Synthesis of complex alkoxyamines using a polymer-supported N-hydroxyphthalimide

Article abstract of DOI:10.1016/j.tet.2004.05.109

The synthesis of a polymer-supported N-hydroxyphthalimide is described. The polystyrene-bound N-hydroxyphthalimide resin 1 has been used to prepare complex alkoxyamines exhibiting both stereochemical and positional diversity. Methods for efficient condens

Full text of DOI:10.1016/j.tet.2004.05.109

Tetrahedron 60 (2004) 8645–8657
Synthesis of complex alkoxyamines using a polymer-supported
N-hydroxyphthalimide
*
Shun Su, Joshua R. Giguere, Scott E. Schaus and John A. Porco, Jr.
*
Department of Chemistry and Center for Chemical Methodology and Library Development, Metcalf Center for Science and Engineering,
Boston University, 590 Commonwealth Avenue, Boston, MA 02215-2507, USA
Received 13 January 2004; accepted 4 May 2004
Available online 14 August 2004
Abstract—The synthesis of a polymer-supported N-hydroxyphthalimide is described. The polystyrene-bound N-hydroxyphthalimide resin 1
has been used to prepare complex alkoxyamines exhibiting both stereochemical and positional diversity. Methods for efficient condensation
of complex alkoxyamines with aldehydes and ketones are also outlined.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
reports the synthesis of a polystyrene-based N-hydroxy-
phthalimide resin and its utility in preparing stereo-
chemically and structurally diverse alkoxyamines. The
alkoxyamines were utilized to synthesize complex oxime
ethers from aldehydes and ketones.
The oxime functional group is present in several natural
products and biologically active molecules.1 The oxime
ether is an attractive functionality to incorporate into library
synthesis due to the chemoselective reaction of alkoxy-
amines2 with aldehydes and ketones.3 However, only a
limited number of alkoxyamines are commercially avail-
able4 and relatively few methods have been reported for the
preparation of chiral variants.5
2. Results and discussion
A report from Aronov and Gelb11 describing the preparation
of a polystyrene-bound phthalimide reagent served as a
starting point for preparation of N-hydroxyphthalimide resin
1. The synthesis of 1 began by transformation of
commercially available anhydride 4 to the N-hydroxy-
phthalimide 5 using hydroxylammonium chloride in reflux-
ing pyridine12 (Scheme 2). Protection of the hydroxyl group
with trityl chloride afforded protected phthalimide 6.
Attachment of the protected phthalimide 6 to aminomethyl
polystyrene (PS-NH2, 1.30 mmol/g, Argonaut) using
HATU-mediated amide bond formation afforded resin 7.
Deprotection of the trityl group using 10:1 CH2Cl2:TFA
completed the synthesis of N-hydroxyphthalimide resin 1.
Unfortunately, extensive screening of reaction conditions
As part of our general interest to construct complex
chemical libraries that contain both stereochemical6 and
positional diversification elements, we devised an approach
towards the synthesis of stereochemically diverse
alkoxyamines employing a polymer-supported N-hydroxy-
phthalimide (Scheme 1).7,8 Alkylation of the phthalimide
hydroxyl group using alkyl halides9 or alcohols via
Mitsunobu etherification10 would provide the corresponding
polymer-supported N-alkoxyphthalimides. These products
could be further modified using solid-phase synthesis.
Hydrazine-mediated cleavage of the alkylation products
would afford the corresponding alkoxyamines. This paper
Scheme 1. Preparation of complex alkoxyamines using a polymer-supported N-hydroxyphthalimide.
Keywords: Polymer-supported; N-Hydroxyphthalimide; Alkoxyamine; Stereochemical diversity; Positional diversity.
*
Corresponding authors. Tel.: þ1-617-353-2493; fax: þ1-617-353-6466; e-mail addresses: seschaus@chem.bu.edu; porco@chem.bu.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.109

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S. Su et al. / Tetrahedron 60 (2004) 8645–8657
Scheme 2. Initial synthesis of an N-hydroxyphthalimide resin. Reagents and conditions: (a) H2NOH·HCl, pyridine, 95 8C, 66%. (b) TrCl, DIEA, CH3CN,
reflux, 34%. (c) HATU, DIEA, PS-NH2, DMF. (d) 10:1 CH2Cl2:TFA.
failed to improve the yield for trityl protection of
N-hydroxyphthalimide 5. Other protecting groups (e.g.,
TMS, TBS, and THP) were also evaluated and found to be
less effective than the trityl group. Attempts to directly
condense anhydride 4 with O-trityl hydroxylamine or
O-(tetrahydro-2H-pyran-2-yl) hydroxylamine were likewise
unsuccessful.
aminomethylated polystyrene (1.10 mmol/g, Novabiochem)
and 4 M HCl in dioxane. The reaction was monitored by
both bead staining with bromophenol blue14 and single-bead
IR analysis. A negative result from the bromophenol blue
stain test and strong carbonyl absorptions (1858, 1781,
1673 cm21) by IR analysis clearly indicated the formation
of anhydride resin 11.15 After resin washing, 11 was
successfully transformed to N-hydroxyphthalimide resin 1
as indicated by the shift of the carbonyl stretches (1788,
1728, 1603 cm21) and the appearance of a strong hydroxyl
stretch by single-bead IR (Scheme 4).
To improve the synthesis of resin 1, amide bond formation
in the presence of the anhydride moiety, followed by
transformation to the hydroxyphthalimide, was investigated
(Scheme 3). A model study was initiated to determine the
effectiveness of amide bond formation with the acid
chloride of compound 4.13 In order to potentially minimize
reaction with the anhydride moiety, we employed benzyl-
amine hydrochloride as a protected form of the amine. Slow
addition of triethylamine gradually liberated the benzyl-
amine to selectively react with the more reactive acid
chloride. According to 1H NMR analysis, no reaction of the
anhydride was observed using 1 equiv. of the amine salt.
Although this transformation provided only moderate
yields, it was anticipated that by using an excess of acid
chloride, high levels of chemoselectivity should be achiev-
able using a solid-supported amine. Following a literature
procedure,12 anhydride 8 was reacted with hydroxylamine
hydrochloride to provide the desired model compound 9.
In order to determine the loading of N-hydroxyphthalimide
resin 1, a Mitsunobu reaction was employed for resin
derivatization (Scheme 5). 4-Biphenylmethanol was reacted
with resin 1 using TMAD/PBu3.16 After resin washing and
subsequent cleavage using NH2NH2 (2 equiv.), the corre-
sponding biaryl alkoxyamine17 was obtained after solvent
removal. The yield was determined by HPLC analysis of the
acetone oxime derivative 13 employing 4-biphenylmetha-
nol as an internal standard. The loading of resin 1 was thus
determined to be 0.68 mmol/g (75% of theoretical loading).
Further efforts to improve the loading of the resin were
investigated. To minimize potential crosslinking of the
anhydride with aminomethyl sites on the resin, other
variables including use of a secondary amine resin15 and
alternative solvents (e.g., THF) were evaluated. However,
none of these variations afforded improved resin loading.
Following solution phase model studies, solid-phase
synthesis was initiated by condensation of acid chloride
10 and PS-NH2·HCl, prepared from commercially available
A recent report18 prompted us to investigate an alternative
Scheme 3. Synthesis of N-hydroxyphthalimide resin via a direct condensation pathway. Reagents and conditions: (a) oxalyl chloride, CH2Cl2, cat. DMF. (b)
PhCH2NH2·HCl, Et3N, CH2Cl2. (c) H2NOH·HCl, pyridine, 95 8C, 45% from 4.
Scheme 4. Second synthesis of N-hydroxyphthalimide resin. Reagents and conditions: (a) PS-NH2, Et3N, CH2Cl2. (b) H2NOH·HCl, pyridine:ClCH2CH2Cl 3:1,
75 8C.

S. Su et al. / Tetrahedron 60 (2004) 8645–8657
8647
Scheme 5. Characterization of the N-hydroxyphthalimide resin. Reagents and conditions: (a) 4-biphenylmethanol, PBu3, TMAD, THF:CH2Cl2¼1:1, rt.
(b) H2NNH2, CH2Cl2, then acetone.
polymer-supported reagent synthesis involving 1,2,3-tria-
zole formation (Scheme 6). Selective condensation of acid
chloride 10 and propargyl amine hydrochloride 14 afforded
anhydride 15, which was converted to hydroxyphthalimide
16 using microwave conditions (150 W, 100 8C, 60 min).19
At this stage, both CuI-catalyzed23a and thermal triazole
formations were evaluated and failed to provide any desired
product. Further studies indicated that the trityl-protected
compound 1720 (prepared from 16 and trityl chloride)
readily underwent cycloaddition using Cu(I) catalysis.
Interestingly, a mixture of 1.4:1 mixture of 1,2,3-triazole
regioisomers (unassigned) was obtained instead of the
expected head-to-tail regioisomer.23 Subsequent deprotec-
tion of both isomers using 10:1 CH2Cl2/TFA successfully
afforded the desired model 1,2,3-triazole 19.
about 1,2,3-triazole regioisomers and potential for com-
promised reactivity. Accordingly, we selected N-hydroxy-
phthalimide resin 1 for further studies to prepare structurally
and stereochemically diverse alkoxyamines.
Due to the high efficiency of the Mitsunobu reaction and the
numerous transformations that potentially can be applied on
tethered alkynes, we focused on attachment of alkyne-
containing alcohols to resin 1. Three diversification
pathways were selected for terminal alkyne modification:
Cu-catalyzed 1,2,3-triazole formation,23 isoxazole syn-
thesis,24 and acetylenic Mannich reactions25 (Scheme 8).
Condensation of N-hydroxyphthalimide resin 1 and diverse
terminal alkyne-containing alcohols was effected using a
Mitsunobu conditions16 to afford alkyne resins 26
(Scheme 9). At this stage, Cu-catalyzed 1,2,3-triazole
formation was investigated.23 A number of Cu(I) sources
were tested along with variation of base, additives, and
ligands. The cycloaddition was monitored by the
disappearance of alkyne C–H stretch (3292 cm21) using
single-bead IR. Optimal reaction conditions were found
using a combination of Cu(MeCN)4PF6, 2,6-lutidine, and
CH2Cl2 as solvent. Resin washing with 10% N,N,N0,N0-
tetramethylethylenediamine efficiently removed the copper
Following the solution phase model studies, compound 17
was employed for solid-phase synthesis (Scheme 7). Copper
(I)-mediated dipolar cycloaddition of benzyl azide resin
2018,21 and propargylamide 17, followed by TFA-mediated
detritylation, afforded the desired resin 21.22 Although
Mitsunobu reactions proceeded smoothly using 21, sub-
sequent functionalization reactions to produce complex
alkoxyamines (acetylenic Mannich reaction, vide infra)
produced inconsistent results leading to general concern
Scheme 6. Model studies towards the synthesis of an N-hydroxyphthalimide resin using 1,2,3-triazole linkage (only one regioisomer of 18 and 19 are shown for
clarity). Reagents and conditions: (a) pyridine, THF. (b) NH2OH·HCl, pyridine, microwave 100 8C, 150 W, 60 min 75%. (c) TrCl, DIEA, MeCN. (d) CuI,
DIEA, THF, PhCH2N3. (e) 10:1 CH2Cl2:TFA, 90% from 16.
Scheme 7. Synthesis of an N-hydroxyphthalimide resin using a triazole linker (only one regioisomer 21 is shown for clarity). Reagents and conditions: (a) CuI,
DIEA, THF. (b) 10:1 CH2Cl2:TFA.

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S. Su et al. / Tetrahedron 60 (2004) 8645–8657
Scheme 8. Plan for synthesis of complex alkoxyamines using the N-hydroxyphthalimide resin.
Scheme 9. Synthesis of 1,2,3-triazole-containing alkoxyamines. Reagents and conditions: (a) alkyne-containing alcohol, TMAD, Bu3P, THF/CH2Cl2¼1:1, rt.
(b) R’N3, Cu(MeCN)4PF6, 2,6 lutidine, CH2Cl2. (c) NH2NH2, CH2Cl2.
salts from the polystyrene support. Subsequent cleavage
using anhydrous hydrazine provided the desired products.
Using this protocol, several alkoxyamine triazoles (Table 1,
29–33) containing both positional and stereochemical
diversity were prepared in yields ranging from 95 to 98%
(71–74% based on loading of the aminomethylated
polystyrene) and high purities (.99%, HPLC-ELSD).
Since tertiary propargylic amines are also of significant
pharmaceutical interest,31 the preparation of propargylic
amine-containing alkoxyamines was next explored
(Scheme 11). Initial reactions employing conventional
reaction conditions (e.g., CuCl/1,4-dioxane25) were not
satisfactory and led to incomplete reactions. After extensive
experimentation, we found that pretreating the secondary
amine with paraformaldehyde and p-toluenesulfonic acid,
followed by addition of CuBr in DMF, provided the desired
Mannich products in high yield and purity after cleavage
with NH2NH2. The washing regimen developed for the solid
phase 1,2,3-triazole synthesis (Scheme 9) was also
employed for removal of copper salts from the polystyrene
support. Following this general procedure, several pro-
pargylic amine-containing alkoxyamines (Table 3, 46–50)
were synthesized employing commercially available amines
in yields ranging from 95 to 99% (71–74% based on
loading of the aminomethylated polystyrene) and high
purities ($97%, HPLC-ELSD).
Isoxazoles are heterocycles which are present in a number
of therapeutic agents.26 Thus, the cycloaddition of nitrile
oxides with alkynes was investigated for preparation of
diverse isoxazole-containing alkoxyamines (Scheme 10).24
Dipolar cycloaddition of alkyne resin 26 was best performed
using in situ generation of a nitrile oxide prepared from
27
oxime 35, NBS, and NaHCO3 in CH2Cl2 at 35 8C. Other
conditions24c,28 employing NCS,24a NaOCl,24b and
(Bu3Sn)2O29 lead to incomplete reactions as evidenced by
single bead IR. Regioisomers were observed for some of the
1
substrates (Table 2) and the ratio was determined by H
NMR. Due to the limited availability of diverse oximes, we
have developed a practical method for the synthesis of
oximes starting from commercially available aldehydes
(inset, Scheme 10). Treatment of aldehydes 34 with
hydroxylamine hydrochloride in the presence of Et3N in
CH2Cl2 provided the desired oximes 35, which can be
readily separated from the hydrochloride salts by eluting
though an SLE30 cartridge containing 1 N HCl. The
resulting oximes were reacted with NBS in CH2Cl2 for
3 h and then incubated with diverse alkyne resins (NaHCO3,
12 h) to afford the corresponding isoxazole-containing
resins. After hydrazinolysis, the desired isoxazole-contain-
ing alkoxyamines (Table 2, 38–42) were obtained in yields
ranging from 92 to 96% (69–72% based on loading of the
aminomethylated polystyrene) and high purities (>92%,
HPLC-ELSD).
The condensation of alkoxyamines with aldehydes or
ketones via oxime formation is an efficient method for the
ligation of two complex fragments (Scheme 12). A small
collection of oxime–ether containing molecules was
targeted to demonstrate the utility of the complex
alkoxyamines for preparation of compounds with stereo-
chemical and positional diversity. Microwave irradiation32
was employed to facilitate expedient product formation.
General conditions for the preparation of oxime ethers
employed a slight excess of alkoxyamine (1.2 equiv.)
relative to ketone or aldehyde. Aldehydes (51–53) reacted
cleanly with alkoxyamines in 1,2-dichloroethane to
produce the desired oxime products (57–59) within minutes
(Table 4). Excess alkoxyamine was scavenged using a solid-
supported methyl isatoic anhydride resin33 to afford the

S. Su et al. / Tetrahedron 60 (2004) 8645–8657
8649
desired products in high yield and purity. The stereo-
1
chemistry of oxime ethers was determined by H NMR
analysis.1a Higher reaction temperatures and use of acetic
acid improved the rate of oxime condensations with ketones
such as estrone 54 and (þ)-griseofulvin34 55 to afford
compounds 60 and 61. Production of structures such as
57–61 using oxime ligation illustrates the potential for
future synthesis of complex hybrid molecule libraries using
convergent approaches.35
3. Conclusion
In summary, the synthesis of a polymer-supported
N-hydroxyphthalimide has been accomplished. In initial
studies, the supported N-hydroxyphthalimide reagent has
been used to prepare complex alkoxyamines containing
stereochemical and positional diversity elements. Attach-
ment of alkynols to the N-hydroxyphthalimide resin using
Mitsunobu reactions has facilitated the synthesis of complex
1,2,3-triazole-, isoxazole- and propargylamine-containing
alkoxyamines via branching reaction pathways. Finally,
methods for efficient condensation of the diverse alkoxy-
amines with both aldehydes and ketones have been
developed leading to the production of highly complex,
hybrid molecules. Further studies concerning the construc-
tion of complex oxime-based libraries using convergent
approaches is currently in progress and will be reported in
due course.
4. Experimental
4.1. General experimental procedures
1H NMR spectra were recorded on a 400 MHz spectrometer
at ambient temperature with CDCl3 as the solvent unless
otherwise stated. 13C NMR spectra were recorded on a
75.0 MHz spectrometer (unless otherwise stated) at ambient
temperature. Chemical shifts are reported in parts per
million relative to chloroform (1H, d 7.24; 13C, d 77.23).
1
Data for H NMR are reported as follows: chemical shift,
integration, multiplicity (app¼apparent, par obsc¼partially
obscure, ovrlp¼overlapping, s¼singlet, d¼doublet, t¼
triplet, q¼quartet, m¼multiplet) and coupling constants.
All 13C NMR spectra were recorded with complete proton
decoupling. Infrared spectra were recorded on a Nicolet
Nexus 670 FT-IR spectrophotometer. Single-bead IR was
performed on Nicolet Nexus 470 FT-IRþContinumM
microscope. Optical rotations were recorded on an
AUTOPOL III digital polarimeter at 589 nm, and are
recorded as [a]D (concentration in grams/100 mL solvent).
HPLC-ELSD-MS analysis was performed on a Waters
HPLC-MS system equipped with Waters 600 HPLC pump,
Waters 2996 photodiode array detector, Micromass ZQ
Quadrupole Mass Spectrometer, Sedere Sedex 75 ELS
reverse phase column (XTerrawRP8, 5 mm, 4.6£30 mm).
Analytical thin layer chromatography was performed on
0.25 mm silica gel 60-F plates. Flash chromatography was
performed using 200–400 mesh silica gel (Scientific
Absorbents, Inc.). Solid-phase synthesis was performed
using Quest 210 and Quest 205 synthesizer (Argonaut
Technologies, Foster City, CA). Liquid–liquid extraction

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S. Su et al. / Tetrahedron 60 (2004) 8645–8657
Scheme 10. Synthesis of isoxazole-containing alkoxyamines. Reagents and conditions: (a) NH2OH·HCl, CH2Cl2, Et3N. (b) SLE, 1 N HCl. (c) NBS, CH2Cl2,
then NaHCO3, 35 8C. (d) NH2NH2, CH2Cl2.
for oxime formation was performed using 5.0 mL ISO-
LUTEw HM-N SPE Columns (Argonaut Technologies).
Aminomethylated polystyrene (cat. No. 01-64-0143,
1.10 mmol/g) was obtained from Novabiochem. Poly-
styrene-NH2 resin (PS-NH2, part. no. 800263,
1.30 mmol/g) was obtained from Argonaut Technologies.
Solid-supported methyl isatoic anhydride resin (PL-MIA,
part # 3405-3679, 2.57 mmol/g) was obtained from Polymer
Laboratories. All other reagents were used as supplied by
Sigma-Aldrich, Lancaster Synthesis, Strem, and Argonaut
Technologies. Methylene chloride, tetrahydrofuran, metha-
nol, benzene were purified by passing through two packed
columns of neutral alumina (Glass Contour, Irvine, CA).
0.30 mmol) were added as solids under N2 followed by
2 mL 1:1 THF–CH2Cl2. After mixing to dissolve the
reagents, P(n-Bu)3 (43.2 mL, 0.30 mmol) was added and
reaction mixture was agitated for 6 h. After filtering the
reaction mixture, the resulting resin was washed with DMF
(2£3 mL), MeOH (2£3 mL), THF (3£3 mL), CH2Cl2
(3£3 mL). Following the addition of 2 mL CH2Cl2,
NH2NH2 (6.3 mL, 0.20 mmol) was added and the reaction
was agitated for 1 h. The filtration was collected and treated
with 2 mL acetone. After concentration, the resulting
sample was subjected to an HPLC analysis using a Waters
AutoPure HPLC systemand an XTerrawRP8, 5 mm,
4.6£30 mm column (4-biphenylmethanol as internal
standard). The loading was determined to be 75%
(0.68 mmol/g).
4.1.1. N-Hydroxyphthalimide resin (1). Pre-swelled
aminomethylated polystyrene resin (5.0 g, 5.50 mmol,
loading: 1.10 mmol/g,) was mixed with 40 mL CH2Cl2 in
an 80 mL reaction vessel on the Quest 205 parallel
synthesizer. After addition of 6.9 mL HCl in dioxane
(4.0 M, 27.4 mmol), the mixture was agitated for 1 h.
Upon filtration, the PS-NH2·HCl resin was washed with
CH2Cl2 (3£30 mL) and transferred to a pre-silylated
250 mL two-neck flask equipped with a mechanical stirrer.
Trimellitic anhydride chloride (5.75 g, 27.4 mmol) was
added followed by 30 mL CH2Cl2 and the reaction was
cooled to 0 8C using an ice bath. A solution of Et3N
(5.26 mL, 38.5 mmol) in 20 mL CH2Cl2 was added to the
reaction mixture over 2 h via syringe pump. The reaction
was stirred at 0 8C for an additional 3 h, warmed to rt, and
stirred for an additional 2 h. After the reaction mixture was
transferred to a reaction vessel on the Quest 205 synthesizer,
the resulting anhydride resin was washed with CH2Cl2
(2£20 mL), DMF (2£20 mL), THF (2£20 mL), and CH2Cl2
(2£20 mL). Following washing, NH2OH·HCl (1.91 g,
27.5 mmol) and 40 mL 3:1 pyridine: 1,2-dichloroethane
were added and the reaction was agitated for 24 h at 75 8C.
The reaction was cooled to rt, the resin was filtered, washed
with MeOH (2£20 mL), DMF (2£20 mL), DMF–H2O¼1:1
(2£30 mL), DMF (1£20 mL), THF (3£20 mL), CH2Cl2
(2£20 mL), Et2O (2£20 mL), and dried under high vacuum
at 50 8C for 12 h. IR (single bead): 3385, 3060, 3027, 2925,
1788, 1728, 1669, 1601, 1514, 1494, 1453, 1374, 1299,
Note. For compounds 29–33, 38–42, and 46–50 (a) all
yields were calculated based on the experimentally
determined loading of the N-hydroxyphthalimide resin (1,
cf. Section 4.1.2); (b) purity and NMR studies were
conducted on the corresponding acetone oxime derivatives.
4.2.1. Representative procedure for synthesis of 1,2,3-
triazole-containing alkoxyamines (acetone oxime of 33).
Resin 1 (56 mg, 0.0385 mmol) was pre-swelled with
CH2Cl2 in a 5 mL reaction vessel on the Quest-210
synthesizer. Azodicarboxylic acid bis[dimethylamide]
(20 mg, 0.116 mmol) was added as a solid under N2
followed by 2 mL 1:1 THF–CH2Cl2 and (R)-(þ)-3-
butyne-2-ol (9.1 mL, 0.116 mmol). After mixing to dissolve
the reagents, P(n-Bu)3 (16.4 mL, 0.116 mmol) was added
and reaction mixture was agitated for 6 h. After filtering the
reaction mixture, the resulting resin was washed with DMF
(2£3 mL), MeOH (2£3 mL), THF (3£3 mL), and CH2Cl2
(3£3 mL). After resin washing, Cu(CH3CN)4PF6 (4.5 mg,
0.012 mmol, 30 mol%) was added to the reaction vessel
followed by the addition of 2 mL CH2Cl2, 2S-2-azido-3-
phenyl-propan-1-ol36 (20.5 mg, 0.116 mmol) and 2,6-
lutidine (13.5 mL, 0.116 mmol). The reaction was agitated
at rt for 12 h 0 and filtered. After resin washing with
10% N,N,N0,N -tetramethylethylenediamine in CH2Cl2
(2£3 mL), CH2Cl2 (1£3 mL), 5% AcOH in CH2Cl2
(2£3 mL), THF (3£3 mL) and CH2Cl2 (3£3 mL), 2 mL
CH2Cl2 and NH2NH2 (2.5 mL, 0.077 mmol) were added and
the reaction was agitated for 1 h. The reaction was filtered,
the resin was washed with CH2Cl2, and the filtrate collected
and evaporated to afford 9.9 mg (0.0377 mmol, 73.5%)
1194, 1141, 1115, 1021, 998, 913, 827, 761, 709 cm21
.
4.2. Loading determination
Resin 1 (100 mg) was pre-swelled with CH2Cl2 in a 5 mL
reaction vessel on the Quest-210 synthesizer and
4-biphenylmethanol (55.2 mg, 0.30 mmol) and azo-
dicarboxylic acid bis[dimethylamide] (51.6 mg,
of (2R)-[4-[(1S)-aminooxy-ethyl)-[1,2,3]triazol-1-yl]-3-
phenyl-propan-1-ol 33 as a colorless oil. 33 was treated
with 2 mL of acetone and then concentrated and the

S. Su et al. / Tetrahedron 60 (2004) 8645–8657
8651
resulting sample was subjected to HPLC-ELSD analysis
using a Waters HPLC-MS system (XTerrawRP8, 5 mm,
1
4.6£30 mm column) to determine the purity (.99%). H
NMR (400 MHz, CDCl3) d 7.28–7.20 (m, 3H), 7.08 (d, 2H,
J¼7.2 Hz), 5.32 (q, 1H, J¼7.2 Hz), 4.67 (m, 1H), 4.07 (m,
2H), 3.25 (m, 2H), 2.01 (m, 1H), 1.84 (s, 3H), 1.83 (s, 3H),
1.61 (d, 3H, J¼6.8 Hz); 13C NMR (75.0 MHz, CDCl3) d
155.3, 149.4, 136.6, 129.1, 128.8, 127.0, 122.1, 73.1, 64.7,
63.6, 37.9, 21.8, 19.8, 15.7; IR (thin film) nmax 3333, 3029,
2926, 2857, 1454, 1372, 1079, 935, 702, 670 cm21; LRMS
[M]þ calculated for C16H22N4O2: 302.4, found: 302.5;
[a]2D3¼257.88 (c¼0.58, CH2Cl2).
4.2.2. (4R)-[4-(4-Aminooxymethyl-phenyl)-[1,2,3]tri-
azol-1-yl]-tetrahydro-furan-(3R)-ol (acetone oxime of
29). White solid. Mp 125.0–126.0 8C. 1H NMR
(400 MHz, CDCl3) d 7.80 (s, 1H), 7.73 (d, 2H, J¼7.6 Hz),
7.39 (d, 2H, J¼7.6 Hz), 5.18 (m, 1H), 5.06 (s, 2H), 4.61 (m,
1H), 4.35 (dd, 1H, J¼5.2, 10.0 Hz), 4.29 (dd, 1H, J¼5.6,
10.0 Hz), 4.20 (dd, 1H, J¼2.0, 10.8 Hz), 3.84 (dd, 1H,
J¼3.2, 9.6 Hz), 1.88 (s, 3H), 1.86 (s, 3H); 13C NMR
(75.0 MHz, CDCl3) d 155.8, 148.0, 138.9, 129.1, 128.5,
125.7, 118.5, 74.7, 74.0, 70.8, 68.5, 21.8, 15.7; IR (thin film)
n
max 3409, 3137, 2960, 2930, 2882, 2856, 1639, 1620, 1496,
;
1442, 1416, 1364, 1232, 1074, 1012, 882, 803, 739 cm21
LRMS [M]þ calculated for C16H20N4O3: 316.4, found:
316.0; [a]2D3¼254.58 (c¼0.67, CH2Cl2).
4.2.3. 2-[4-(4-Aminooxymethyl-phenyl)-[1,2,3]triazol-1-
yl]-(1R)-(3-methoxy-phenyl)-ethanol (acetone oxime of
1
30). Colorless oil. H NMR (400 MHz, CDCl3) d 7.79 (s,
1H), 7.70 (s, 1H), 7.65 (d, 1H, J¼8.0 Hz), 7.30 (m, 3H),
6.98 (m, 2H), 6.86 (m, 1H), 5.22 (dd, 1H, J¼3.2, 8.8 Hz),
5.05 (s, 1H), 4.66 (dd, 1H, J¼3.2, 14.0 Hz), 4.44 (dd, 1H,
J¼8.8, 13.6 Hz), 3.79 (s, 3H), 1.98 (s, 1H), 1.89 (s, 3H),
1.85 (s, 3H); 13C NMR (75.0 MHz, CDCl3) d 160.1, 155.7,
147.3, 141.9, 139.0, 130.4, 130.0, 128.9, 127.7, 125.1,
124.9, 121.4, 118.1, 114.1, 111.3, 75.0, 72.8, 57.5, 55.2,
21.8, 15.7; IR (thin film) nmax 3305, 3141, 2923, 1601, 1489,
1458, 1434, 1367, 1266, 1073, 10489, 790, 699 cm21
;
LRMS [M]þ calculated for C21H24N4O3: 380.4, found:
380.2; [a]2D3¼224.48 (c¼0.54, CH2Cl2).
4.2.4. (4R)-[4-(2-Aminooxymethyl-phenyl)-[1,2,3]tri-
azol-1-yl]-tetrahydro-furan-(3R)-ol (acetone oxime of
1
31). Colorless oil. H NMR (400 MHz, CDCl3) d 7.93 (s,
1H), 7.88 (dd, 1H, J¼1.2, 7.6 Hz), 7.41 (m, 3H), 5.20 (m,
1H), 5.04 (m, 2H), 4.61 (m, 1H), 4.36 (dd, 1H, J¼5.2,
10.4 Hz), 4.24 (dd, 1H, J¼5.6, 10.4 Hz), 4.18 (dd, 1H,
J¼3.2, 10.4 Hz), 3.83 (dd, 1H, J¼3.2, 10.0 Hz), 1.98 (s,
1H), 1.88 (s, 3H), 1.84 (s, 3H); 13C NMR (75.0 MHz,
CDCl3) d 156.4, 146.3, 134.1, 131.0, 130.3, 129.0, 128.8,
128.5, 121.5, 74.0, 73.97, 70.8, 68.3, 21.8, 15.7; IR (thin
film) nmax 3362, 2925, 2880, 1648, 1435, 1368, 1269, 1227,
1074, 914, 767 cm21
;
LRMS [M]þ calculated for
C16H20N4O3: 316.4, found: 316.0; [a]2D3¼252.88 (c¼0.59,
CH2Cl2).
4.2.5. 1-[4-[(1S)-Aminooxy-ethyl)-[1,2,3]triazol-1-yl]-3-
isopropoxy-propan-(2R)-ol (acetone oxime of 32). Color-
less oil. 1H NMR (400 MHz, CDCl3) d 7.57 (s, 1H), 5.37 (q,
1H, J¼6.8 Hz), 4.52 (dd, 1H, J¼3.6, 14.0 Hz), 4.39 (dd, 1H,
J¼6.4, 14.0 Hz), 4.13 (m, 1H), 3.56 (m, 1H), 3.44 (dd, 1H,

8652
S. Su et al. / Tetrahedron 60 (2004) 8645–8657
Scheme 11. Synthesis of propargylic amine-containing alkoxyamines. Reagents and conditions: (a) CH2Cl2, p-TsOH·H2O, (CH2O)n. (b) CuBr, DMF, 50 8C.
(c) NH2NH2, CH2Cl2.
J¼5.2, 9.6 Hz), 3.34 (dd, 1H, J¼6.0, 9.6 Hz), 1.83 (s, 6H),
1.63 (d, 3H, J¼8.4 Hz), 1.13 (s, 3H), 1.12 (s, 3H); 13C NMR
(75.0 MHz, CDCl3) d 155.2, 150.0, 122.8, 73.2, 72.4, 69.3,
68.7, 52.7, 21.9, 21.8, 19.9, 15.7; IR (thin film) nmax 3333,
(75.0 MHz, CDCl3) d 170.4, 163.1, 155.9, 140.9, 130.1,
129.1, 129.0, 128.3, 127.5, 126.9, 126.7, 125.9, 97.4, 74.5,
21.8, 15.7; IR (thin film) nmax 3106, 2922, 2856, 1620, 1566,
1503, 1463, 1367, 1074, 950, 816, 767, 671 cm21; LRMS
[M]þ calculated for C19H18N2O2: 306.4, found: 306.2.
2972, 2924, 1457, 1371, 1262, 1130, 1078, 935, 668 cm21
;
LRMS [M]þ calculated for C13H24N4O3: 284.4, found:
284.5; [a]2D3¼þ11.98 (c¼0.55, CH2Cl2).
4.2.8. O-[3-(3-Phenyl-isoxazol-5-yl)-benzyl]-hydroxyl-
1
amine (acetone oxime of 39). Pale yellow oil. H NMR
4.2.6. Representative procedure for synthesis of isoxa-
zole-containing alkoxyamines (acetone oxime of 41).
(400 MHz, CDCl3) (spectrum of the major isomer reported)
d 7.85 (m, 2H), 7.84 (s, 1H), 7.76 (d, 1H, J¼6.8 Hz), 7.46
(m, 5H), 6.82 (s, 1H), 5.12 (s, 2H), 1.91 (s, 3H), 1.87 (s, 3H);
13C NMR (75.0 MHz, CDCl3) (spectrum of the mixture of
both isomers reported) d 170.5, 163.1, 155.9, 155.8, 139.6,
138.7, 137.0, 130.1, 129.7, 129.1, 129.0, 128.8, 128.5,
128.4, 128.3, 127.5, 126.9, 125.2, 125.1, 121.4, 103.0, 97.6,
74.62, 74.56, 21.8, 15.7; IR (thin film) nmax 3063, 2920,
2869, 1608, 1573, 1484, 1468, 1447, 1401, 1366, 1271,
1073, 1019, 921, 791, 767, 694 cm21; CIHRMS [M]þ
calculated for C19H18N2O2: 306.4, found: 306.2.
Cyclohexanecarboxaldehyde
(21.6 mg,
0.193 mmol),
hydroxylamine hydrochloride (26.7 mg, 0.385 mmol) were
mixed with 1 mL CH2Cl2 in the presence of Et3N (79 mL,
0.578 mmol). The reaction mixture was stirred for 1 h,
diluted with CH2Cl2, and subsequently applied to an SLE
cartridge (5.0 mL) containing 1 N HCl. After elution with
15 mL CH2Cl2, the resulting oxime solution was concen-
trated and reacted with NBS in CH2Cl2 for 3 h. The reaction
mixture was transferred to a 5 mL reaction vessel on the
Quest-210 synthesizer containing the alkyne resin
(0.0385 mmol, see procedure for preparation of 33) and
NaHCO3 (16.4 mg, 0.193 mmol). The reaction was agitated
at 35 8C for 12 h to afford the corresponding isoxazole-
containing resin. After filtration and resin washing with H2O
(2£3 mL), MeOH (1£3 mL), DMF (2£3 mL), THF
(3£3 mL) and CH2Cl2 (3£3 mL), 2 mL CH2Cl2 and
NH2NH2 (2.5 mL, 0.077 mmol) were added and the reaction
was agitated for 1 h. The reaction was filtered, the resin
washed with CH2Cl2, and the filtrate collected and
evaporated to provide 7.8 mg (0.0374 mmol, 72.4%) of
O-[(1S)-(3-cyclohexyl-isoxazol-5-yl)-ethyl]-hydroxylamine
41 as a colorless oil. 41 was treated with 2 mL acetone and
then concentrated, and the resulting sample was subjected to
HPLC-ELSD analysis using a Waters HPLC-MS system
(XTerrawRP8, 5 mm, 4.6£30 mm column) to determine the
purity (.99%). 1H NMR (400 MHz, CDCl3) d 5.98 (s, 1H),
5.27 (q, 1H, J¼7.2 Hz), 2.70 (m, 1H), 1.96 (m, 2H), 1.86 (s,
3H), 1.84 (s, 3H), 1.75 (m, 3H), 1.38 (m, 5H); 13C NMR
(75.0 MHz, CDCl3) d 172.9, 168.3, 156.1, 99.4, 72.9, 35.8,
31.9, 25.88, 25.77, 21.7, 18.8, 15.7; IR (thin film) nmax 2985,
2929, 2854, 1603, 1450, 1423, 1371, 1343, 1269, 1155, 1087,
986, 933, 891, 803 cm21; LRMS [M]þ calculated for
C14H22N2O2: 250.3, found: 250.4; [a]2D3¼22.98 (c¼0.28,
CH2Cl2).
4.2.9. O-{(1S)-[3-(2,4,6-Trimethyl-phenyl)-isoxazol-5-
yl]-ethyl}-hydroxylamine (acetone oxime of 40). Color-
less oil. 1H NMR (400 MHz, CDCl3) d 6.91 (s, 2H), 6.07 (s,
1H), 5.38 (q, 1H, J¼6.8 Hz), 2.29 (s, 3H), 2.12 (s, 6H), 1.88
(s, 3H), 1.85 (s, 3H), 1.66 (d, 3H, J¼7.2 Hz); 13C NMR
(75.0 MHz, CDCl3) d 173.5, 161.9, 156.1, 138.7, 137.3,
128.3, 102.75, 102.67, 72.9, 21.6, 21.0, 20.1, 18.7, 15.6; IR
(thin film) nmax 2986, 2923, 1613, 1445, 1373, 1268, 1090,
1030, 986, 933, 890, 671, 656 cm21; LRMS [M]þ
calculated for C17H22N2O2: 286.4, found: 286.6;
[a]2D3¼þ12.18 (c¼1.57, CH2Cl2).
4.2.10. O-{(1S)-[3-(2,4-Dimethoxy-phenyl)-isoxazol-5-
yl]-ethyl}-hydroxylamine (acetone oxime of 42). Pale
1
yellow oil. H NMR (400 MHz, CDCl3) d 7.44 (d, 1H,
J¼2.8 Hz), 6.92 (m, 2H), 6.67 (s, 1H), 5.36 (q, 1H,
J¼6.8 Hz), 3.82 (s, 3H), 3.79 (s, 3H), 1.87 (s, 3H), 1.84
(s, 3H), 1.64 (d, 3H, J¼7.2 Hz); 13C NMR (75.0 MHz,
CDCl3) d 172.9, 159.8, 156.1, 153.7, 151.7, 118.6, 117.2,
113.6, 113.1, 102.9, 72.7, 56.1, 55.8, 21.7, 18.6, 15.7; IR
(thin film) nmax 2990, 2937, 1602, 1511, 1471, 1438, 1372,
1275, 1226, 1045, 857, 745, 669 cm21; LRMS [M]þ
calculated for C16H20N2O4: 304.3, found: 304.2;
[a]2D3¼þ4.58 (c¼1.33, CH2Cl2).
4.2.7. O-[4-(3-Phenyl-isoxazol-5-yl)-benzyl]-hydroxyl-
amine (acetone oxime of 38). Colorless oil. 1H NMR
(400 MHz, CDCl3) d 7.84 (m, 4H), 7.46 (m, 5H), 6.80 (s,
1H), 5.10 (s, 2H), 1.91 (s, 3H), 1.87 (s, 3H); 13C NMR
4.2.11. Representative procedure for synthesis of pro-
pargylic amine-containing alkoxyamines (acetone oxime
of 50). (R)-(þ)-1-(4-Methoxybenzyl)-1,2,3,4,5,6,7,8-octa-
hydroisoquinolline (49.6 mg, 0.193 mmol) was mixed with

S. Su et al. / Tetrahedron 60 (2004) 8645–8657
8653
Scheme 12. Oxime formation. Reagents and conditions: (a) ClCH2CH2Cl,
120 8C, 150 W, 15 min. (b) HOAc, EtOAc, 150 8C, 150 W, 30 min. (c) PL-
MIA, CH2Cl2, 4 h.
paraformaldehyde (9.2 mg, 0.29 mmol), p-TsOH·H2O
(36.7 mg, 0.193 mmol), and 1 mL CH2Cl2. The reaction
mixture was stirred for 3 h and then concentrated. The
resulting solid was mixed with 2 mL DMF and transferred
to a 5 mL reaction vessel on the Quest-210 synthesizer
containing the alkyne resin (0.0385 mmol, see procedure for
preparation of 33) and CuBr (2.7 mg, 0.0193 mmol,
50 mol%). The reaction was agitated at 50 8C for 12 h to
afford the corresponding propargylic amine-containing
resin. After filtration and resin washing with H2O
(2£3 mL), MeOH (1£3 mL), DMF (2£3 mL), MeOH
(1£3 mL), 10% N,N,N0,N0-tetramethylethylenediamine in
CH2Cl2 (2£3 mL), CH2Cl2 (1£3 mL), 5% AcOH in CH2Cl2
(2£3 mL), THF (3£3 mL) and CH2Cl2 (3£3 mL), 2 mL
CH2Cl2 and NH2NH2 (2.5 mL, 0.077 mmol) was added and
the reaction was agitated for 1 h. The reaction was filtered,
the resin was washed with CH2Cl2, and the filtrate was
collected and evaporated to provide 12.9 mg (0.0363 mmol,
70.7%) of O-{4-[(1R)-(4-methoxy-benzyl)-3,4,5,6,7,8-
hexahydro-1H-isoquinolin-2-yl]-(1S)-methyl-but-2-ynyl}-
hydroxylamine 50 as a pink oil. 50 was treated with 2 mL
acetone, concentrated, and the resulting sample subjected to
HPLC-ELSD analysis using a Waters HPLC-MS system
(XTerrawRP8, 5 mm, 4.6£30 mm column) to determine the
1
purity (97%). H NMR (400 MHz, CDCl3) d 7.18 (d, 2H,
J¼8.4 Hz), 6.77 (d, 2H, J¼8.4 Hz), 4.81 (q, 1H, J¼6.7 Hz),
3.75 (s, 3H), 3.51 (dd, 2H, J¼16.4, 38.0 Hz), 3.26 (s, 1H),
2.90 (m, 1H), 2.78 (m, 3H), 1.90 (m, 2H), 1.85 (s, 3H), 1.84
(s, 3H), 1.64 (m, 8H), 1.44 (d, 3H, J¼6.8 Hz); 13C NMR
(75.0 MHz, CDCl3) d 157.8, 155.4, 132.6, 130.2, 129.1,
127.7, 113, 68.4, 62.3, 55.1, 45.3, 43.5, 35.7, 30.0, 28.1,
27.9, 23.0, 22.7, 21.8, 21.1, 15.7; IR (thin film) nmax 2086,
2928, 2832, 1613, 1512, 1440, 1368, 1326, 1247, 1176,
1072, 1038, 931, 824, 659 cm21; CIHRMS [M]þ calculated
for C25H34N2O2: 394.5, found: 394.3; [a]2D3¼24.38
(c¼0.55, CH2Cl2).
4.2.12. O-[4-(3-Morpholin-4-yl-prop-1-ynyl)-benzyl]-
1
hydroxylamine (acetone oxime of 46). Colorless oil. H
NMR (400 MHz, CDCl3) d 7.40 (d, 2H, J¼8.0 Hz), 7.27 (d,
2H, J¼8.4 Hz), 5.02 (s, 2H), 3.77 (t, 4H, J¼4.8 Hz), 3.50 (s,
2H), 2.65 (t, 4H, J¼3.6 Hz), 1.86 (s, 3H), 1.85 (s, 3H); 13C
NMR (75.0 MHz, CDCl3) d 155.7, 138.7, 131.7, 127.7,
122.1, 85.7, 83.6, 74.7, 66.7, 52.2, 48.0, 21.8, 15.7; IR (thin
film) nmax 2922, 2855, 2814, 1510, 1454, 1367, 1117, 1072,
1012, 828, 669, 655 cm21; LRMS [M]þ calculated for
C17H22N2O2: 286.4, found: 285.9.
4.2.13. O-[3-(3-Morpholin-4-yl-prop-1-ynyl)-benzyl]-
1
hydroxylamine (acetone oxime of 47). Colorless oil. H
NMR (400 MHz, CDCl3) d 7.40 (m, 2H), 7.29 (m, 1H), 7.20
(m, 1H), 5.21 (s, 2H), 3.77 (t, 4H, J¼4.4 Hz), 3.56 (s, 2H),
2.67 (t, 4H, J¼4.4 Hz), 1.90 (s, 3H), 1.86 (s, 3H); 13C NMR
(75.0 MHz, CDCl3) d 155.6, 140.2, 132.4, 128.4, 127.7,
127.3, 121.5, 88.2, 83.5, 73.4, 66.7, 52.1, 48.0, 21.8, 15.7;

Table 4. Synthesis of complex oximes
Alkoxyamines
29
41
50
29
41
Aldehyde/ketone
51
52
53
54
55
Products
57a
95
98
58b
96
59c
93
60
86
97
61b
89
Yield (%)
Purity (%)d
99
99
98
a
Isolated as a 2:1 (E:Z) mixture of oximes, as determined by 1H NMR (see Ref. 1a).
Isolated as a 1:1 (E:Z) mixture of oximes, as determined by 1H NMR (see Ref. 1a).
Isolated as a 7:1 (E:Z) mixture of oximes, as determined by 1H NMR (see Ref. 1a).
Purity determined by HPLC-ELSD analysis.
b
c
d

S. Su et al. / Tetrahedron 60 (2004) 8645–8657
8655
IR (thin film) nmax 2958, 2921, 2855, 2815, 1484, 1452,
1366, 1117, 1072, 1011, 761, 666 cm21; CIHRMS [M]þ
calculated for C17H22N2O2: 286.4, found: 285.9.
4.2.17. 1,4-Dioxa-spiro[4.5]decane-2-carbaldehyde O-{4-
[1-[(4R)-hydroxy-tetrahydro-furan-(3R)-yl]-1H-
[1,2,3]triazol-4-yl]-benzyl}-oxime 57. Pale yellow oil
1
isolated as a 2:1 mixture of E:Z oxime ethers. H NMR
4.2.14. O-[2-(3-Morpholin-4-yl-prop-1-ynyl)-benzyl]-
1
hydroxylamine (acetone oxime of 48). Colorless oil. H
(400 MHz, CDCl3) d 7.83 (s, 1H), 7.78 (d, 2H, J¼7.9 Hz),
7.39 (m, 2H), 7.36 (d, 1H, J¼8.2 Hz, E), 6.93 (d, 1H,
J¼4.3 Hz, Z), 5.14 (m, 1H), 5.09 (s, 2H, E), 5.08 (s, 2H, Z),
4.69 (m, 1H), 4.61 (dd, 1H, J¼6.3, 12.9 Hz), 4.38 (dd, 1H,
J¼5.4, 10.4 Hz), 4.30 (dd, 1H, J¼5.4, 10.1 Hz), 4.23 (dd,
1H, J¼2.5, 10.4 Hz, 1H), 4.13 (dd, 1H, J¼6.6, 8.6 Hz, E),
3.86–3.83 (m, 2H), 3.72 (dd, 1H, J¼6.8, 8.4 Hz, Z), 1.59
(m, 8H), 1.38 (m, 2H); 13C NMR (75.0 MHz, CDCl3) d
153.0, 149.3, 147.9, 137.8, 137.6, 129.6, 128.9, 128.7,
128.4, 125.8, 125.7, 118.5, 110.9, 110.4, 77.1, 76.6, 75.9,
75.7, 74.0, 72.8, 70.8, 70.5, 68.5, 67.6, 67.0, 60.4, 36.0,
35.5, 34.8, 34.7, 29.6, 25.7, 24.9, 23.76, 23.72, 23.68, 20.9,
14.0; IR (thin film) nmax 3410, 3137, 2933, 2856, 1447,
1366, 1232, 1164, 1110, 1076, 1041, 1014, 975, 930, 803,
696, 655 cm21; LRMS [M]þ calculated for C22H28N4O5:
428.2, found: 428.2; [a]2D3¼220.28 (c¼0.67, CH2Cl2).
NMR (400 MHz, CDCl3) d 7.40 (s, 1H), 7.29 (m, 3H), 5.00
(s, 2H), 3.78 (t, 4H, J¼4.0 Hz), 3.51 (s, 2H), 2.65 (m, 4H),
1.87 (s, 3H), 1.85 (s, 3H); 13C NMR (75.0 MHz, CDCl3) d
155.6, 138.7, 131.1, 131.0, 128.3, 127.8, 122.9, 85.8, 83.6,
74.6, 66.7, 52.3, 48.0, 21.8, 15.7; IR (thin film) nmax 2956,
2924, 2855, 1484, 1453, 1367, 1267, 1118, 1073, 1006, 797,
692, 671 cm21; LRMS [M]þ calculated for C17H22N2O2:
286.4, found: 285.9.
4.2.15. O-{(1S)-Methyl-4-[(2S)-methyl-piperidin-1-yl]-
but-2-ynyl}-hydroxylamine (acetone oxime of 49). Color-
less oil. 1H NMR (400 MHz, CDCl3) d 4.83 (q, 1H,
J¼5.3 Hz), 3.69 (dd, 1H, J¼2.0, 15.2 Hz), 3.36 (par obsc,
1H), 2.77 (m, 1H), 2.44 (m, 1H), 2.36 (m, 1H), 1.86 (s, 3H),
1.84 (s, 3H), 1.61 (m, 4H), 1.46 (d, 3H, J¼6.8 Hz), 1.26 (m,
2H), 1.06 (d, 3H, J¼6.0 Hz); 13C NMR (75.0 MHz, CDCl3)
d 155.6, 86.0, 78.4, 68.3, 54.7, 53.2, 43.5, 34.5, 26.0, 24.4,
21.8, 21.2, 19.8, 15.7; IR (thin film) nmax 3283, 2931, 2855,
2801, 1650, 1544, 1440, 1372, 1322, 1157, 1074, 990, 932,
892, 656 cm21; LRMS [M]þ calculated for C14H24N2O:
236.4, found: 236.0; [a]2D3¼þ6.08 (c¼0.61, CH2Cl2).
4.2.18. 1,2-O-Cyclohexylidene-a-D-xylopentodialdo-1,4-
furanose O-[(1S)-(3-cyclohexyl-isoxazol-5-yl)-ethyl]-
oxime 58. Pale yellow oil isolated as a 1:1 mixture of E:Z
1
oxime ethers. H NMR (400 MHz, CDCl3) d 7.54 (d, 1H,
J¼5.3 Hz, E), 6.85 (d, 1H, J¼3.0 Hz, Z), 6.0 (s, 1H), 5.97
(d, 1H, J¼3.6 Hz), 5.37 (dd, 1H, J¼6.9, 13.7 Hz, Z), 5.31
(dd, 1H, J¼6.9, 13.7 Hz, E), 5.01 (t, 1H, J¼3.0 Hz, Z), 4.67
(m, 1H), 4.55 (t, 1H, J¼3.3 Hz), 4.34 (d, 1H J¼2.6 Hz, E),
2.74–2.67 (m, 1H), 1.96–1.94 (m, 2H), 1.81–1.78 (m, 2H),
1.72–1.64 (m, 4H), 1.60 (dd, 3H, J¼6.9, 8.2 Hz), 1.57–1.52
(m, 4H), 1.49–1.31 (m, 6H), 1.28–1.23 (m, 2H); 13C NMR
(75.0 MHz, CDCl3) d 172.2, 172.0, 168.9, 168.8, 150.7,
148.2, 113.1, 113.0, 105.1, 104.6, 100.7, 100.4, 85.0, 84.9,
78.4, 78.0, 76.7, 76.0, 74.3, 74.1, 36.8, 36.7, 36.1, 35.9,
32.3, 32.2, 32.1, 26.2, 26.1, 26.0, 25.1, 24.2, 24.1, 23.8,
18.8, 18.7; IR (thin film) nmax 3415, 2934, 2865, 1604, 1451,
1371, 1341, 1291, 1232, 1076, 1019, 940, 867, 808, 759,
4.2.16. Representative procedure for the synthesis of
oxime ethers from aldehydes. To a standard microwave
reaction vessel (CEM Corp.) equipped with a stir bar was
charged (S)-citronellal 53 (0.0044 mL, 0.024 mmol), O-{4-
[(3R)-(4-methoxy-benzyl)-3,4,5,6,7,8-hexahydro-1H-iso-
quinolin-2-yl]-(1S)-methyl-but-2-ynyl}-hydroxylamine 50,
(0.0104 g, 0.0293 mmol, 1.2 equiv.), and dichloroethane
(0.075 mL, 0.3 M). The mixture was heated under micro-
wave irradiation for 15 min at 120 8C (300 W). The reaction
mixture was cooled to rt and charged with PL-MIA resin
(0.0063 g, 0.0162 mmol, 3 equiv.) and stirred at room
temperature for 4 h. The resin was filtered and rinsed with
CH2Cl2 (3£1 mL). The filtrate was concentrated under
reduced pressure to yield (3S),7-dimethyl-oct-6-enal O-{4-
[(1R)-(4-methoxy-benzyl)-3,4,5,6,7,8-hexahydro-1H-iso-
quinolin-2-yl]-(1S)-methyl-but-2-ynyl}-oxime 59
(0.0109 g, 0.0222 mmol, 93% yield) as a pink oil (7:1
mixture of E:Z oxime ethers). The product was subjected to
an HPLC-ELSD analysis using a Waters HPLC-MS system
(XTerrawRP8, 5 mm, 4.6£30 mm column) to determine the
696, 674 cm21
;
CIHRMS [MþH]þ calculated for
C22H32N2O6: 420.2, found: 420.2; [a]2D3¼211.18 (c¼1.22,
CH2Cl2).
4.2.19. Representative procedure for synthesis of oxime
ethers from ketones. To a standard microwave reaction
vessel (CEM Corp.) equipped with a stir bar was charged
estrone 54 (0.0079 g, 0.029 mmol), O-alkylhydroxylamine
30, (0.0097 g, 0.035 mmol, 1.2 equiv.), acetic acid
(0.025 mL, 0.44 mmol, 15 equiv.), and ethyl acetate
(0.50 mL, 0.06 M). The mixture was heated under micro-
wave irradiation for 30 min at 150 8C (300 W). The cooled
reaction mixture was concentrated under reduced pressure.
The mixture was re-suspended in dichloromethane
(0.20 mL), and charged with PL-MIA (0.0071 g,
0.018 mmol, 3 equiv) and stirred at room temperature for
4 h. The resin was filtered and rinsed with CH2Cl2
(3£1 mL). The filtrate was concentrated under reduced
pressure to yield 3-hydroxylestra-1,3,5(10)-triene-17-one O-
{4-[1-[(4R)-hydroxy-tetrahydro-furan-(3R)-yl]-1H-[1,2,3]-
triazol-4-yl]-benzyl}-oxime 60 (0.0133 g, 0.025 mmol,
86% yield) as a clear, yellow oil. The product was subjected
to an HPLC-ELSD analysis using a Waters HPLC-MS
system (XTerrawRP8, 5 mm, 4.6£30 mm column) to
1
purity (99%). H NMR (400 MHz, CDCl3) d 7.38 (t, 1H,
J¼6.6 Hz, E), 7.16 (d, 2H, J¼8.6 Hz), 6.76 (d, 2H,
J¼8.6 Hz), 6.69 (t, 1H, J¼5.4 Hz, Z), 5.07–5.03 (m, 1H),
4.84–4.79 (m, 1H), 3.76 (s, 3H), 3.44 (dd, 2H, J¼17.0,
42.4 Hz), 3.21 (m, 1H), 2.89–2.87 (m, 1H), 2.76 (m, 3H),
2.22–2.15 (m, 1H), 2.06–1.80 (m, 6H), 1.66 (s, 3H), 1.58,
(s, 3H), 1.43 (d, 3H, J¼6.6 Hz), 1.39–1.27 (m, 2H), 1.23–
1.14 (m, 3H), 0.90 (d, 3H, J¼6.6 Hz); 13C NMR (75.0 MHz,
CDCl3) d 151.1, 130.6, 130.2, 127.8, 124.4, 113.4, 77.2,
68.6, 62.3, 55.1, 45.3, 43.4, 36.7, 36.6, 36.3, 35.7, 32.6,
30.8, 30.5, 30.1, 29.6, 28.1, 25.6, 25.3, 23.0, 22.7, 21.0,
19.6, 19.3, 17.5; IR (thin film) nmax 2926, 2834, 2739, 1613,
1512, 1458, 1376, 1327, 1247, 1177, 1072, 1040, 935, 830,
775, 661; LRMS [M]þ calculated for C32H46N2O2: 490.4,
found: 490.6; [a]2D3¼þ4.28 (c¼0.28, CH2Cl2).
1
determine the purity (97%). H NMR (400 MHz, CDCl3)

8656
S. Su et al. / Tetrahedron 60 (2004) 8645–8657
Tamaoki, T.; Kurebayashi, J.; Schulte, T. W.; Neckers,
L. M.; Akinaga, S. Cancer Chem. Pharm. 2001, 48,
435–445. (d) Protease inhibitors: Renaudet, O.; Reymond,
J. L. Org. Lett. 2003, 5, 4693–4696. (e) Circular DNA
analogues: Edupuganti, O. P.; Defrancq, E.; Dumy, P. J. Org.
Chem. 2003, 68, 8708–8710. (f) g turn: Yang, D.; Li, W.; Qu,
J.; Luo, S. W.; Wu, Y. D. J. Am. Chem. Soc. 2003, 125,
13018–13019. Examples of oxime-containing natural
products: (g) oximidine II: Kim, J. W.; Shin-ya, K.; Furihata,
K.; Hayakawa, Y.; Seto, H. J. Org.Chem. 1999, 64, 153–155.
(h) Synthesis : Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc.
2003, 125, 6040–6041. (i) Lobatamide C: Galinis, D. L.;
McKee, T. C.; Pannell, L. K.; Cardellina, J. H., II; Boyd, M. R.
J. Org. Chem. 1997, 62, 8968–8969. (j) Synthesis: Shen, R. C.;
Lin, C. T.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr.
J. Am. Chem. Soc. 2003, 125, 6040–6041.
d 7.80 (s, 1H), 7.68 (d, 2H, J¼8.2 Hz), 7.30 (d, 2H,
J¼7.9 Hz), 6.99 (d, 1H, J¼8.6 Hz), 6.52 (dd, 1H, J¼2.6,
8.6 Hz), 6.46 (s, 1H), 5.01 (m, 1H), 4.97 (s, 2H), 4.47 (m,
1H), 4.25 (dd, 1H, J¼5.6, 10.2 Hz), 4.16–4.11 (m, 2H),
3.71 (dd, 1H, J¼3.3, 9.9 Hz), 2.73–2.69 (m, 2H), 2.48–2.38
(m, 2H), 2.24–2.20 (m, 1H), 2.14–2.09 (m, 1H), 1.95–1.90
(m, 1H), 1.81–1.75 (m, 2H), 1.52–1.22 (m, 6H), 1.16–1.12
(m, 2H), 0.82 (s, 3H); 13C NMR (75.0 MHz, CDCl3) d
171.5, 153.7, 138.9, 138.1, 132.3, 129.1, 128.6, 128.4,
128.3, 126.5, 125.6, 118.5, 115.3, 112.8, 77.1, 74.9, 74.1,
70.1, 68.4, 52.8, 44.3, 43.8, 38.0, 34.0, 29.6, 29.4, 27.1,
26.0, 22.9, 17.2; IR (thin film) nmax 3314, 3147, 3056, 2927,
2868, 1732, 1652, 1612, 1583, 1501, 1453, 1418, 1371,
1285, 1247, 1232, 1099, 1078, 1048, 1015, 983, 915, 853,
736, 667 cm21; CIHRMS [MþH]þ calculated for
C31H36N4O4: 528.3, found: 528.5; [a]2D3¼23.88 (c¼0.16,
CH2Cl2).
2. For recent examples of library syntheses employing alkoxy-
amines as diversity reagents, see: (a) Maly, D. J.; Choong, I. C.;
Ellman, J. A. Proc. Natl. Acad. Sci. U.S.A. 2000, 97,
2419–2424. (b) Pelish, H. E.; Westwood, N. J.; Feng, Y.;
Kirchhausen, T.; Shair, M. D. J. Am. Chem. Soc. 2001, 123,
6740–6741. (c) Wipf, P.; Reeves, J. T.; Balachandran, R.;
Day, B. W. J. Med. Chem. 2002, 45, 1901–1917. (d) Ishikawa,
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Okonogi, K.; Miyake, A. J. Antibiot. 2000, 53, 1071–1085.
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4.2.20. (2S)-trans-7-Chloro-20,4,6-trimethoxy-(60S)-
methyl spiro(benzofuran-2[3H], 10-[2]cyclohexene)-3,40-
dione-40 O-[(1S)-(3-cyclohexyl-isoxazol-5-yl)-ethyl]-
oxime 61. Pale yellow oil isolated as a 1:1 mixture of E:Z
oxime ethers. 1H NMR (400 MHz, CDCl3) d 6.15 (s, 1H, Z),
6.08 (s, 1H), 6.01 (s, 1H), 5.56 (s, 1H, E), 5.28 (m, 1H), 3.99
(s, 3H), 3.94 (s, 3H), 3.58 (s, 3H, E), 3.51 (s, 3H, Z), 3.03
(dd, 1H, J¼4.9, 16.8 Hz, Z), 2.92 (dd, 1H, J¼13.2, 15.0 Hz,
E), 2.74–2.65 (m, 1H), 2.64 (d, 1H, J¼16.8 Hz, Z), 2.58–
2.50 (m, 1H), 2.36 (dd, 1H, J¼4.1, 15.0 Hz, E), 1.95 (m,
2H), 1.81–1.68 (m, 3H), 1.61 (d, 3H, J¼6.6 Hz), 1.49–1.25
(m, 5H), 0.91 (d, 3H, J¼6.3 Hz); 13C NMR (75.0 MHz,
CDCl3) d 194.3, 194.2, 172.7, 172.6, 169.6, 168.4, 164.5,
161.4, 158.8, 157.6, 157.5, 155.3, 152.0, 105.6, 99.7, 99.6,
99.0, 97.1, 93.2, 91.4, 91.3, 89.2, 89.1, 73.5, 73.4, 56.9,
56.3, 56.1, 55.9, 36.4, 35.8, 35.2, 31.9, 31.0, 29.6, 26.2,
25.9, 25.8, 18.7, 18.6, 14.2, 14.1; IR (thin film) nmax 2930,
2853, 1707, 1613, 1590, 1466, 1351, 1220, 1141, 1099, 949,
912, 881, 733 cm21; CIHRMS [MþH]þ calculated for
C28H33ClN2O7: 544.2, found: 544.1; [a]2D3¼þ85.68
(c¼0.76, CH2Cl2).
˜
3. For a review of oxime formation, see: Abele, E.; Lukevics, E.
Org. Prep. Proced. Int. 2000, 32, 235–264.
4. There are 56 commercially available alkoxyamines in the
ChemACX database of commercially available compounds
(Cambridgesoft, Inc.). Only 2 of the 56 compounds are
optically active.
5. For the preparation of alkoxyamines using capture-ROMP-
release of a norbornenyl tagged N-hydroxysuccinimide, see:
(a) Harned, A. M.; Hanson, P. R. Org. Lett. 2002, 4,
1007–1010. For the preparation of alkoxyamines, see:
(b) Theilacker, W.; Ebke, K. Angew. Chem. 1956, 68, 303.
(c) Kim, J. N.; Kim, K. M.; Ryu, E. K. Syn. Commun. 1992, 22,
1427–1432. (d) Grochowski, E.; Jurczak, J. Synthesis 1976,
10, 682–684.
6. For recent reports concerning stereochemical diversity in
library design, see: (a) Smith, M. E. B.; Lloyd, M. C.; Derrien,
N.; Lloyd, R. C.; Taylor, S. J. C.; Chaplin, D. A.; Casy, G.;
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Acknowledgements
Financial support from the NIGMS CMLD initiative (P50
GM067041) is gratefully acknowledged. We thank Dr.
Aaron Beeler and Mr. Chaomin Li (Boston University) for
helpful discussions and Dr. Jeff Labadie and Owen Gooding
(Argonaut Technologies) for providing a secondary amine
resin.
References and notes
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