, 2984, 2938, 1736, 1469, 1457, 1375, 1338,
1329, 1301, 1276, 1247, 1198, 1175, 1148, 1107, 1064, 961,
913, 848, 825 cm21; CIMS, m/z (rel int): 303(17), 245(70),
203(68), 189(11), 161(100), 143(49), 99(11), 59(78),
55(10), 45(14), 43(99); HRCIMS, m/z calcd for
C15H26O6þH)þ: 303.1808, found 303.1812.
4.1.4. (3R,4R)-O-Isopropylidenehexane-1,6-diol.9 To a
flame dried 500 mL RBF equipped with a magnetic stir
bar was added lithium aluminum hydride (15 g, 330 mmol,
10 equiv.) as a grey solid. THF (50 mL) was added and the
slurry was stirred at rt. Diisopropyl (3R,4R)-3,4-isopropyl-
idenehexane-1,6-dioate (10 g, 33 mmol) was dissolved in
THF (50 mL) and added to the RBF via cannula followed by
rinsing with THF (10 mL). The reaction was heated to reflux
and stirred overnight. Quenching was accomplished by
cooling the reaction flask to 0 8C and addition of H2O
(12 mL) and 15% aq. NaOH (3 mL) followed by dilution
with EtOAc (excess). The salts were then filtered through a
pad of Celite and the solvent was concentrated in vacuo to
afford the diol (4.9 g, 78%). Rf¼0.08 (EtOAc), as a yellow
oil (used without purification). 1H NMR (400 MHz, CDCl3)
d 3.88–3.81 (m, 6H), 2.43 (br s, 2H), 1.90–1.73 (m, 4H),
1.41 (s, 6H); 13C NMR (100 MHz, CDCl3) d 109.0, 80.1,
60.8, 34.5, 27.4.
4.1.1. Diisopropyl 3-hexen-1,6-dioate. To a flame dried
500 mL RBF equipped with a magnetic stir bar was added
2-isopropanol (ca. 250 mL) and the flask was cooled to 0 8C.
Acetyl chloride (25 mL, 346.9 mmol, 5 equiv.) was added
slowly in portions (CAUTION: exotherm!) and the solution
was allowed to stir at 0 8C for ca. 5 min. Then trans-b-
hydromuconic acid (10 g, 69.4 mmol) was added as a solid
as fast as possible and the reaction was heated, following
attachment of a reflux condenser equipped with a CaCl2
drying tube, overnight. The reaction was then cooled and
concentrated in vacuo and diluted with ethyl acetate
(250 mL) and washed with saturated aqueous NaHCO3
(2£10 mL) and brine (10 mL), then dried over anhydrous
MgSO4. Concentration in vacuo produced the diester
(15.5 g, 98%) as a white solid. 1H NMR (400 MHz,
CDCl3) d 5.69 (tt, J¼4.6, 1.6 Hz, 2H), 5.00 (sept, J¼
6.2 Hz, 2H), 3.05 (dd, J¼4.6, 1.6 Hz, 4H), 1.24 (d, J¼
6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 171.3, 126.1,
68.1, 38.4, 21.9.
4.1.2. Diisopropyl (3R,4R)-3,4-dihydroxyhexane-1,6-dio-
ate. To a 1 L RBF equipped with a magnetic stir bar was
added AD-mix-b (71.5 g, 1.4 g (mmol SM)21), methane-
sulfonamide (4.8 g, 50.8 mmol, 1 equiv.), and NaHCO3
(12.8 g, 152.4 mmol, 3 equiv.) as solids. Then H2O
(340 mL) and t-BuOH (340 mL) were added and this
mixture was allowed to stir at rt for 15 min. and was then
cooled to 0 8C. Diisopropyl 3-hexen-1,6-dioate (11.6 g,
50.8 mmol) was then added as a solid and the reaction
stirred overnight at 0 8C. Upon completion by TLC, Na2SO3
(77 g, 609.6 mmol, 12 equiv.) was added and allowed to stir
for 10 min. at 0 8C then the reaction was warmed to rt and
diluted with EtOAc (100 mL), H2O (25 mL), and EtOH
(3 mL) and stirred for 1 h. The organic layer was decanted
off and washed with brine (10 mL). The aqueous layer was
added back to the flask and the reaction mixture extracted
with EtOAc (100 mL). The organic layer was washed with
brine (10 mL). H2O (ca. 150 mL) was added to dissolve the
salts and was then extracted with EtOAc (4£100 mL). All
organic layers were combined and dried over anhydrous
Na2SO4. Flash chromatography (70% ether/hexanes).
Rf¼0.18 (50% ether/hexane, visualization with p-anis-
aldehyde stain), afforded the diol (8.53 g, 64%) as a white
4.1.5. Toluene-4-sulfonic acid 2-[5-(2-hydroxyethyl)-2,2-
dimethyl-[1,3]-dioxolan-4-yl] ethyl ester (3).6 To a flame
dried 250 mL RBF equipped with a magnetic stir bar was
added tosyl chloride (1.77 g, 9.15 mmol, 1.05 equiv.),
DMAP (135 mg, 0.87 mmol, 0.1 equiv.) as solids followed
by (3R,4R)-O-isopropylidene-hexane-1,6-diol (1.68 g, 8.71
mmol) and CH2Cl2 (87 mL). The reaction vessel was cooled
to 0 8C and NEt3 (1.5 mL, 10.45 mmol, 1.2 equiv.) was
added and the reaction was allowed to stir overnight. The
reaction was followed by TLC and upon completion was
concentrated in vacuo. After flash chromatography (50%
EtOAc/hexanes) the corresponding mono-tosylated product
(1.51 g, 50%) was isolated as a clear oil. Rf¼0.27 (50%
EtOAc/hexanes).3 1H NMR (400 MHz, CDCl3) d 7.80 (m,
2H), 7.36 (m, 2H), 4.25–4.12 (m, 2H), 3.79–3.67 (m, 4H),
2.65 (br s, 1H), 2.45 (s, 3H), 2.01–1.67 (m, 4H), 1.32 (s, 6H).

B. H. Lipshutz et al. / Tetrahedron 60 (2004) 4443–4449
4447
4.1.6. 7-Benzyloxy-2-naphthol (5). To a flame dried 1 L
RBF equipped with a magnetic stir bar was added
2,7-dihydroxynaphthalene (11.2 g, 70.0 mmol), K2CO3
(12.1 g, 84 mmol, 1.2 equiv.), and DMF (ca. 350 mL). To
the resulting reaction mixture was added benzyl chloride
(8.4 mL, 73.5 mmol, 1.05 equiv.) at rt. The reaction vessel
was then warmed to 65 8C and let stir overnight. Upon
completion by TLC, the reaction was filtered through Celite
to remove residual solids and the reaction solvent
evaporated under reduced pressure. The resulting oil was
recrystallized from MeOH and the solids were heated in
boiling water and filtered hot. Recrystallizations from
MeOH/H2O gave the corresponding monobenzylated
material (7.27 g, 42%) as a pink solid.3 1H NMR
(400 MHz, CDCl3) d 7.68–7.66 (m, 2H), 7.49–7.47 (m,
2H), 7.42–7.39 (m, 2H), 7.36–7.32 (m, 1H), 7.09–7.06 (m,
2H), 7.04 (d, J¼2.6 Hz, 1H), 6.94 (dd, J¼8.8, 2.6 Hz, 1H),
5.16 (s, 2H), 4.86 (s, 1H).
poured into H2O (100 mL) and the aqueous phase extracted
with EtOAc (3£100 mL). The organic layer was dried over
anhydrous Na2SO4. Flash chromatography (40% EtOAc/
hexane, 1% NEt3 dope) afforded the corresponding naphthol
(5.55 g, 75%) as an orange solid. Rf¼0.46 (40% EtOAc/
1
hexane. H NMR (400 MHz, CDCl3) d 7.55 (d, J¼8.6 Hz,
1H), 7.54 (d, J¼8.6 Hz, 1H), 7.41–7.24 (m, 5H), 6.87 (d,
J¼2.6 Hz, 1H), 6.79 (dd, J¼8.6, 2.6 Hz, 1H), 6.74 (dd,
J¼8.6, 2.0 Hz, 1H), 6.65 (d, J¼2.0 Hz, 1H), 4.74 (br s, 1H),
4.40 (s, 2H), 4.16 (br s, 1H); 13C NMR (100 MHz, CDCl3) d
154.4, 146.5, 139.3, 136.7, 129.7, 129.1, 128.9, 127.8,
127.5, 123.1, 115.7, 113.9, 108.2, 103.6, 48.5.
4.1.9. Toluene-4-sulfonic acid 2-{5-[2-(7-benzyloxy-
naphthalen-2-yloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-
4-yl} ethyl ester (9). To a flame dried 10 mL RBF equipped
with a magnetic stir bar was added toluene-4-sulfonic acid
2-[5-(2-hydroxyethyl)-2,2-dimethyl-[1,3]-dioxolan-4-yl]
ethyl ester (353 mg, 1.0 mmol) as a neat oil, 7-benzyloxy-2-
naphthol (274 mg, 1.09 mmol, 1.09 equiv.) as a solid, and
Cs2CO3 (420 mg, 1.30 mmol, 1.3 equiv.) as a solid. DMF
(2 mL) was then added and the heterogeneous reaction
mixture was heated to ca. 65 8C and allowed to stir
overnight. Upon completion by TLC (18 h) the reaction
was diluted with EtOAc and filtered using a Buchner funnel.
The solvent was concentrated in vacuo, redissolved in
toluene (10 mL), and concentrated (repeat 3 times) in vacuo
and put on the high vacuum for 2 h. Tosyl chloride (427 mg,
2.2 mmol, 2.2 equiv.) and DMAP (16 mg, 0.1 mmol,
0.1 equiv.) were added as solids and dissolved in CH2Cl2
(2 mL) and cooled to 0 8C. NEt3 (0.31 mL, 2.2 mmol,
2.2 equiv.) was added and the reaction was monitored by
TLC. Upon completion (4 h) the reaction was concentrated
in vacuo. Flash chromatography (20% EtOAc/hexanes)
afforded the corresponding tosylated alcohol derivative
(425.4 mg, 74%) as an orangish oil. Rf¼0.24 (20% EtOAc/
4.1.7. 2-(1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-oxysulfo-
nyl)-7-(tert-butyldimethylsilyl)-naphthalene (6). To a
flame dried 500 mL RBF equipped with a magnetic stir
bar was added 7-(tert-butyldimethylsilyl)-2-naphthol
(7.88 g, 28.7 mmol) in THF (50 mL) via cannula. The
dissolved naphthol was cooled to 0 8C and NaH (1.6 g,
40.2 mmol, 1.4 equiv.) was added as a solid (CAUTION:
gas evolution!) and allowed to stir for 30 min. Perfluoro-
butane sulfonyl fluoride (7.2 mL, 40.2 mmol, 1.4 equiv.)
was added via syringe (CAUTION: foaming!) and the
reaction was allowed to stir overnight. Upon completion by
TLC the reaction was poured into brine (200 mL) and
extracted with ether (3£250 mL). The organic layer was
collected and dried over anhydrous Na2SO4. Flash chroma-
tography (hexane/1% ether to 2% ether/hexane gradient)
afforded the corresponding nonaflate (8.88 g, 55%) as a
light yellow oil. Rf¼0.62 (2% ether/hexane). 1H NMR
(400 MHz, CDCl3) d 7.82 (d, J¼9.2 Hz, 1H), 7.76 (d, J¼
8.8 Hz, 1H), 7.60 (d, J¼2.4 Hz, 1H), 7.23 (dd, J¼9.2,
2.4 Hz, 1H), 7.20 (d, J¼2.2 Hz, 1H), 7.14 (dd, J¼8.8,
2.2 Hz, 1H), 1.02 (s, 9H), 0.26 (s, 6H); 13C NMR (100 MHz,
CDCl3) d 155.3, 148.1, 135.1, 130.5, 129.7, 128.3, 123.7,
118.2, 117.5, 115.2. 25.8, 24.1.
1
hexanes). H NMR (400 MHz, CDCl3) d 7.78 (app d, J¼
8.0 Hz, 2H), 7.66 (d, J¼9.0 Hz, 1H), 7.65 (d, J¼8.8 Hz,
1H), 7.48 (app d, J¼7.6 Hz, 2H), 7.42–7.27 (m, 5H), 7.12
(d, J¼2.4 Hz, 1H), 7.08 (dd, J¼8.8, 2.4 Hz, 1H), 7.04 (d,
J¼2.6 Hz, 1H), 6.98 (dd, J¼9.0, 2.6 Hz, 1H), 5.16 (s, 2H),
4.25–4.11 (m, 4H), 3.87–3.75 (m, 2H), 2.40 (s, 3H), 2.06–
1.78 (m, 4H), 1.34 (s, 3H), 1.33 (s, 3H). EIMS m/z (rel int):
576(14), 97(23), 91(100), 43(9); HREIMS, m/z calcd for
C33H36O7S: 576.2182, found 576.2164.
4.1.8. 7-Benzylamino-2-naphthol (4). To a flame dried 2 L
RBF equipped with a magnetic stir bar was added Pd(dba)2
(520 mg, 0.895 mmol, 0.03 equiv.), NaO-t-Bu (4.4 g,
44.75 mmol, 1.5 equiv.), and racemic BINAP (940 mg,
1.50 mmol, 0.05 equiv.) as solids in a glove box. Toluene
(500 mL) was added and 2-(1,1,2,2,3,3,4,4,4-nonafluoro-
butane-1-oxysulfonyl)-7-(tert-butyldimethylsilyl)-naphtha-
lene (16.6 g, 29.83 mmol), dissolved in toluene (500 mL) in
a separate flame dried 1 L RBF, was transferred to the 2 L
RBF via cannula. Benzylamine (5.0 mL, 44.75 mmol,
1.5 equiv.) was added via syringe and the reaction was
heated to 95–100 8C and the dark wine-red colored
homogeneous reaction mixture was allowed to stir over-
night. Upon completion by TLC the wine-red heterogeneous
reaction mixture was cooled to rt and filtered through a pad
of Celite with copious EtOAc washings and the solvent was
concentrated in vacuo. The crude material was redissolved
in THF (ca. 300 mL) and TBAF (1.0 M in THF) (60 mL,
60 mmol, 2.0 equiv.) was added via syringe and the reaction
was monitored by TLC. Upon completion, the reaction was
4.1.10. Benzyl-[7-(2-{5-[2-(7-benzyloxynaphthalen-2-
yloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-yl}-ethoxy)-
naphthalen-2-yl]-amine (10). To a flame dried 25 mL RBF
equipped with a magnetic stir bar was added toluene-4-
sulfonic acid 2-{5-[2-(7-benzyloxynaphthalen-2-yloxy)-
ethyl]-2,2-dimethyl-[1,3]dioxolan-4-yl} ethyl ester (2.93 g,
5.09 mmol), 7-benzylamino-2-naphthol (1.55 g, 6.11 mmol,
1.2 equiv.), and DMF (10 mL). Then Cs2CO3 (2.06 g,
6.11 mmol, 1.2 equiv.) was added as a solid as fast as
possible. The resulting heterogeneous mixture was warmed
to 65 8C and stirred until complete by TLC (24 h). The
reaction was dumped into H2O (100 mL) and extracted with
EtOAc (5£50 mL). The organic layer was collected and
concentrated in vacuo. Flash chromatography afforded the
corresponding product (3.18 g, 95%) as a tan foam. Rf¼0.49
(50% ether/hexanes). 1H NMR (400 MHz, CDCl3) d 7.65 (d,
J¼8.8 Hz, 1H), 7.63 (d, J¼9.2 Hz, 1H), 7.54 (d, J¼8.8 Hz,

4448
B. H. Lipshutz et al. / Tetrahedron 60 (2004) 4443–4449
2H), 7.48–7.28 (m, 10H), 7.09–7.07 (m, 2H), 7.05 (d, J¼
2.4 Hz, 1H), 6.99 (dd, J¼8.8, 2.4 Hz, 1H), 6.93 (d, J¼
2.4 Hz, 1H), 6.86 (dd, J¼8.8, 2.4 Hz, 1H), 6.76 (dd, J¼8.8,
2.4 Hz, 1H), 6.70 (d, J¼2.4 Hz, 1H), 5.14 (s, 2H), 4.40 (s,
2H), 4.29–4.01 (m, 6H), 2.25–2.04 (m, 4H), 1.42 (s, 6H).
EIMS, m/z (rel int) 654(21), 653(47), 97(15), 91(100);
HREIMS, m/z calcd for C43H43NO5: 653.3141, found
653.3162.
108.7, 105.9, 105.4, 76.5, 76.4, 63.8, 63.7, 32.6, 27.3. EIMS,
m/z (rel int): 472(31), 471(100), 317(17), 97(15), 59(11),
43(31); HREIMS, m/z calcd for C29H29NO5: 471.2046,
found 471.2040.
4.1.13. Polymer supported (R)-cyclo-NOBIN (15). To a
5 mL CV was added (R)-cyclo-NOBIN (331 mg, 0.7 mmol).
THF (1.8 mL), H2O (1.8 mL), and conc. HCl (ca. 10 drops)
were added and the CV was fitted with a yellow-cap and
allowed to stir overnight. Upon completion by TLC (40%
EtOAc/hexanes; ca. 14.5 h), the reaction was poured into
sat. aq. NaHCO3 (ca. 10 mL) and extracted with EtOAc
(5£10 mL). The organic layer was collected and concen-
trated in vacuo followed by azeotropically drying with
toluene (3£20 mL) and high vacuum overnight. Poly-
styrene-1% cross-linked divinylbenzene supported alde-
hyde (505.8 mg, 1 mmol/g) and p-toluenesulfonic acid
monohydrate (26.9 mg, 0.14 mmol) were added as solids
followed by toluene (10 mL). The reaction was set up with a
Dean Stark trap and heated to 130–135 8C where it was
allowed to stir for 24 h. After cooling to rt, addition of sat.
aq. NaHCO3 (ca. 10 drops) and filtration through a Buchner
funnel with solvent washes (EtOAc, CH2Cl2, ether, THF,
H2O, EtOH; ca. 20 mL each) afforded polymer-bound
cyclo-NOBIN (new polymer weight¼632.9 mg corresponds
to 0.675 mmol/g), after drying under high vacuum over-
night; IR (KBr pellet) 3491, 3387, 3024, 2917, 2347, 1944,
4.1.11. 7-(-2-{5-[2-(7-Aminonaphthalen-2-yloxy)-ethyl]-
2,2-dimethyl-[1,3]dioxolan-4-yl}-ethoxy)-naphthalen-2-
ol (11). To a flame dried 100 mL RBF equipped with a
magnetic stir bar was added benzyl-[7-(2-{5-[2-(7-benzyl-
oxynaphthalen-2-yloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-
4-yl}-ethoxy)-naphthalen-2-yl]-amine (3.17 g, 4.84 mmol)
and 10%-Pd/C (1.3 g, 1.21 mmol, 25 mol% Pd) as solids.
THF (50 mL) was added and the solution was purged well
with H2. The reaction flask was then equipped with a reflux
condenser and was warmed to 70 8C (bath temperature, not
reflux). Upon completion by TLC (52 h) the reaction was
cooled to room temperature and purged with Ar for 15 min.
The reaction was then filtered through a pad of Celite and
washed with copious amounts of EtOAc (ca. 250 mL total
volume of solvent). The solvent was then concentrated
in vacuo and azeotropically dried with toluene (25 mL)
followed by high vacuum overnight. The corresponding
aminonaphthol (2.24 g, 98%) was isolated as an off-white
solid. Rf¼0.39 (40% EtOAc/hexanes). 1H NMR (400 MHz,
CDCl3) d 8.55 (s, 1H), 7.66 (d, J¼8.8 Hz, 1H), 7.65 (d,
J¼9.2 Hz, 1H), 7.53 (d, J¼8.8 Hz, 1H), 7.51 (d, J¼8.8 Hz,
1H), 7.11 (m, 2H), 6.98–6.93 (m, 3H), 6.85 (app s, 1H),
6.82 (m, 1H), 6.79 (d, J¼2.4 Hz, 1H), 4.83 (s, 2H), 4.27–
4.04 (m, 6H), 2.23–2.04 (m, 4H), 1.37 (s, 6H). EIMS, m/z
(rel int): 473(10), 92(45), 91(100), 65(10), 56(14), 44(30),
43(27); HREIMS, m/z calcd for C29H31NO5: 473.2202,
found 473.2194.
1872, 1809, 1715, 1607, 1499, 1446, 1208, 1061, 756 cm21
.
Acknowledgements
We warmly thank the NIH (GM 40287) and AstraZeneca
(sabbatical leave for C.O.) for financial support. We are also
grateful to Mr. John Unger (UCSB) for outstanding
assistance with this project.
4.1.12. (R)-cyclo-NOBIN (12/13). To a flame dried 50 mL
RBF equipped with a magnetic stir bar was added CuCl2
(197.4 mg, 1.44 mmol, 4.0 equiv.) as a solid. The flask was
then charged with degassed MeOH (18 mL) and the green
solution was cooled to 0 8C. The flask was then charged
with racemic a-methylbenzylamine (0.74 mL, 5.76 mmol,
16.0 equiv.) and to the blue reaction mixture was then
quickly added 7-(-2-{5-[2-(7-aminonaphthalen-2-yloxy)-
ethyl]-2,2-dimethyl-[1,3]dioxolan-4-yl}-ethoxy)-naphthalen-
2-ol (11; 170 mg, 0.36 mmol) as a solid. Upon completion
by TLC (55 h) the reaction was poured into saturated
aqueous NH4Cl (50 mL) and extracted with EtOAc
(3£50 mL). The organic layer was dried over anhydrous
Na2SO4. Flash chromatography (200:1 silica/theoretical
yield (170 mg), 5% acetone/5% CH2Cl2/toluene, 1% NEt3
dope) afforded (124 mg, 73%) of the (R)-diastereomer as an
orange foam (106 mg) along with the minor isomer (18 mg).
1H NMR (major isomer; 400 MHz, CDCl3) d 7.80 (d,
J¼8.8 Hz, 1H), 7.75 (d, J¼8.8 Hz, 1H), 7.71 (d, J¼8.8 Hz,
1H), 7.67 (d, J¼8.8 Hz, 1H), 7.23 (d, J¼8.8 Hz, 1H), 7.0
(app d, J¼2.4 Hz, 1H), 6.97 (d, J¼8.8 Hz, 1H), 6.91 (dd,
J¼8.8, 2.3 Hz, 1H), 6.36 (d, J¼2.4 Hz, 1H), 6.25 (d, J¼
2.3 Hz, 1H), 5.71 (br s, 1H), 4.04–3.60 (m, 6H), 1.63–1.62
(m, 4H), 1.36 (s, 6H); 13C NMR (100 MHz, CDCl3) d 157.1,
156.8, 152.6, 143.6, 135.1, 134.3, 130.55, 130.50, 130.49,
130.4, 124.9, 123.9, 117.5, 116.5, 116.0, 115.9, 113.7,
References and notes
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