Efficient and flexible solid-phase synthesis of N-hydroxypolyamine derivatives

Article abstract of DOI:10.1002/ejoc.200800677

Orthogonally protected, N-hydroxylated, linear tri- and tetra-amines were efficiently synthesised on Merrifield resin, which was modified with a phenethyl bromide linker. The polyamine frameworks were convergently prepared from the centre with reductive aminations and nucleophilic substitutions to elongate the polyamine backbone. The required N-hydroxy groups were introduced during the cleavage of the polyamine derivatives from the resin through Cope elimination. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800677

FULL PAPER
DOI: 10.1002/ejoc.200800677
Efficient and Flexible Solid-Phase Synthesis of N-Hydroxypolyamine
Derivatives
Michaël Méret[a] and Stefan Bienz*[a]
Keywords: Polyamine / Hydroxylamine / Solid-phase synthesis / Elimination / Toxin
Orthogonally protected, N-hydroxylated, linear tri- and tetra-
amines were efficiently synthesised on Merrifield resin,
which was modified with a phenethyl bromide linker. The
polyamine frameworks were convergently prepared “from
the centre” with reductive aminations and nucleophilic sub-
stitutions to elongate the polyamine backbone. The required
N-hydroxy groups were introduced during the cleavage of
the polyamine derivatives from the resin through Cope elimi-
nation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
flexible method based on the inexpensive Merrifield
resin.[12,13] Starting with the construction of the polyamine
backbone from the centre, we were able to efficiently syn-
thesise and derivatise a number of asymmetric polyamines.
Until now, our method has been applied to the prepara-
tion of terminally acylated polyamines only. A number of
natural products, however, are additionally derivatised at
the internal N atoms (e.g. the N-hydroxylated spider toxins
Agel 448 and Agel 452 of Agelenopsis aperta, Figure 1).[14]
In connection with our ongoing studies in the isolation and
analysis of spider toxins, we were interested in extending
our solid-phase strategy for the preparation of N-hydroxyl-
ated polyamine derivatives, too. We were confident that the
Cope elimination provided an efficient transformation for
the concurrent introduction of the desired N-hydroxy func-
tionality and the cleavage of the final products from the
resin. This reaction was already applied to the synthesis of
N-hydroxylated compounds on solid-phase by Seo et al.,[15]
but for simple systems only. The new challenge for us was
to expand the method to the synthesis of more complex
compounds, which requires not only an orthogonal protec-
tive group strategy – as for the synthesis of common poly-
amine derivatives on the solid phase – but also, and particu-
Introduction
Aliphatic di- and polyamines are widespread natural
products found in microorganisms, plants and animals.
They often occur as conjugates to a number of different
biological structures but also in free form (called biogenic
amines). In addition to the almost ubiquitous spermine and
the equally abundant putrescine and spermidine, a great
number of other biogenic polyamines are known. Poly-
amines display a wide range of biological effects, and the
last 30 years have witnessed increasing research activity in
the field of polyamines, particularly concerning their bio-
logical functions in microorganisms as well as plant and
animal systems. Polyamines play important roles in DNA
stabilisation[1] and modification,[2] protein biosynthesis,[3]
the modification of neuroreceptors and their associated ion
channels in the mammalian central nervous system[4] and
interact with phospholipids in biological membranes.[5] Be-
cause polyamine derivatives are therapeutic leads for the
treatment of a variety of brain disorders such as Parkin-
son’s[6] and Alzheimer’s diseases,[7] new and efficient meth-
ods for their synthesis are being sought.
The synthesis of polyamines in solution is a laborious
task since it involves the intensive use of protective group
strategies[8] and often requires difficult purification steps
due to the high polarity of the compounds. Solid-phase syn-
thesis (SPS) of polyamines and polyamine derivatives facili-
tates the procedures; the work-up and purification opera-
tions are largely reduced to simple filtrations and wash-
ings.[9–11] So far, we have contributed to the topic of poly-
amine synthesis on solid-phase with the elaboration of a
[a] Institute of Organic Chemistry, University of Zürich,
Winterthurerstrasse 190, 8057 Zürich, Switzerland
Fax: +41-44-635-6812
E-mail: sbienz@oci.uzh.ch
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Two representatives of N-hydroxylated polyamine spider
toxins from Agelenopsis aperta.
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Solid-Phase Synthesis of N-Hydroxypolyamines
larly, protective groups that are resistant to oxidative condi- tration revealed the complete substitution of the halogens.
tions. In the following, we show that we were, in fact, able In the case of resins 9 and 10 with their Boc- and Alloc-
to efficiently apply solid-phase chemistry and the Cope eli- protected amines, FT-IR analysis showed the typical ab-
mination to the synthesis of a number of differently pro- sorption for the carbamate carbonyl group at 1707 cm–1.
tected, asymmetric, N-hydroxylated tri- and tetra-amines.
Concerning the Ns (2-nitrophenylsulfonyl) protecting
group, FT-IR analysis showed the typical absorptions at
1509 and 1339 cm–1 for the nitro group and at 1362 and
1163 cm–1 for the sulfonamide. The elongation of the poly-
amine backbones was performed by reductive aminations
with 3-phthalimidopropanal (11).[17] The treatment of res-
ins 8–10 with aldehyde 11 for 2 h at 23 °C, followed by the
reaction with NaBH(OAc)3 in DMF for 2 h at 23 °C, af-
forded resins 12–14. Their FT-IR spectra showed the typi-
cal absorptions for the carbonyls of the phthalimide groups
at 1770 cm–1 in addition to the bands at 1708 cm–1 for the
absorptions of the carbamates or the bands at 1509, 1362,
1339 and 1163 cm–1 for the absorptions of the Ns groups.
To obtain the first set of N-hydroxylated polyamine de-
rivatives, resins 12–14 were oxidised at 23 °C with m-CPBA
(3-chloroperbenzoic acid) in CH2Cl2. The intermediary N-
oxide resins 15–17 were not further characterised but were
immediately heated in toluene at 90 °C to effect the Cope
elimination and liberate the desired N-hydroxylated spermi-
dine derivatives 18–20. These products were contaminated
with approximately 1% of over-oxidised products – possibly
nitrones such as the APCI decomposition products ob-
Results and Discussion
The linker introduced by Seo et al. contains the phen-
ethyl bromide moiety we used to attach the amine to the
resin.[15] The phenethyl group should secure the regioselec-
tivity of the planned Cope elimination. Due to the en-
hanced acidity of the benzylic H atoms, the Cope elimi-
nation of an N-oxide of type 3 should predominantly pro-
ceed toward the linker side of the N atom – forming a sty-
rene derivative together with the desired polyamine deriva-
tives 4 – rather than to the side of the polyamine backbone
(Scheme 1).
For the on-resin synthesis of the differently protected
polyamine derivatives, resin 2, prepared analogously to Seo
et al., was initially loaded with several polyamine starters
by nucleophilic substitution. The treatment of resin 2 with
an excess of the monoprotected diamines 5–7, prepared ac-
cording to the literature,[16] in the presence of DIEA (N-
diisopropylethylamine) in NMP (N-methylpyrrolidinone) at
50 °C gave rise to resins 8–10 (Scheme 2). A Volhard ti-
Scheme 1.
Scheme 2.
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M. Méret, S. Bienz
FULL PAPER
served with hydroxylamines[18] – as revealed by HPLC-MS amide 12, but HPLC-MS of mixtures obtained after the
of the crude mixtures. Reversed-phase HPLC finally fur- treatment of the anions with bromides 21–23 followed by
nished the bis-protected, N-hydroxylated triamines 18–20 in oxidative cleavage revealed that the alkylation reactions did
30–32% overall yields (from resin 2). Though apparently not proceed to completion; the major product was the non-
low, these yields are comparable to those obtained in the alkylated N-hydroxy “starting material”, triamine derivative
SPS of non-hydroxylated polyamine derivatives,[12] and they 18. The use of alkyl iodides instead of the bromides was
are very competitive with the yields obtained in the synthe- not advantageous.
ses of N-hydroxylated polyamine derivatives in solution.[19]
Other synthetic methods to effect the elongation of the
The products 18–20 were fully characterised by NMR, ESI- polyamine backbone were tested, too, but proved to be no
MS and MS/MS, which confirmed the proposed structures better (Scheme 4). Our attempts to construct the tetra-
as shown in Scheme 2.
amine derivatives by successive reductive aminations failed
The synthetic process was extended to the preparation completely: the successive treatment of resin 30 with allyl-
of a collection of triprotected N-hydroxylated tetra-amines N-(3-oxopropyl)carbamate 31 and NaBH(OAc)3, analo-
(Scheme 3). To this purpose, intermediate 12 was alkylated gously to the conversions of resins 8–10 into resins 12–14,
at the Ns-protected N atom with three differently N-pro- gave a resin showing “negative” Kaiser reaction[20] as was
tected aminobromides. The treatment of the resin with 21– expected for the supposedly formed secondary amine. After
23 at 50 °C in the presence of Cs2CO3 in DMF gave tetra- treatment with trifluoroacetyl chloride and the usual oxi-
amine resins 24–26, which were submitted to the usual oxi- dative cleavage, however, diprotected N-hydroxylated tri-
dation/cleavage conditions to furnish N-hydroxyl spermine amine derivative 33, rather than the desired, triprotected,
derivatives 27–29 (28–30% yield from resin 2).
N-hydroxylated tetra-amine 32, was obtained. Evidently,
The extension of the polyamine backbone was not as and despite the “negative” Kaiser test of the intermediate
trivial as it might appear from the Scheme shown above. resin, the reductive amination was not successful.
For the synthesis of 27–29, the combination of Cs2CO3 and
The alternative approach, applying the Mitsunobu reac-
protected aminobromides in the elongation step proved to tion[10] to couple diprotected diamine 35 to the resin
be superior to a number of alternative conditions. Initially, through substitution of alcoholic resin 34, was problematic
we employed NaOMe as the base to deprotonate sulfon- as well. In fact, after oxidative cleavage, tetra-amine deriva-
Scheme 3.
Scheme 4.
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Solid-Phase Synthesis of N-Hydroxypolyamines
Scheme 5.
tive 36 was obtained by this procedure, but the method was polyamine portion by reductive aminations, direct alky-
not reproducible in our hands.
lations of amines and sulfonamides as well as substitutions
Since spider toxins vary in the succession of the oligo- of halides. Thus, we have laid the basis for the SPS of any
methylene units in between the N atoms, a second set of N-hydroxylated polyamine derivative. The synthesised N-
protected N-hydroxytetra-amines with the N(CH2)3N(OH)- hydroxypolyamine derivatives will be used as precursors for
(CH2)3N moiety in the backbone was prepared (Scheme 5). synthetic polyamine natural products and as reference com-
To show the flexibility of our approach, the construction of pounds for the study and identification of constituents of
the backbone followed a different scheme. Resin 2 was venom samples from the spider Agelenopsis aperta, by
loaded with amino alcohol 37 in the presence of DIEA in HPLC-MS.
NMP, affording resin 38. Alternatively to the reductive
amination performed before, the amine of this resin was
directly alkylated by treatment with protected aminobro-
mide 21 (DIEA, NMP), leading to resin 34. Oxidative cleav-
age revealed that no over-alkylated product was formed in
this transformation.
The hydroxy group of resin 34 was then substituted for
a bromide by reaction with PPh3 and CBr4 in CH2Cl2 (resin
39).[11,15,21] The treatment of this resin with nosyl deriva-
tives 35, 40 and 41 in the presence of Cs2CO3 in DMF –
Experimental Section
General Methods: Unless otherwise stated, starting materials were
obtained from commercial suppliers and used without further puri-
fication. Resin used: Merrifield polymer 200–400 mesh, 2% divi-
nylbenzene, loading ca. 2.1 mmol Cl g–1 from Fluka. For the solid-
phase reactions, an Advanced ChemTech PLS 6 Organic syn-
thesiser was used. IR spectra were recorded with a Perkin–Elmer
1600 Series FT-IR spectrophotometer, and for the final products,
reversing the reactivities of the resin and the reagents rela- an OMNILAB FT/IR 4100 spectrophotometer. N-Hydroxypoly-
amine derivatives were purified by preparative HPLC; chromato-
grams were recorded with a Dynamax solvent delivery system
model SD-300 coupled with a Dynamax absorbance detector
tive to the alkylations of resin 12 with bromides 21–23 –
resulted in resins 42–44, which were oxidatively cleaved as
before to furnish the spermine derivatives 36, 45 and 46
(18–21% yield from resin 2).
1
model UV-1; column: Kromasil KR100–10C18. H NMR spectra
were measured with a Bruker AV-600 (600 MHz) spectrometer; δ
relative to CHCl3 (δ = 7.26 ppm). 13C-NMR spectra were measured
with a Bruker AV-600 (150 MHz) spectrometer; δ relative to CDCl3
(δ = 77.0 ppm); multiplicities were determined from DEPT-135 and
DEPT-90 experiments; the assignment of carbon resonances fol-
lowed from HSQC experiments. ESI mass spectroscopy was per-
formed with a Bruker ESQUIRE-LC quadrupole ion-trap instru-
ment (Bruker Daltonik GmbH, Bremen, Germany), equipped with
a combined Hewlett–Packard Atmospheric Pressure Ion (API)
source (Hewlett–Packard, Palo Alto, CA, USA). HR MS: High-
resolution (Ն10Ј000 FWHM) electrospray ionization mass spec-
trometry was performed with a Finnigan MAT 900 (Thermo Finni-
Conclusions
In conclusion, we succeeded in synthesising diprotected
N-hydroxy spermidines and triprotected N-hydroxylated
spermines and spermine analogues on solid support, and
we have demonstrated that Ns, Boc, Alloc and phthaloyl
protecting groups are compatible with the oxidative cleav-
age procedure. We have shown that the approach for the
synthesis of the polyamine backbones on the solid support
is flexible, allowing for the construction of the resin-bound gan, San Jose, CA; USA) double-focusing, magnetic-sector, mass
Eur. J. Org. Chem. 2008, 5518–5525
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M. Méret, S. Bienz
FULL PAPER
spectrometer. Ten spectra were acquired for each sample. A mass
accuracy Յ2 ppm was obtained in the peak-matching acquisition
mode with a solution containing 2 µL PEG200, 2 µL PPG450 and
1.5 mg of NaOAc (all obtained from Sigma–Aldrich, Buchs, Swit-
zerland) dissolved in 100 mL of MeOH (HPLC Supra grade, Schar-
lau, Barcelona, Spain) as an internal standard. Proof of the struc-
ture and purity of the final polyamine derivatives was provided by
NMR spectra and MS/MS. Elemental analyses were not appropri-
ate for the polyamine derivatives, since these compounds are waxy
or glassy solids from which residual traces of solvents could not be
removed.
Alkylation of Resin 12 with tert-Butyl N-(3-Bromopropyl)carbamate
(22) to Form Resin 25: According to the general procedure, resin
12 (0.3 mmol) was elongated with 22 to give resin 25. IR: ν = 1770
˜
(CO of Phth), 1707 (CO of Phth/Boc), 1509 (NO2), 1364 (SO2),
1339 (NO2), 1162 (SO2) cm–1.
Alkylation of Resin 12 with Allyl N-(3-Bromopropyl)carbamate (23)
to Form Resin 26: According to the general procedure, resin 12
(0.6 mmol) was elongated with 23 to give resin 26. IR: ν = 1770
˜
(CO of Phth), 1708 (CO of Phth/Alloc), 1509 (NO2), 1363 (SO2),
1340 (NO2), 1163 (SO2) cm–1.
Alkylation of Resin 38 with N-(3-Bromopropyl)phthalimide to Form
Resin 34: Resin 38 (1.6 mmol) was swelled in NMP (20 mL) for
Synthesis of Solid-Supported Tri- and Tetra-amine Derivatives
Loading with N-(2-Nitrophenylsulfonyl)-1,4-diaminobutane to Form 15 min. DIEA (1.37 mL, 8.00 mmol) and N-(3-bromopropyl)-
Resin 8. General Procedure for the Loading of Resin 2: Resin 2
(3.2 mmol, prepared according to Seo et al.,[15] 1.6 gmol–1 as deter-
mined by Volhard titration)[22] was swelled in NMP (20 mL) for
15 min. DIEA (2.74 mL, 16.0 mmol) and N-(2-nitrophenylsulfo-
nyl)-1,4-diaminobutane (5, 4.37 g, 16.0 mmol) were added, and the
suspension was agitated for 24 h at 50 °C. Resin 8 was filtered off,
washed successively with NMP, CH2Cl2 and MeOH and dried in
phthalimide (21, 2.14 g, 8.0 mmol) were added, and the suspension
was agitated for 24 h at 50 °C. Resin 34 was filtered off, washed
successively with NMP, CH2Cl2 and MeOH and dried in vacuo.
IR: ν = 3350 (br., OH), 1770 (CO), 1708 (CO) cm–1.
˜
Bromination of Resin 34 to Resin 39: Resin 34 (1.6 mmol) was
swelled in dry CH2Cl2 (15 mL). PPh3 (2.098 g, 8.00 mmol) was
added at 0 °C, followed by CBr4 (2.653 g, 8.00 mmol) dissolved in
dry CH2Cl2. The suspension was agitated for 12 h under Ar. Resin
39 was filtered off, washed successively with DMF, CH2Cl2 and
vacuo. IR: ν = 1509 (NO ), 1362 (SO ), 1339 (NO ), 1163 (SO )
˜
2
2
2
2
cm–1.
Loading of Resin 2 with tert-Butyl N-(4-Aminobutyl)carbamate (6)
to Form Resin 9: According to the general procedure, resin 2
MeOH and dried in vacuo. IR: ν = 1770 (CO), 1708 (CO) cm–1.
˜
Substitution of Bromo Resin 39 with tert-Butyl N-[4-(2-Nitrophen-
ylsulfonamido)butyl]carbamate (35) to Form Resin 42. General Pro-
cedure for the Substitution of Resin 39: Resin 39 (0.3 mmol) was
(0.2 mmol) was loaded with 6 to give resin 9. IR: ν = 1707 (CO)
˜
cm–1.
Loading of Resin 2 with Allyl N-(4-Aminobutyl)carbamate (7) to swelled in DMF (10 mL) at 50 °C for 15 min. Cs2CO3 (0.488 g,
Form Resin 10: According to the general procedure, resin 2
1.5 mmol) and tert-butyl N-[4-(2-nitrophenylsulfonamido)butyl]-
carbamate (35, 0.560 g, 1.5 mmol) were added, and the suspension
was agitated at 50 °C for 24 h. Resin 42 was filtered off, washed
successively with DMF, NMP/H2O (1:1), NMP, MeOH and
(0.2 mmol) was loaded with 7 to give resin 10. IR: ν = 1708 (CO)
˜
cm–1.
Loading of Resin 2 with 3-Amino-1-propanol (37) to Form Resin 38:
CH Cl and dried in vacuo. IR: ν = 1770 (CO of Phth), 1707 (CO
˜
2
2
According to the general procedure, resin 2 (1.6 mmol) was loaded
of Phth/Boc), 1509 (NO2), 1364 (SO2), 1162 (SO2) cm–1.
with 37 to give resin 38. IR: ν = 3260 (br., OH) cm–1.
˜
Substitution of Bromo Resin 39 with N-[4-(2-Nitrophenylsulfon-
amido)butyl]phthalimide (40) to Form Resin 43: According to the
general procedure, resin 39 (0.3 mmol) was elongated with 40 to
Reductive Amination of Resin 8 with 3-Phthalimidopropanal (11) to
Form Resin 12. General Procedure for Reductive Aminations: Resin
8 (3.2 mmol) was swelled in DMF (20 mL) for 15 min. 3-Phthalimi-
dopropanal (11, 3.26 g, 16.0 mmol) was added, and the suspension
was agitated at 23 °C for 2 h. NaBH(OAc)3 (3.38 g, 16.0 mmol) was
added, and the suspension was agitated at 23 °C for an additional
2 h. Resin 12 was filtered off, washed successively with MeOH,
give resin 43. IR: ν = 1770 (CO), 1709 (CO), 1509 (NO ), 1363
˜
2
(SO2), 1339 (NO2), 1163 (SO2) cm–1.
Substitution of Bromo Resin 39 with Allyl N-[4-(2-Nitrophenylsul-
fonamido)butyl]carbamate (41) to Form Resin 44: According to the
general procedure, resin 39 (0.7 mmol) was elongated with 41 to
DMF/AcOH (5%), CH Cl and MeOH and dried in vacuo. IR: ν
˜
2
2
= 1770 (CO), 1707 (CO), 1509 (NO2), 1362 (SO2), 1339 (NO2),
give resin 44. IR: ν = 1770 (CO of Phth), 1707 (CO of Phth/Alloc),
˜
1163 (SO2) cm–1.
1509 (NO2), 1363 (SO2), 1340 (NO2), 1162 (SO2) cm–1.
Reductive Amination of Resin 9 with 3-Phthalimidopropanal (11) to Liberation of the Tri- and Tetra-amine Derivatives from the Resins
Form Resin 13: According to the general procedure, resin 9
Oxidation/Cope Elimination (General Procedure): The resin (ob-
tained from 0.3 mmol of resin 2) was swelled in CH2Cl2 (5 mL) for
15 min. m-CPBA (0.259 g, 1.50 mmol) in CH2Cl2 (5 mL) at 0 °C
(0.2 mmol) was elongated with 11 to give resin 13. IR: ν = 1770
˜
(CO of Phth), 1708 (CO of Boc/Phth) cm–1.
Reductive Amination of Resin 10 with 3-Phthalimidopropanal (11) to was added, and the suspension was agitated for 3 h at 23 °C. The
Form Resin 14: According to the general procedure, resin 10
resulting resin was filtered off, washed successively with DMF,
MeOH and CH2Cl2 and dried in vacuo. Toluene (10 mL) was
added, and the suspension was heated to 90 °C for 2 h. The resin
was filtered off and washed with toluene and CH2Cl2. The com-
bined filtrates were concentrated to give a yellow oil, which was
purified by HPLC as described below.
(0.2 mmol) was elongated with 11 to give resin 14. IR: ν = 1770
˜
(CO of Phth), 1708 (CO of Alloc/Phth) cm–1.
Alkylation of Resin 12 with N-(3-Bromopropyl)phthalimide (21) to
Form Resin 24. General Procedure for the Alkylations of Resin 12:
Resin 12 (0.3 mmol) was swelled in DMF (10 mL) at 50 °C for
15 min. Cs2CO3 (1.30 g, 4.0 mmol) and N-(3-bromopropyl)phthal-
imide (21, 0.72 g, 2.7 mmol) were added, and the suspension was
agitated at 50 °C for 24 h. Resin 24 was filtered off, washed success-
ively with DMF, NMP/H2O (1:1), NMP, MeOH and CH2Cl2 and
N-[4-Hydroxy-8-(2-nitrophenylsulfonamido)-4-azaoctyl]phthalimide
(18) from Resin 12 (obtained from 0.3 mmol of resin 2): HPLC (H2O/
MeCN/TFA, 60:40:0.1, 25 mLmin–1, λ = 280 nm) gave 18 as a
colourless oil (0.043 g, 0.09 mmol, 30% from resin 2). IR: ν = 1771
˜
dried in vacuo. IR: ν = 1770 (CO), 1708 (CO), 1509 (NO ), 1362
(CO), 1708 (CO), 1364 (SO2), 1340 (NO2), 1163 (SO2) cm–1. 1H
˜
2
(SO2), 1339 (NO2), 1163 (SO2) cm–1.
NMR (600 MHz, CDCl3, 278 K): δ = 8.10–8.09 (m, 1 H, arom. H
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Solid-Phase Synthesis of N-Hydroxypolyamines
o to NO2), 7.85–7.83 (m, 3 H, arom. H o to SO2 and 2 arom. gave 27 as a colourless solid (0.059 g, 0.09 mmol, 30% from resin
CCHCH of Phth), 7.77–7.76 (m, 2 H, arom. H p to NO2 and arom.
2). M.p. 67–70 °C. IR: ν = 1769 (CO), 1708 (CO), 1370 (SO ), 1341
˜
2
1
H p to SO2), 7.75–7.73 (m, 2 H, 2 arom. CCHCH of Phth), 3.81 (NO2), 1161 (SO2) cm–1. H NMR (600 MHz, CDCl3, 278 K): δ =
3
3
4
(t, JH,H
=
6.3 Hz,
2
H, PhthNCH2), 3.39–3.20 (m,
4
H,
7.96 (dd, JH,H = 7.7, JH,H = 1.3 Hz, 1 H, arom. H o to NO2),
CH2NOHCH2), 3.13–3.09 (m, 2 H, NsNHCH2), 2.24–2.11 (m, 2 7.86–7.81 (m, 4 H, 4 arom. CCHCH of Phth), 7.75–7.72 (m, 4 H,
3
4
H, PhthNCH2CH2), 1.93–1.78 (m, 2 H, NsNHCH2CH2CH2), 1.65 4 arom. CCHCH of Phth), 7.71 (app. td, JH,H = 7.7, JH,H
=
3
3
[quint, JH,H = 7.2 Hz, 2 H, NsNHCH2CH2] ppm. 13C NMR
1.3 Hz, 1 H, arom. H p to NO2), 7.66 (app. td, JH,H = 7.7,
3
(150 MHz, CDCl3, 278 K): δ = 168.5 (s, 2ϫCO), 147.9 (s, arom.
CNO2), 134.4 (d, 2 arom. CCHCH of Phth), 133.8 (d, arom. CH
p to NO2), 133.1 (s, arom. CSO2), 132.9 (d, arom. CH p to SO2),
131.7 (s, 2 arom. C of Phth), 131.1 (d, arom. CH o to NO2), 125.5
(d, arom. CH o to SO2), 123.6 (d, 2 arom. CCH of Phth), 59.2,
57.1 (2 t, CH2NOHCH2), 42.9 (t, NsNHCH2), 34.6 (t, PhthNCH2),
4JH,H = 1.3 Hz, 1 H, arom. H p to SO2), 7.61 (dd, JH,H = 7.7,
4JH,H = 1.3 Hz, 1 H, arom. H o to SO2), 3.83 [t, JH,H = 6.2 Hz,
3
3
2 H, PhthNCH2(CH2)2NOH], 3.67 [t, JH,H = 7.5 Hz, 2 H,
4 H, CH2NNsCH2),
3.33–3.28 (m, 4 H, CH2NOHCH2), 2.23–2.16 (m, 2 H, Phth-
PhthNCH2(CH2)2NNs], 3.38–3.34 (m,
3
NCH2CH2CH2OH), 1.92 (quint, JH,H
=
7.5 Hz,
2
H,
26.4 (t, NsNHCH2CH2), 23.6 (t, PhthCH2CH2), 20.6 (t, NsNCH2CH2CH2-NPhth), 1.86–1.78 [m, 2 H, OHNCH2CH2-
NsNHCH2CH2CH2) ppm. ESI-MS: m/z (%) = 477.2 (100) [M +
(CH2)2NNs], 1.77–1.71 [m, 2 H, OHN(CH2)2CH2CH2NNs] ppm.
13C NMR (150 MHz, CDCl3, 278 K): δ = 168.3, 168.2 (2 s, 2ϫCO
of Phth), 148.0 (s, arom. CNO2), 134.3, 134.1 (2 d, 2ϫ2 arom.
CCHCH of Phth), 133.8 (d, arom. CH p to NO2), 132.8 (s, arom.
CSO2), 131.9 (d, arom. CH p to SO2), 131.8 (s, 4 arom. C of Phth),
130.7 (d, arom. CH o to NO2), 124.3 (d, arom. CH o to CSO2),
123.5, 123.3 (2 d, 2ϫ2 arom. CCH of Phth), 58.9, 56.9 (2 t,
CH2NNsCH2), 47.1, 45.8 (2 t, CH2NOHCH2), 35.6 [t, PhthNCH2-
(CH2)3NNs], 34.7 [t, PhthNCH2(CH2)2NOH], 27.4 (t,
OHNCH2CH2CH2CH2NNs), 25.6 (t, PhthNCH2CH2CH2NNs),
23.6 (t, PhthNCH2CH2CH2NOH), 20.4 [t, OHNCH2CH2-
(CH2)2NNs] ppm. ESI-MS: m/z (%) = 702.3 (12) [M + K]+, 686.3
(28) [M + Na]+, 664.4 (100) [M + H]+, 646.3 (9). HRMS: calcd.
for C32H34N5O9S1 664.2077; found 664.2086.
H]+. HRMS: calcd. for C21H25N4O7S1 477.1444; found 477.1449.
tert-Butyl N-(5-Hydroxy-8-phthalimido-5-azaoctyl)carbamate (19)
from Resin 13 (obtained from 0.2 mmol of resin 2): HPLC (H2O/
MeCN/TFA, 60:40:0.1, 25 mLmin–1, λ = 280 nm) gave 19 as a
colourless oil (0.025 g, 0.06 mmol, 32% from resin 2). IR: ν = 1773
˜
1
(CO of Phth), 1710 (CO of Boc/Phth) cm–1. H NMR (600 MHz,
CDCl3, 278 K): δ = 7.90–7.88 (m, 2 H, 2 arom. CCHCH of Phth),
7.79–7.77 (m, 2 H, 2 arom. CCHCH of Phth), 4.67 (br. s, 1 H,
NH), 3.85 (t, 3JH,H = 6.2 Hz, 2 H, PhthNCH2), 3.35–3.26 (m, 4 H,
CH2NOHCH2), 3.19–3.14 (m, 2 H, BocNHCH2), 2.28–2.15 (m, 2
H, PhthNCH2CH2), 1.95–1.75 (m, 2 H, BocNHCH2CH2CH2),
3
1.59 (quint, JH,H = 7.1 Hz, 2 H, BocNHCH2CH2), 1.45 (s, 9 H,
CMe3) ppm. 13C NMR (150 MHz, CDCl3, 278 K): δ = 168.3 (s,
2ϫCO of Phth), 156.1 (s, CO of Boc), 134.4 (d, 2 arom. CCHCH
of Phth), 131.8 (s, 2 arom. C of Phth), 123.6 (d, 2 arom. CCH of
Phth), 79.6 (s, Me3C), 59.2, 57.0 (2 t, 2ϫCH2), 39.4 (t,
BocNHCH2), 34.8 (t, PhthNCH2), 28.3 (q, Me3C), 27.0 (t,
tert-Butyl N-[9-Hydroxy-4-(2-nitrophenylsulfonyl)-12-phthalimido-
4,9-diazadodecyl]carbamate (28) from Resin 25 (obtained from
0.3 mmol of resin 2): HPLC (H2O/MeCN/TFA, 55:45:0.1,
25 mLmin–1, λ = 280 nm) gave 28 as a colourless oil (0.053 g,
0.08 mmol, 28% from resin 2). IR: ν = 1773 (CO of Phth), 1712
˜
BocNHCH2CH2),
26.6
(t,
PhthNCH2CH2),
20.6
(t,
(CO of Phth/Boc), 1367 (SO2), 1345 (NO2), 1163 (SO2) cm–1. 1H
BocNHCH2CH2CH2) ppm. ESI-MS: m/z (%) = 392.3 (100) [M +
H]+, 336.3 (13). HRMS: calcd. for C20H30N3O5 392.2185; found
392.2186.
3
NMR (600 MHz, CDCl3, 278 K): δ = 7.96 (d, JH,H = 7.2 Hz, 1
H, arom. H o to NO2), 7.87–7.86 (m, 2 H, 2 arom. CCHCH of
Phth), 7.77–7.75 (m, 2 H, 2 arom. CCHCH of Phth), 7.74 (ap. td,
4
3JH,H = 7.7, JH,H = 1.6 Hz, 1 H, arom. H p to NO2), 7.71 (ap. td,
Allyl N-(5-Hydroxy-8-phthalimido-5-azaoctyl)carbamate (20) from
Resin 14 (obtained from 0.2 mmol of resin 2): HPLC (H2O/MeCN/
TFA, 60:40:0.1, 25 mLmin–1, λ = 280 nm) gave 20 as a colourless
3JH,H = 7.6, 4JH,H = 1.6 Hz, 1 H, arom. H p to SO2), 7.65 (d, 3JH,H
3
= 7.4 Hz, 1 H, arom. H o to SO2), 3.82 (t, JH,H = 6.3 Hz, 2 H,
oil (0.022 g, 0.06 mmol, 30% from resin 2). IR: ν = 1771 (CO of
˜
PhthNCH2), 3.35–3.23 (m, 10 H, CH2NOHCH2, CH2NNsCH2,
CH2NHBoc), 2.18–2.11 (m, 2 H, PhthNCH2CH2), 1.82–1.63 [m, 6
H, OHNCH2(CH2)2CH2NNs, BocNHCH2CH2], 1.42 (s, 9 H,
Me3C) ppm. 13C NMR (150 MHz, CDCl3, 278 K): δ = 168.5 (s,
2ϫCO of Phth), 156.2 (s, CO of Boc), 147.9 (s, arom. CNO2),
134.4 (d, 2 arom. CCHCH of Phth), 133.8 (d, arom. CH p to NO2),
132.6 (s, arom. CSO2), 131.9 (d, arom. CH p to SO2), 131.6 (s, 2
arom. C of Phth), 130.4 (d, arom. CH o to NO2), 124.3 (d, arom.
CH o to SO2), 123.6 (d, 2 arom. CCH of Phth), 79.5 (s, Me3C),
58.9, 57.0 (2 t, CH2NNsCH2), 46.8, 45.4 (2 t, CH2NOHCH2), 37.2
(t, BocNHCH2), 34.6 (t, PhthNCH2), 28.5 (t, CH2), 28.3 (q, Me3C),
25.2 (t, BocNHCH2CH2), 23.5 (2 t, PhthNCH2CH2, Boc-
NHCH2CH2), 20.4 (t, CH2) ppm. ESI-MS: m/z (%) = 672.3 (10)
[M + K]+, 656.3 (10) [M + Na]+, 634.3 (100) [M + H]+. HRMS:
calcd. for C29H40N5O9S1 634.2547; found 634.2543.
Phth), 1705 (CO of Alloc/Phth) cm–1. 1H NMR (600 MHz, CDCl3,
278 K): δ = 7.88–7.84 (m, 2 H, 2 arom. CCHCH of Phth), 7.77–
3
7.72 (m, 2 H, 2 arom. CCHCH of Phth), 5.90 (ddt, Jtrans = 17.1,
3Jcis = 10.6, 3Jvic = 5.3 Hz, 1 H, CH2=CH), 5.30 (dd, 3Jtrans = 17.1,
3
3Jgem = 1.5 Hz, 1 H, CH2=CH), 5.21 (d, Jcis = 10.6 Hz, 1 H,
3
CH2=CH), 4.87 (br. s, 1 H, NH), 4.54 (d, JH,H = 5.3 Hz, 2 H,
3
OCH2), 3.83 (t, JH,H = 6.2 Hz, 2 H, PhthNCH2), 3.32–3.22
(m, 4 H, CH2NOHCH2), 3.19–3.22 (m, 2 H, AllocNHCH2),
2.22–2.10 (m,
AllocNHCH2CH2CH2), 1.60 (quint, JH,H
2
H, PhthNCH2CH2), 1.94–1.74 (m,
2
2
H,
H,
3
=
7.0 Hz,
AllocNHCH2CH2) ppm. 13C NMR (150 MHz, CDCl3, 278 K): δ
= 168.4 (s, 2ϫCO of Phth), 156.4 (s, CO of Alloc), 134.3 (d, 2
arom. CCHCH of Phth), 132.8 (d, CH2=CH), 131.8 (s, 2 arom. C
of Phth), 123.6 (d, 2 arom. CCH of Phth), 117.8 (t, CH2=CH),
65.7 (t, CH2=CHCH2), 59.2, 57.1 (2 t, 2ϫCH2), 39.9 (t,
AllocNHCH2), 34.8 (t, PhthNCH2), 26.9 (t, NHCH2CH2), 23.6 (t,
PhthNCH2CH2), 20.6 (t, NHCH2CH2CH2) ppm. ESI-MS: m/z (%)
= 376.3 (100) [M + H]+, 360.3 (10). HRMS: calcd. for C19H26N3O5
376.1872; found 376.1871.
Allyl N-[9-Hydroxy-4-(2-nitrophenylsulfonyl)-12-phthalimido-4,9-di-
azadodecyl]carbamate (29) from Resin 26 (obtained from 0.2 mmol
of resin 2): HPLC (H2O/MeCN/TFA, 60:40:0.1, 25 mLmin–1, λ =
280 nm) gave 29 as a colourless oil (0.022 g, 0.06 mmol, 30% from
resin 2). IR: ν = 1772 (CO of Phth), 1711 (CO of Phth/Alloc), 1371
˜
[4-Hydroxy-9-(2-nitrophenylsulfonyl)-4,9-diazadodecane]-1,12-di- (SO2), 1142 (SO2) cm–1. H NMR (600 MHz, CDCl3, 278 K): δ =
1
3
4
phthalimide (27) from Resin 24 (obtained from 0.3 mmol of resin 2):
7.96 (dd, JH,H = 7.4, JH,H = 1.7 Hz, 1 H, arom. H o to NO2),
7.88–7.86 (m, 2 H, 2 arom. CCH of Phth), 7.77–7.76 (m, 2 H, 2
HPLC (H2O/MeCN/TFA, 60:40:0.1, 25 mLmin–1, λ = 280 nm)
Eur. J. Org. Chem. 2008, 5518–5525
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5523

M. Méret, S. Bienz
arom. CCHCH of Phth), 7.75 (ap. td, JH,H = 7.4, JH,H = 1.5 Hz, (CH2)3NNs], 3.53–3.22 (m, 8 H, CH2NOHCH2CH2CH2NNsCH2),
FULL PAPER
3
4
3
4
1 H, arom. H p to NO2), 7.72 (ap. td, JH,H = 7.5, JH,H = 1.5 Hz, 2.28–2.03 (m, 2 H, PhthNCH2CH2CH2NOH), 2.08–2.03 (m, 2 H,
3
4
1 H, arom. H p to SO2), 7.66 (dd, JH,H = 7.5, JH,H = 1.5 Hz, 1
NOHCH2CH2CH2NNs), 1.70–1.65 (m, 2 H, NsNCH2CH2CH2-
CH2NPhth), 1.61–1.51 (m, 2 H, NsNCH2CH2CH2CH2NPhth)
3
3
3
H, arom. H o to SO2), 5.90 (ddt, Jtrans = 17.3, Jcis = 10.7, Jvic
=
5.5 Hz, 1 H, CH2=CH), 5.30 (dd, Jtrans = 17.1, Jgem = 1.3 Hz, 1 ppm. 13C NMR (150 MHz, CDCl3, 278 K): δ = 168.4, 168.3 (2 s,
3
3
3
3
H, CH2=CH), 5.21 (dd, Jcis = 10.7, Jgem = 1.3 Hz, 1 H,
CH2=CH), 4.53 (d, Jvic = 5.5 Hz, 2 H, OCH2), 3.83 (t, JH,H
6.3 Hz, 2 H, PhthNCH2), 3.36–3.21 (m, 10 H, CH2NOHCH2,
2ϫ2 CO of Phth), 147.8 (s, arom. CNO2), 134.2, 134.1 (2 d, 2ϫ2
arom. CCHCH of Phth), 133.8 (d, arom. CH p to NO2), 132.2 (s,
arom. CSO2), 132.0 (d, arom. CH p to SO2), 131.8, 131.7 (2 s, 2ϫ2
3
3
=
CH2NNsCH2, AllocNHCH2), 2.19–2.14 (m, 2 H, PhthNCH2CH2), arom. C of Phth), 131.3 (d, arom. CH o to NO2), 123.9 (d, arom.
1.82–1.73 (m, 4 H, OHNCH2CH2CH2CH2NNs), 1.72–1.65 (m, 2 CH o to CSO2), 123.5, 123.3 (2 d, 2ϫ2 arom. CCH of Phth), 57.8,
H, AllocNHCH2CH2) ppm. 13C NMR (150 MHz, CDCl3, 278 K): 56.9 (2 t, CH2NNsCH2), 47.7, 44.3 (2 t, CH2NOHCH2), 36.9 [t,
δ = 168.4 (s, 2ϫCO of Phth), 156.4 (s, CO of Alloc), 147.8 (s, PhthNCH2(CH2)3NNs], 34.7 [t, PhthNCH2(CH2)2NOH], 25.6 (2 t,
arom. CNO2), 134.4 (d, 2 arom. CCHCH of Phth), 133.9 (d, arom. PhthNCH2CH2CH2CH2NNs), 23.4 (t, PhthNCH2CH2CH2NOH),
CH p to NO2), 132.8 (d, CH=CH2), 132.5 (s, arom. CSO2), 131.9
(d, arom. CH p to SO2) 131.6 (s, 2 arom. C of Phth), 130.5 (d,
arom. CH o to NO2), 124.4 (d, arom. CH o to SO2), 123.6 (d, 2
arom. CCH of Phth), 117.7 (t, CH2=CH), 65.6 (t, CH2=CHCH2),
58.9, 57.1 (2 t, CH2NNsCH2), 46.9, 45.3 (2 t, CH2NOHCH2), 37.5
(t, AllocNHCH2), 34.5 (t, PhthNCH2), 28.3 (t, CH2), 25.3 (t,
AllocNHCH2CH2), 23.5 (t, PhthNCH2CH2), 20.4 (t, CH2) ppm.
ESI-MS: m/z (%) = 618.3 (100) [M + H]+. HRMS: calcd. for
C28H36N5O9S1 618.2234; found 618.2228.
22.7 (t, OHNCH2CH2CH2NNs) ppm. ESI-MS: m/z (%) = 702.2
(12) [M + K]+, 686.2 (18) [M + Na]+, 664.3 (100) [M + H]+.
HRMS: calcd. for C32H34N5O9S1 664.2077; found 664.2074.
Allyl N-[9-Hydroxy-5-(2-nitrophenylsulfonyl)-12-phthalimido-5,9-di-
azadodecyl]carbamate (46) from Resin 44 (obtained from 0.3 mmol
of resin 2): HPLC (H2O/MeCN/TFA, 60:40:0.1, 25 mLmin–1, λ =
280 nm) gave 46 as a colourless oil (0.037 g, 0.06 mmol, 20% from
resin 2). IR: ν = 1770 (CO of Phth), 1708 (CO of Phth/Alloc), 1368
˜
1
(SO2), 1345 (NO2), 1142 (SO2) cm–1. H NMR (600 MHz, CDCl3,
3
4
tert-Butyl N-[9-Hydroxy-5-(2-nitrophenylsulfonyl)-12-phthalimido-
5,9-diazadodecyl]carbamate (36) from Resin 42 (obtained from
0.3 mmol of resin 2): HPLC (H2O/MeCN/TFA, 55:45:0.1,
25 mLmin–1, λ = 280 nm) gave 36 as a colourless oil (0.032 g,
278 K): δ = 8.22 (dd, JH,H = 7.2, JH,H = 1.5 Hz, 1 H, arom. H o
to NO2), 7.86–7.84 (m, 2 H, 2 arom. CCHCH of Phth), 7.75–7.70
(m, 3 H, 2 arom. CCHCH of Phth, 1 arom. H p to NO2), 7.71 (dd,
3JH,H = 7.6, JH,H = 1.7 Hz, 1 H, arom. H p to SO2), 7.62 (dd,
4
4
3JH,H = 7.0, JH,H = 2.0 Hz, 1 H, arom. H o to SO2), 5.89 (ddt,
0.05 mmol, 18% from resin 2). IR: ν = 1772 (CO of Phth), 1710
˜
(CO of Phth/Boc), 1398 (SO2), 1345 (NO2), 1144 (SO2) cm–1. 1H
3Jtrans = 17.2, 3Jcis = 10.4, 3Jvic = 5.4 Hz, 1 H, CH2=CH), 5.28 (dd,
3Jtrans = 17.2, 3Jgem = 1.5 Hz, 1 H, CH2=CH), 5.20 (dd, 3Jcis = 10.5,
3Jgem = 1.4 Hz, 1 H, CH2=CH), 4.52 (dt, 3Jvic = 5.4, 4JH,H = 1.3 Hz,
2 H, OCH2), 3.87–3.79 (m, 2 H, PhthNCH2), 3.64–3.59 (m, 1 H,
3
NMR (600 MHz, CDCl3, 278 K): δ = 8.26 (d, JH,H = 8.3 Hz, 1
H, arom. H o to NO2), 7.85–7.84 (m, 2 H, 2 arom. CCHCH of
Phth), 7.75–7.70 (m, 4 H, 2 arom. CCHCH of Phth, arom. H p to
3
4
NO2, arom. H p to SO2), 7.62 (dd, JH,H = 7.4, JH,H = 1.5 Hz, 1
NOHCH2CH2CH2NNs), 3.52–3.47 (m,
1 H, NOHCH2CH2-
3
H, arom. H o to SO2), 4.68 (app. t, JH,H = 6.0 Hz, 1 H, BocNH),
CH2NNs), 3.41–3.25 [m, H, CH2NOHCH2, NsNCH2-
6
3
3
3.87–3.79 (m, 2 H, PhthNCH2), 3.67–3.62 (m, 1 H, NOHCH2-
CH2CH2NNs), 3.52–3.47 (m, 1 H, NOHCH2CH2CH2NNs), 3.40–
3.23 [m, 6 H, CH2NOHCH2, NsNCH2(CH2)3NHBoc], 3.10 (app.
(CH2)3NHAlloc], 3.18 (td, JH,H = 6.5, JH,H = 6.5 Hz, 2 H,
AllocNHCH2), 2.24–2.19 (m, 2 H, PhthNCH2CH2), 2.08–2.04 (m,
2 H, NOHCH2CH2CH2NNs), 1.62–1.56 (m, 2 H, NsNCH2-
CH2CH2CH2NHAlloc), 1.52–1.48 (m, 2 H, NsNCH2CH2CH2-
CH2NHAlloc) ppm. 13C NMR (150 MHz, CDCl3, 278 K): δ =
168.4 (s, 2ϫCO of Phth), 156.6 (s, CO of Alloc), 148.0 (s, arom.
CNO2), 134.5 (d, 2 arom. CCHCH of Phth), 134.1 (d, arom. CH
p to NO2), 133.0 (d, CH=CH2), 132.4 (s, arom. CSO2), 132.3 (d,
arom. CH p to SO2), 131.9 (s, 2 arom. C of Phth), 131.4 (d, arom.
CH o to NO2), 124.2 (d, arom. CH o to SO2), 123.7 (d, 2 arom.
CCH of Phth), 117.9 (t, CH2=CH), 65.7 (t, CH2=CHCH2), 58.1 [t,
NsNCH2(CH2)3NPhth], 57.1 [t, NOH(CH2)2CH2], 48.2 [t,
PhthN(CH2)2CH2NOH], 44.7 [t, NOHCH2(CH2)2NNs], 40.3 (t,
AllocNHCH2), 34.8 (t, PhthNCH2), 27.2 (t, AllocNHCH2CH2),
26.0 (t, AllocNHCH2CH2CH2), 23.7 (t, PhthNCH2CH2), 22.9 (t,
NOHCH2CH2CH2NNs) ppm. ESI-MS: m/z (%) = 618.2 (100) [M
+ H]+. HRMS: calcd. for C28H36N5O9S1 664.2234; found 618.2232.
3
3
td, JH,H = 6.6, JH,H = 6.0 Hz, 2 H, BocNHCH2), 2.27–2.16 (m,
2 H, PhthNCH2CH2), 2.07–2.03 (m, 2 H, NOHCH2CH2CH2NNs),
1.62–1.51 (m, 2 H, NsNCH2CH2CH2CH2NHBoc), 1.50–1.43 (m,
2 H, NsNCH2CH2CH2CH2NHBoc), 1.41 (s, 9 H, Me3C) ppm. 13
C
NMR (150 MHz, CDCl3, 278 K): δ = 168.4 (s, 2ϫCO of Phth),
156.1 (s, CO of Boc), 147.8 (s, arom. CNO2), 134.3 (d, 2 arom.
CCHCH of Phth), 133.8 (d, arom. CH p to NO2), 132.3 (s, arom.
CSO2), 132.1 (d, arom. CH p to SO2), 131.7 (s, 2 arom. C of Phth),
131.3 (d, arom. CH o to NO2), 124.0 (d, arom. CH o to SO2), 123.5
(d, 2 arom. CCH of Phth), 57.9 [t, NsNCH2(CH2)3NPhth], 56.9 [t,
NOH(CH2)2CH2], 47.9 [t, PhthN(CH2)2CH2NOH], 44.2 [t,
NOHCH2(CH2)2NNs], 39.6 (t, BocNHCH2), 34.6 (t, PhthNCH2),
28.3 (q, Me3C), 27.1 (t, BocNHCH2CH2), 25.7 (t,
BocNHCH2CH2CH2), 23.5 (t, PhthNCH2CH2), 22.6 (t,
NOHCH2CH2CH2NNs) ppm. ESI-MS: m/z (%) = 634.3 (100) [M
+ H]+. HRMS: calcd. for C29H40N5O9S1 634.2547; found 634.2552.
Supporting Information (see also the footnote on the first page of
this article): NMR spectra of the final products.
[4-Hydroxy-8-(2-nitrophenylsulfonyl)-4,8-diazadodecane]-1,12-
diphthalimide (45) from Resin 43 (obtained from 0.3 mmol of resin
2): HPLC (H2O/MeCN/TFA, 60:40:0.1, 25 mLmin–1, λ = 280 nm)
gave 45 as a colourless solid (0.040 g, 0.06 mmol, 21% from resin
Acknowledgments
We thank the Swiss National Science Foundation for generous fin-
ancial support.
2). M.p. 66–69 °C. IR: ν = 1771 (CO of Phth), 1709 (CO of Phth/
˜
1
Alloc), 1371 (SO2), 1155 (SO2) cm–1. H NMR (600 MHz, CDCl3,
278 K): δ = 8.26–8.25 (m, 1 H, arom. H o to NO2), 7.85–7.83 (m,
4 H, 4 arom. CCHCH of Phth), 7.75–7.68 (m, 6 H, 4 arom.
CCHCH of Phth, 1 arom. H p to NO2, 1 arom. H p to SO2), 7.56–
[1] J. S. Tropp, A. G. Redfield, Nucleic Acids Res. 1983, 11, 2121–
2231.
7.55 (m,
1
H, arom.
H
o
to SO2), 3.85–3.82 [m,
2 H,
[2] a) S. Jain, G. Zon, M. Sundaralingam, Biochemistry 1989, 28,
PhthNCH2(CH2)2NOH], 3.68–3.64 [m,
2
H, PhthNCH2-
2355–2359; b) T. J. Thomas, U. B. Gunnia, T. Thomas, J. Biol.
5524
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: July 9, 2008
Published Online: October 10, 2008
Eur. J. Org. Chem. 2008, 5518–5525
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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