New solution free and polymer anchored chiral bispidine-based amino alcohols. Synthesis and screening for the enantioselective addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1016/S0957-4166(03)00483-X

A new approach has been evaluated for the preparation of solution free and polymer supported chiral bicyclic amino alcohols. This strategy involves the use of readily available starting materials and allows chiral ligands characterised by the bispidine co

Full text of DOI:10.1016/S0957-4166(03)00483-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2453–2458
New solution free and polymer anchored chiral bispidine-based
amino alcohols. Synthesis and screening for the enantioselective
addition of diethylzinc to benzaldehyde
Giordano Lesma,* Bruno Danieli, Daniele Passarella, Alessandro Sacchetti and Alessandra Silvani*
Dipartimento di Chimica Organica e Industriale e Centro Interdisciplinare Studi biomolecolari e applicazioni Industriali (CISI),
Universita` degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy
Received 27 May 2003; accepted 12 June 2003
Abstract—A new approach has been evaluated for the preparation of solution free and polymer supported chiral bicyclic amino
alcohols. This strategy involves the use of readily available starting materials and allows chiral ligands characterised by the
bispidine core, bearing a stereogenic centre b to one of the nitrogen atoms to be obtained. The first results obtained from the
application of these ligands in the asymmetric addition reaction of diethylzinc to benzaldehyde are discussed.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
ligand can be used. This reaction, affording chiral
secondary alcohols, thus provides a yardstick for the
efficiency and enantioselectivity of a catalyst. Despite
the variety of chiral ligands, mostly bearing a b-amino
alcohol moiety,3 that have been synthesised and tested,
the development of cost-effective catalysts exhibiting
high reactivity and enantioselectivity remains an active
research topic. In particular, the recovery and reuse of
chiral ligands or catalysts is an important feature in
asymmetric reactions.4 To this end, polymer anchored
molecules have intrinsic advantages in that they can be
separated from the products and reused virtually with-
out loss of catalytic activity or enantioselectivity.
According to this, many examples of asymmetric cata-
lysts that employ polymer bound chiral ligands have
been reported. Even if various chiral 1,2-amino alco-
hols have been attached to polymers5 and successfully
employed in asymmetric reactions in a heterogeneous
system, a persisting drawback is that catalytic activity
and enantioselectivity of supported catalysts are usually
lower than those recorded with their homogeneous
counterparts. As a consequence, continued efforts in
this area seem to be fully warranted.
One of the most extensively studied methodologies for
asymmetric carbonꢀcarbon bond formation is the
nucleophilic addition of organometallic reagents to car-
bonyl compounds. In order to perform these reactions,
appropriate chiral ligands must be introduced, with the
aim of complexing one or more participants in the
reaction.1 A frequent disadvantage of these enantiose-
lective reactions is that one or more equivalents of
chiral ligand have to be used. In fact, some
organometallics are able to react with carbonyls even in
the absence of a ligand and, in many cases, the rate of
complexation between ligand and substrate molecule is
slower than the rate of the reaction between uncom-
plexed substrates. Within this class of reactions, the
addition of diethylzinc to aldehydes is one of the few
enantioselective reactions involving organometallics in
which only catalytic amounts of a chiral agent need to
be used to obtain asymmetric induction.2 In fact, unco-
ordinated organozinc reactants are virtually inert and
the reaction requires a compound coordinating to the
metal atom to enhance nucleophilicity. Due to the
increased reactivity of the reagent when it is involved in
the coordinated complex, a catalytic amount of the
2. Results and discussion
We report here a rapid approach for the solution-phase
and solid-phase preparation of bispidine-based amino
* Corresponding authors. Tel.: +39-0250314080; fax: +39-
0250314078; e-mail: alessandra.silvani@unimi.it
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00483-X

2454
G. Lesma et al. / Tetrahedron: Asymmetry 14 (2003) 2453–2458
alcohols and their evaluation in asymmetric addition to
aldehydes. Bispidine 1 (Fig. 1) is the central bicyclic
diaza substructure of the alkaloid sparteine 2, widely
used as efficient ligand in various asymmetric reac-
tions.6 The diazabicyclo[3.3.1]nonane ring system of
bispidine has already been embodied in some different
class of chiral ligands,7 but, to the best of our knowl-
edge, examples of bispidine-based amino alcohols on
solid support have not been reported.
port, thus introducing an element of diversity in the
ligand molecules in the last step of the sequence.
We envisioned the bispidine 3 as an appropriate start-
ing material, carrying a terminal hydroxyl group as a
convenient site for attachment onto the solid support
and, at the same time, suitable for easy protection. The
chirality is introduced in the last step, after the hetero-
cyclic framework has been built up, by N-alkylation
with chiral epoxides. In principle, this scheme allows
different ligands to be available from a single resin, by
simple variation of the chiral epoxide used in the alkyl-
ation process. By means of this strategy, we synthesized
the free ligands 4–5, and the corresponding support-
bound ligands 6–7, anchored to a chloromethyl-
polystyrene (Merrifield resin) polymer backbone. The
bicyclic skeleton of 3 was built up in successive trans-
formations starting from N-Boc-4-oxo-piperidine and
5-aminopentan-1-ol, via bispidinone 8 (Scheme 2).
Figure 1.
To synthesize differently substituted chiral bispidine
amino alcohols, both as free and support-bound lig-
ands, we pursued the two parallel routes shown in
Scheme 1. In the preparation of anchored ligands, the
first part of the synthesis was performed in solution and
then the appropriate scaffold was attached to the sup-
The crucial double Mannich reaction to 8 was per-
formed with formaldehyde in MeOH at reflux and
proceeded in only 57% yield due to formation of
oligomers. The successive deoxygenation of 8 was
Scheme 1. Reagents and conditions: (a) NaH, TBAI, BnBr, DMF (93%); (b) 25% TFA, DCM (95%); (c) 2 equiv. of chiral epoxide,
toluene, reflux (45–50%); (d) NaH, TBAI, 0.5 equiv. of Merrifield resin, DMF; (e) 20% TFA, DCM 1 h then washing with 25%
DIPEA, DCM; (f) n-BuLi, THF, 5 equiv. of chiral epoxide.
Scheme 2. Reagents and conditions: (a) 5-amino-pentan-1-ol, CH2O, AcOH, MeOH, reflux (57%); (b) 1. TsNHNH2, EtOH, 2.
NaBH4, 4:1 THF/H2O, then reflux (85%).

G. Lesma et al. / Tetrahedron: Asymmetry 14 (2003) 2453–2458
2455
structures of ligands 6 and 7 were confirmed by 13C
gel-phase NMR. Enantiopurity of soluble ligands 4 and
5 was confirmed by comparison with the corresponding
racemic compounds, by means of chiral HPLC.
accomplished through the reduction of the correspond-
ing tosylhydrazone by means of NaBH4, affording 3 in
high yield. The hydroxyl moiety of 3 was then con-
verted either to the benzyl ether 9 or linked onto
chloromethylated polystyrene to give polymer 10. We
chose the Merrifield resin, since the contained
chloromethyl groups provide a convenient site for O-
linkage of our bispidine ligands. Besides, this resin
swells efficiently in toluene, which is the solvent of
choice in the enantioselective addition of diethylzinc to
aldehydes. The linkage was performed by deprotona-
tion of 3 with an excess of sodium hydride in DMF and
subsequent reaction of the resulting alkoxide with the
Merrifield resin for 12 h. The process of the reaction
was monitored by 13C gel-phase NMR (Fig. 2) and the
final loading was estimated as about 1.1 mmol g−1 (83%
loading), from elemental analysis data.
The activity of the ligands was then tested in the
enantioselective addition of diethylzinc to benzaldehyde
(Table 1). The reaction was carried out in toluene at
0°C with 10% mol of ligand and two equivalents of
diethylzinc.
Table 1.
Entry
Ligand
Yield (%)a
E.e. (%)b
Config.b
Removal of the Boc group from 9 and 10 yielded the
corresponding N–H compounds, which were N-alkyl-
ated with the chiral epoxides (R)-styrene oxide and
(S)-1,2-epoxybutane. In order to obtain the desired
regiochemistry, solution phase ring opening reactions
were carried out thermically in refluxing toluene to give
the final products 4 and 5 in moderate yields. On the
other hand, the supported ligands 6–7 were obtained by
deprotonation of the nitrogen with BuLi in THF and
quenching of the anion with the epoxide. In order to
achieve a quantitative conversion, five equivalents of
the chiral epoxide were used. Also in this case the ring
opening proceeds with complete regioselectivity, to
afford amino alcohols 6 and 7 in high yields. In the case
of solid-phase reactions, the yields were determined by
gravimetric and elemental analyses and the expected
1
2
3
4
4
5
6
7
94
93
95
95
96
35
25
5
R
S
R
S
a Isolated yield.
b Determined by HPLC (see Section 4).
Excellent enantioselectivity could be achieved by
employing the free solution ligand 4 (entry 1). The
comparison with the 35% e.e. obtained with the ligand
5 (entry 2) highlights the necessity of a bulky group on
the stereocentre of the ligand in order to achieve high
e.e. Supporting of these ligands (entries 3 and 4) results
in a drastic lowering of the e.e. However, in all cases
the high conversions of benzaldehyde to the secondary
Figure 2. Comparison between 13C NMR-APT spectrum of compound 9 (a) and 13C NMR gel-phase of polymer 10 (b).

2456
G. Lesma et al. / Tetrahedron: Asymmetry 14 (2003) 2453–2458
alcohol demonstrate the good activity of both the solu-
tion free and the polymer supported ligands. This con-
firms the chelating ability of these compounds even
when supported onto an insoluble polymer matrix.
Notably, the configuration of the addition product is
the same as the aminoalcohol ligand, in accord to the
model proposed by Noyori3 for which an (R)-aminoal-
cohol leads to an (R)-product and vice versa. This rule
is also followed by the supported ligands.
methanol was slowly added. After 3 h the reaction was
cooled to room temperature and the solvent was evapo-
rated in vacuo. The residue was treated with 20 ml of a
5 M ammonia solution and then extracted with AcOEt.
After evaporation of the solvent, the crude product was
purified by flash chromatography on silica gel (AcOEt/
hexane 7/3, as eluant) to yield the product 8 as a yellow
oil (928 mg, 57%). 1H NMR (200 MHz, DMSO, 140°C):
l 4.33 (d, J=13 Hz, 2H), 3.45 (t, J=6 Hz, 2H), 3.29 (dd,
J=13 Hz, J=5 Hz, 2H), 3.11 (dd, J=12 Hz, J=2 Hz,
2H), 2.67 (dd J=12 Hz, J=5 Hz, 2H), 2.50 (m, 2H), 2.30
(t, J=7 Hz, 2H), 1.80 (s, 1H), 1.48–1.25 (m, 15H). 13C
NMR (75.4 MHz, CDCl3): l 213.51, 154.87, 79.83, 62.44,
59.78, 58.18, 57.25, 50.65, 49.81, 47.92, 32.58, 28.47,
26.68, 23.56. MS (EI) m/z (%): 326 (51) [M+].
3. Conclusions
In conclusion, we performed an easy and enantioselective
synthesis of solution free and polymer supported chiral
bispidine-based aminoalcohols. The results obtained
from the application of the new chiral ligands in a model
4.2.2. 3-tert-Butyloxycarbonyl-7-(5-hydroxypentyl)-3,7-
diazabicyclo[3.3.1]nonane, 3. To a solution of bispidinone
10 (3.33 g, 10.2 mmol) in 50 ml of ethanol, tosylhydrazine
(2.29 g, 12.3 mmol) was added. The reaction was refluxed
for 3 h, then the solvent was evaporated. To the crude
tosylhydrazone derivative, dissolved in 50 ml of THF–
water 4:1 and cooled to 0°C, NaBH4 (3.78 g, 0.1 mol)
was slowly added. The solution was stirred overnight at
rt, then it was refluxed for 2 h. After cooling at rt, water
was added and the mixture was extracted with AcOEt.
Evaporation of the solvent afforded an oil which was
purified by flash chromatography on silica gel (AcOEt/
hexane 7/3, as eluant) to yield the desired product 3 (2.71
g, 85%). 1H NMR (300 MHz, DMSO, 140°C): l 3.95 (d,
J=13.8 Hz, 2H), 3.44 (t, J=6.0 Hz, 2H), 3.08 (dd,
J=13.8 Hz, J=3.8 Hz, 2H), 2.88 (d, J=11.3 Hz, 2H),
2.21 (d, J=11.3 Hz, 2H), 2.18 (t, J=7.7 Hz, 2H), 1.83
(m, 2H), 1.64–1.59 (m, 2H), 1.48–1.25 (m, 15H). 13C
NMR (75.4 MHz, CDCl3): l 155.20, 78.68, 62.43, 58.64,
57.83, 57.59, 48.73, 47.65, 32.65, 31.36, 29.00, 28.55,
26.36, 23.25. MS (EI) m/z (%): 312 (15) [M+].
reaction—the
diethylzinc
addition
to
benz-
aldehyde—are good in terms of conversion (with high e.e.
for the homogeneous ligand 4 and modest e.e. for the
heterogeneous ones). Studies are in progress to improve
the supported ligands’ activity by changing the type of
solid support and linker or, alternatively, the anchoring
site of the molecule. Moreover, this ligand family, being
equipped with O and N as chelating atoms, will be
exploited in other asymmetric reactions involving differ-
ent transition metals, such as Cu, Sn, Ti, Sc, Ni and
lanthanides.
4. Experimental
4.1. General
All solvents were distilled and properly dried, when
necessary, prior to use.—During usual workup, all
organic extracts were dried (Na2SO4 or MgSO4) and
evaporated.—All reactions were monitored by thin layer
chromatography (TLC) on precoated silica gel 60 F254
(Merck); spots were visualized with UV light or by
treatment with 1% aqueous KMnO4 solution. Products
were purified by flash chromatography (FC) on Merck
silica gel 60 (230–400 mesh).—1H and 13C NMR spectra
were recorded with Bruker AC 300 (1H, 300 MHz; 13C,
75.4 MHz) spectrometer in CDCl3 solutions (if not
otherwise stated) with TMS as internal standard.—HR,
EI (70 eV) and FAB mass spectra in the positive mode,
were measured on VG 70–70 EQ–HF instrument
equipped with its standard sources.—Optical rotations
were measured with Perkin–Elmer 241 polarimeter.—
Analytical liquid chromatography was carried out with
a Kontron HPLC system equipped with a UV detector
and a Chiracel OD HPLC column
4.2.3. 3-tert-Butyloxycarbonyl-7-(5-benzyloxypentyl)-3,7-
diazabicyclo[3.3.1]nonane, 9. The bispidine 3 (4.24 g, 13.6
mmol), TBAI (502 mg, 1.36 mmol) and NaH (391 mg,
16.3 mmol) in 90 ml of dry THF were stirred under a
nitrogen atmosphere. After 30 min, benzyl bromide (1.62
ml, 13.6 mmol) was added. The reaction was stirred
overnight. Then water was added and the mixture was
extracted with AcOEt. The obtained solution was treated
with 10 g of Floresil, filtered and the filtrate was washed
with AcOEt. The combined organic layers were dried and
evaporated yielding the pure product 9 (5.10 g, 93%). 1H
NMR (300 MHz, DMSO, 140°C): l 7.35 (m, 5H), 4.47
(s, 2H), 3.95 (d, J=13.8 Hz, 2H), 3.44 (t, J=6.0 Hz, 2H),
3.08 (dd, J=13.8 Hz, J=3.8 Hz, 2H), 2.88 (d, J=11.3
Hz, 2H), 2.21 (d, J=11.3 Hz, 2H), 2.18 (t, J=7.7 H, 2H),
1.83 (m, 2H), 1.64–1.59 (m, 2H), 1.48–1.25 (m, 15H). 13
C
4.2. Preparation of ligands 4–7
NMR (50.3 MHz, CDCl3): l 155.15, 138.69, 128.29,
127.58, 127.45, 78.44, 72.84, 70.46, 59.26, 59.08, 58.44,
48.81, 47.77, 31.63, 29.69, 29.28, 29.18, 28.65, 26.65,
24.09. MS (EI) m/z (%): 402 (34) [M+].
4.2.1.
3-tert-Butyloxycarbonyl-7-(5-hydroxypentyl)-9-
oxo-3,7-diazabicyclo[3.3.1]nonane, 8. To a solution of
5-aminopentan-1-ol (550 mg, 5 mmol) in 20 ml of dry
methanol, acetic acid (0.29 ml, 5 mmol), hydrochloric
acid (0.21 ml, 2.5 mmol) and paraformaldehyde (312 mg,
10 mmol) were added. To the refluxing reaction mixture
a solution of N-Boc-4-oxo-piperidine (1 g, 5 mmol) in dry
4.2.4.
(R)-2-[7-(5-Benzyloxypentyl)-3,7-diazabicyclo-
[3.3.1]non-3-yl]-1-phenylethanol, 4. The starting material
9 (1.15 g, 2.86 mmol) was dissolved in a 20% TFA/DCM
solution and stirred for 1 h. A 5 M ammonia solution

G. Lesma et al. / Tetrahedron: Asymmetry 14 (2003) 2453–2458
2457
was added to pH 9–10 and the aqueous phase was
extracted with DCM. The combined organic layers are
dried and evaporated, to yield the desired free amine
(820 mg, 2.70 mmol) in 95% yield. 1H NMR (200 MHz,
CDCl3): l 7.30 (m, 5H), 4.47 (s, 2H), 3.48 (t, J=6.0 Hz,
2H), 3.39 (d, J=13.0 Hz, 2H), 3.12 (d, J=13.0 Hz,
2H), 2.42 (d, J=12.0 Hz, 2H), 2.33 (d, J=12.0 Hz,
2H), 2.29 (t, J=7.7 Hz, 2H), 2.09 (m, 2H), 1.64–1.59
(m, 2H), 1.40–1.25 (m, 6H). 13C NMR (50.3 MHz,
CDCl3): l 138.57, 128.29, 127.58, 127.45, 72.80, 69.98,
58.36, 49.51, 30.74, 29.45, 27.09, 26.18, 23.94. MS (EI)
m/z (%): 402 (29) [M+].
DIPEA/DCM solution and then with MeOH and
DCM twice.
4.2.8. General procedure for chiral epoxide ring opening
on solid phase: preparation of 6 and 7. Under a nitrogen
atmosphere the resin was suspended in 5 ml of dry
THF in a fritted filtration syringe. After cooling to 0°C,
butyllithium was added (1.6 M in hexane, 2 equiv.).
The reaction was mechanically stirred for 1 h, then the
temperature was raised to room temperature. The chiral
epoxide (5 equiv.) was added and the mixture was
mechanically stirred overnight. Then the resin was
filtered and washed with MeOH and DCM twice.
The obtained amine (1.22 g, 4.02 mmol) was dissolved
in 5 ml of dry toluene, then (R)-styrene oxide (0.505 ml,
4.42 mmol) was added. The mixture was refluxed for 24
h. After cooling, the solution was treated with 2 ml of
HCl 1N and stirred for 30%. Then, 5 M ammonia
solution was added until pH 9–10 and the aqueous
phase was extracted with AcOEt. After drying and
evaporating the solvent, the obtained crude product
was purified by flash chromatography on silica gel
(AcOEt/MeOH/TEA 78/19/3 as eluant), to afford 4 in
45% yield (766 mg, 1.81 mmol). [h]2D0=−82 (c=0.33,
4.2.9. General procedure for the addition of diethylzinc to
benzaldehyde in presence of the ligands. To a solution of
benzaldehyde (1 equiv.) in dry toluene, the ligand (10%
mol, 0.1 equiv.) was added. To the mixture cooled to
0°C, diethylzinc was added (1 M in hexane, 2 equiv.).
The reaction was allowed to warm to room temperature
overnight then it was quenched with 1 M HCl. The
aqueous phase was extracted with AcOEt. After drying
and evaporating the solvent, the crude product was
used for HPLC analysis to determine the enantiomeric
excess (Chiracell OD column with 2.5% propan-2-ol in
hexane as eluant and 0.600 ml/min flow: retention times
of 18% for the (R)-enantiomer and 21% for the (S)-enan-
tiomer, see Table 1).
1
EtOH); H NMR (200 MHz, CDCl3): l 7.35 (m, 10H),
4.73 (dd, J=10.5 Hz, J=4.5 Hz, 1H), 4.48 (s, 2H), 3.49
(t, J=6.0 Hz, 2H), 3.10–2.20 (m, 12H), 1.83 (m, 2H),
1.65 (m, 2H), 1.60–1.30 (m, 6H). 13C NMR (75.4 MHz,
CDCl3): l 143.33, 138.74, 128.29, 128.12, 127.60,
127.38, 126.95, 125.87, 72.84, 70.43, 69.04, 64.52, 60.03,
59.15, 54.64, 32.47, 30.66, 29.60, 26.28, 24.32. MS (EI)
m/z (%): 422 (17) [M+].
Acknowledgements
This work is supported by FIRB ‘Fondo per gli Investi-
menti della Ricerca di Base’, 2001.
4.2.5.
(S)-2-[7-(5-Benzyloxypentyl)-3,7-diazabicyclo-
[3.3.1]non-3-yl]butan-2-ol, 5. The same procedure as for
4 was followed, except that (S)-1,2-epoxybutane (345
ml, 4.01 mmol) was used. The product 5 was obtained
with 50% yield (544 mg 1.45 mmol). [h]2D0=+36 (c 0.33,
References
1
EtOH) H NMR (200 MHz, CDCl3): l 7.35 (m, 5H),
1. Catalytic Asymmetric Synthesis; Ojima, I., Ed.; John Wiley
& Sons, Inc., Publ., New York, 2000
2. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833–856.
3. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49–70; (b) Bolm, C.; Schlingloff, G.; Harms, K.
Chem. Ber. 1992, 125, 1191–1203.
4.48 (s, 2H), 4.05 (m, 1H), 3.49 (t, J=6.0 Hz, 2H),
3.10–2.30 (m, 10H), 2.18 (t, J=7.7 Hz, 2H), 1.83 (m,
2H), 1.65 (m, 2H), 1.60–1.30 (m, 8H), 0.94 (s, J=8.0
Hz, 3H). 13C NMR (75.4 MHz, CDCl3): l 138.58,
128.35, 127.65, 127.49, 72.88, 70.33, 67.35, 62.09, 59.53,
59.21, 50.78, 31.95, 29.52, 28.42, 28.18, 26.52, 24.07,
11.43. MS (EI) m/z (%): 374 (14) [M+].
4. Fan, Q.-H.; Li, Y.-M.; Chan, A. S. C. Chem. Rev. 2002,
102, 3385–3466.
5. (a) Vidal-Ferran, A.; Bampos, N.; Moyano, A.; Perica`s,
M. A.; Riera, A.; Sanders, J. K. M. J. Org. Chem. 1998,
63, 6309; (b) Liu, G.; Ellmann, J. A. J. Org. Chem. 1995,
60, 7712; (c) Watanabe, M.; Soai, K. J. Chem. Soc., Perkin
4.2.6. Coupling of ligand precursor 3 to the solid phase.
The bispidine 3 (645 mg, 2.07 mmol), TBAI (78 mg,
0.21 mmol) and NaH (60 mg, 2.48 mmol) in 30 ml of
dry THF were stirred under a nitrogen atmosphere.
After 30 min, Merrifield resin (837 mg, 1.03 mmol,
loading 1.23 mmol/g) was added. The reaction was
mechanically stirred overnight. Then the resin was
filtered and washed with MeOH and DCM twice (83%
loading from elemental analysis data).
Trans.
1 1994, 837; (d) Soai, K.; Watanabe, M.;
Yamamoto, A. J. Org. Chem. 1990, 55, 4832; (e) Itsuno,
S.; Fre´chet, J. M. J. J. Org. Chem. 1987, 52, 4140.
6. (a) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 2282–2316; (b) Beak, P.; Basu, A.; Gallagher, D.
J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996,
29, 552–560; (c) Schwerdtfeger, J.; Hoppe, D. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1505–1507; (d) Muci, A.
R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995,
117, 9075–9076; (e) Curtis, M. D.; Beak, P. J. Org. Chem.
1999, 64, 2996–2997; (f) Denmark, S. E.; Stiff, C. M. J.
Org. Chem. 2000, 65, 5875–5878; (g) Hodgson, D. M.;
4.2.7. Cleavage of the Boc protecting group on solid
support. The resin 10 was suspended in a 20% TFA/
DCM solution in a fritted filtration syringe and
mechanically stirred. After 3 h the solution was filtered
and the resin was washed three times with a 20%

2458
G. Lesma et al. / Tetrahedron: Asymmetry 14 (2003) 2453–2458
P. J. Am. Chem. Soc. 1997, 119, 10537–10538; (d) Hutten-
Norsikian, S. L. M. Org. Lett. 2001, 3, 461–463; (h)
loch, O.; Laxman, E.; Waldmann, H. Chem. Commun.
2002, 673; (e) Huttenloch, O.; Spieler, J.; Waldmann, H.
Eur. J. Org. Chem. 2000, 6, 391–399; (f) Huttenloch, O.;
Laxman, E.; Waldmann, H. Chem. Eur. J. 2002, 20,
4767–4780.
Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475–7476.
7. (a) Haack, K. J.; Goddard, R.; Porschke, K. R. J. Am.
Chem. Soc. 1997, 119, 7992–7999; (b) Park, Y. S.; Weisen-
burger, G. A.; Beak, P. J. Am. Chem. Soc. 1997, 119,
10537–10538; (c) Park, Y. S.; Weisenburger, G. A.; Beak,