Fukuyama-Mitsunobu alkylation in amine synthesis on solid phase revisited: N-alkylation with secondary alcohols and synthesis of curtatoxins

Article abstract of DOI:10.1016/j.tet.2005.04.027

The Fukuyama-Mitsunobu amination strategy has emerged as an efficient means of N-alkylation of peptides and sulfonamides, as well as a method for synthesis of polyamines on solid phase. Here, an array of reagent combinations for solid-phase alkylation wit

Full text of DOI:10.1016/j.tet.2005.04.027

Tetrahedron 61 (2005) 6046–6055
Fukuyama–Mitsunobu alkylation in amine synthesis
on solid phase revisited: N-alkylation with secondary alcohols
and synthesis of curtatoxins
b
c
a
Christian A. Olsen,a, Matthias Witt, Steen H. Hansen, Jerzy W. Jaroszewski
*
and Henrik Franzyka,
*
aDepartment of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
bBruker Daltonik GmbH, Fahrenheitstrasse 4, D-28359 Bremen, Germany
cDepartment of Analytical Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
Received 14 January 2005; revised 29 March 2005; accepted 15 April 2005
Available online 17 May 2005
Abstract—The Fukuyama–Mitsunobu amination strategy has emerged as an efficient means of N-alkylation of peptides and sulfonamides,
as well as a method for synthesis of polyamines on solid phase. Here, an array of reagent combinations for solid-phase alkylation with
secondary alcohols was examined in various solvents. The classical reagents DEAD–PPh3 as well as DEAD–PEt3 proved applicable for a
single alkylation step. Sharply dropping yields in successive alkylation steps were identified as the most serious limitation of the use of
Fukuyama–Mitsunobu reaction in SPS of polyamines using primary and in particular secondary alcohols.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
containing toxins, known as curtatoxins, are shown in
Figure 1. Compounds 4 and 6, for instance, were isolated
from both venom mixtures (which explains the two different
names assigned to each of these compounds). Only the
H. curta venom contains long-chain non-hydroxylated
toxins such as compound 5. The structurally similar wasp
toxin component, philanthotoxin-433 (7),8 has been the
subject of extensive structure–activity relationship (SAR)
studies on various receptor types.9
Polyamines and their derivatives play important roles in
biochemistry and their pharmacological significance con-
tinues to increase. Simple polyamines such as spermidine
(1) and spermine (2) are ubiquitous in eukaryotic cells,
where they conduct important roles in cellular physiology,
for example, in cell proliferation and DNA synthesis.1
Relatively simple n-alkylated analogs of 2 have been shown
to possess anticancer activity in various cell lines.2
Polyamine-based cationic lipids have proved to be efficient
gene-delivery agents.3 Moreover, certain polyamine deriva-
tives have been shown to interact with ion channels in the
central nervous system (CNS).4 Thus, polyamine neuro-
toxins isolated from venoms of spiders and wasps
antagonize various classes of ionotropic receptors such as
nicotinic acetylcholine receptors (nAChRs) and ionotropic
glutamate receptors (iGluRs).5 A variety of polyamine
neurotoxins with closely related structures have been
isolated from venoms of the funnel web spiders Hololena
curta6 and Agelenopsis aperta.7 Some of these indole-
In order to obtain pure natural toxins in useful quantities as
well as unnatural analogs for biological studies, efficient
synthetic strategies are necessary. Since solution-phase
methods for polyamine synthesis10 often require extensive
use of protecting groups as well as tedious purification steps,
the development of solid-phase synthesis (SPS) method-
ologies has received considerable attention in recent years.
The subsequent attachment of the amino acid and/or acyl
residues to the polyamines may be achieved by well-
established solid-phase peptide synthesis (SPPS) protocols.
The synthetic strategies for construction of polyamines on
solid phase may be classified into three major groups:
(1) simple SN2 alkylation reactions;11 (2) methods based
on reduction of intermediary imines12 or amides;13 and
(3) Fukuyama amination reactions.14 In the latter approach,
Keywords: Solid-phase synthesis; Fukuyama–Mitsunobu alkylation;
Amines; Spider toxins.
Corresponding authors. Tel.: C45 35306499; fax: C45 35306041
(C.A.O.); e-mail addresses: cao@dfuni.dk; hf@dfuni.dk
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.027

C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
6047
Figure 1. Structures of polyamines and acylpolyamine neurotoxins isolated from venom mixtures of spiders and wasps. The numerals in the names of 3–6
denote the molecular masses. In PhTX-433 (7) the digits denote the number of methylene groups that separate the amino functionalities, starting from the
tyrosine end.
alkylation of secondary sulfonamides is achieved with alkyl
halides under mildly basic conditions or with alcohols under
Mitsunobu conditions.15 Fukuyama and co-workers have
applied the alkyl bromide approach in mixed solution/solid-
phase total syntheses of several spider and wasp toxins. Ns-
is of interest, since the Fukuyama–Mitsunobu method has
been optimized to give O99% yield in a single alkylation
step,22c yet the overall yields of philanthotoxins obtained
after two alkylations only amounted to 23–40%.22c,e
Accordingly, the present work reports on the use of
Fukuyama–Mitsunobu protocols for the SPS of curtatoxins,
which contain polyamine moieties of different lengths, and
thus constitutes an interesting test case.
Protected acylpolyamines (corresponding to 416 and 616b
)
were prepared in solution, and the syntheses were
completed after anchoring of the terminal amino group to
a solid support. Furthermore, two Fukuyama-type
approaches based entirely on SPS have been employed in
the total synthesis of philanthotoxins,17 and two SPS Ns-
strategies for site-selective N-methylation in peptide
synthesis were reported by Miller and Scanlan.18 The
Fukuyama–Mitsunobu conditions have recently emerged as
a versatile and general SPS method used, for instance, in N-
alkylation of peptides,19 peptide nucleic acid (PNA)
monomer synthesis,20 preparation of N-alkylated sulfona-
mides,21 and in synthesis of polyamine neurotoxins.22
2. Results and discussion
2.1. Screening of SPS reagent combinations for N-alkyl-
ation with secondary alcohols
Numerous combinations of solvents, bases, azo reagents and
phosphines24 have previously been applied in Mitsunobu
reactions, and it was decided to select a range of reagents for
a combinatorial screening in order to identify suitable
conditions for Fukuyama–Mitsunobu SPS alkylations with
secondary alcohols. Bycroft and co-workers22a as well as
Hone and Payne22b have employed the traditional reagent
pair diethyl azocarboxylate (DEAD) and PPh3 in their
original reports on polyamine SPS using Fukuyama–
Mitsunobu amination, and hence these reagents were
included in the present investigation. The two azo reagents
used under Tsunoda conditions, that is0, 1,10-(azodicarbo-
nyl)dipiperidide (ADDP) and N,N,N0,N -tetramethylazodi-
carboxamide (TMAD),25 were likewise included, since both
of these reagents in combination with PMe3 were previously
found to give acceptable to good yields in alkylation of
Although a relatively large amount of work has already been
devoted to SPS of amines using Fukuyama–Mitsunobu
alkylation, we addressed two important issues in order to
define the scope and limitations of this strategy. The first
issue concerns investigation of alkylation conditions
suitable for SPS employing sterically hindered alcohols as
building blocks (application of secondary alcohols is also
challenging in solution-phase Mitsunobu reactions23). The
second issue concerns the number of consecutive chain
elongation steps that are possible to carry out in a
satisfactory overall yield, that is, the length limit of
polyamines obtainable by this method. The latter question

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C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
Table 1. Effect of reagent combinations on the yield of single Fukuyama–Mitsunobu solid-phase alkylations with a secondary alcohol in CH2Cl2–THF (1:1)a
Yields
No base
iPr2EtN
TMAD %a/%b
ADDP %a/%b
DEAD %a/%b
TMAD %a/%b
ADDP %a/%b
DEAD %a/%b
PMe3
PEt3
PPh3
46/49
60/71
24/30
37/39
29/47
Trace
19/14
71/60
70/92
51/52
71/74
14/19
49/53
38/54
Trace
21/16
69/71
68/93
a Yields estimated from 1H NMR.
b Product purities calculated from RP-HPLC as ratios {[9]/([9]C[10])}!100.
Table 2. Effect of various solvents on the yield of single Fukuyama–Mitsunobu solid-phase alkylations with a secondary alcohola
PPh3, DEAD, iPr2EtN
CH2Cl2–PhMe 1:1
O95%
PEt3, DEAD, iPr2EtN
CH2Cl2–PhMe 1:1
82%
THF–PhMe 1:1
PhMe
76%
THF–PhMe 1:1
53%
PhMe
38%
O95%
a Product purities calculated from RP-HPLC as ratios {[9]/([9]C[10])}!100.
sulfonamides with secondary alcohols in solution.26 Thus,
the phosphines selected were the traditional PPh3 and the
least sterically hindered trialkylphosphine, PMe3, along
with PEt3. All three phosphines have recently been reported
to give acceptable to high conversion in C–C bond
formation reactions with secondary benzylic alcohols.27
Tributylphosphine, which previously has been widely used,
was omitted in the present study due to the recently reported
lack of reactivity in combination with ADDP and TMAD in
solution-phase reactions.26
proved quite efficient in the alkylation. The reagent
combinations containing PMe3 proved not to be superior
as opposed to previous solution-phase studies.26,27 How-
ever, acceptable yields were only obtained with this
phosphine when combined with ADDP or TMAD, parallel-
ing the previous solution-phase experiments.26 The
RP-HPLC evaluation of the influence of the solvent showed
good yields for 1:1 mixtures of THF–PhMe and CH2Cl2–
1
PhMe (Table 2), but the H NMR spectra of all of the six
crude products revealed the presence of more impurities
than observed in CH2Cl2–THF (1:1). Thus, the latter solvent
combination was applied in the subsequent experiments.
The above-mentioned phosphines and azo reagents com-
prise nine reagent combinations. The presence of base in
Fukuyama–Mitsunobu reactions has previously been
reported to enhance the tolerance towards steric bulk of
the alcohol (using imidazole28) as well as to increase the
reaction rate (using iPr2EtN20). Hence, the effect of the
presence of iPr2EtN was also investigated (Table 1).
N-Alkylation of the sulfonamide (Ns-derivative) of resin-
bound glycine (11) with a secondary alcohol (cyclopenta-
nol) was subsequently performed with the most promising
reagent combinations found in the above screening. A good
yield (78%) was obtained when using PPh3 as the
phosphine, while PEt3 did not furnish a satisfactory yield
(Scheme 1). The two phosphines gave similar conversions
in the investigation shown in Tables 1 and 2, which suggests
that optimal conditions for N-alkylation is likely to be
sensitive to the type of substrate and/or linker used.
In the initial N-alkylation experiments described below we
relied on the findings by Strømgaard et al.22c concerning the
effect of solvent, concentration, order of reagent addition,
and the number of repetitions. However, longer reaction
times were applied (2!3 and 16 h), as this was found
advantageous in our previous solution-phase experiments
with secondary alcohols.26 The results of 1H NMR and
RP-HPLC analyses of the product mixtures are shown in
Table 1. Subsequently, the two best reagent combinations
were further tested in additional solvent mixtures (Table 2).
Scheme 1. Resin 11 was alkylated with cyclopentanol (12) under
Fukuyama–Mitsunobu conditions (DEAD/PPh3/iPr2EtN or DEAD/PEt3/
iPr2EtN in CH2Cl2–THF (1:1), and the product (13) was cleaved with TFA–
CH2Cl2 (95:5). aIsolated yields after vacuum liquid chromatography (VLC)
based on the original resin loading.
The general observations about the SPS alkylation of
sulfonamide 8 with 2-pentanol that emerged from these
investigations are as follows: (1) triphenylphosphine
worked well in combination with DEAD; (2) triethylphos-
phine combinations generally afforded acceptable con-
versions; (3) the presence of base did not increase the
conversion significantly; (4) the reagent pairs DEAD/PPh3,
DEAD/PEt3 and TMAD/PEt3 (with and without base) all
2.2. Building block synthesis
The possibility of synthesizing long-chain polyamines
(pentaamines or higher homologs) on solid phase using

C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
6049
the Fukuyama–Mitsunobu approach was examined with
curtatoxin analogs as the example. For this purpose, chain
elongation building blocks 14–18 were prepared along with
resin 19, necessary for synthesis of 3–5 and their branched
analogs. The diamine building blocks were mono-(2-
trimethylsilylethoxy)carbonyl (Teoc) protected and Ns-
activated, as previously described.26 Thus, compounds 14
and 15 were obtained in 70–73% overall yield. Compound
16 was obtained in 80% yield by treatment of 3-amino-1-
propanol with (2-trimethylsilyl)ethyl p-nitrophenyl carbon-
ate in MeOH–CH2Cl2 (1:1), and the crude product was used
without further purification. Diols were mono-protected as
the tert-butyldiphenylsilyl (TBDPS) ethers under the
conditions described by Wacowich-Sgarbi and Bundle,29
affording 17 and 18 in 77 and 73% yield, respectively. It was
decided to start from resin 19 shown in Scheme 2. In order
to avoid the potential risk of resin cross-linking upon
loading with an unprotected amino alcohol, the loading was
accomplished with temporarily O-trimethylsilyl (TMS)
protected 3-aminopropanol, employing similar conditions
as used for attachment of amino acids via the N-terminal
onto polystyrene trityl resins.30
2.3. SPS of curtatoxins using multiple Fukuyama–
Mitsunobu amination steps
Scheme 2. Reagents and conditions: (a) 2-(trimethylsilyl)ethyl p-nitro-
phenyl carbonate, MeOH, CH2Cl2; (b) NsCl, iPr2EtN, CH2Cl2; (c) NaH
(1 equiv), THF, 30 min; (d) TBDPS-Cl (1 equiv); (e) TMS-Cl, CH2Cl2,
40 8C, then Et3N at room temperature followed by trityl chloride resin;
(f) TBAF, DMF, 50 8C.
An efficient SPS strategy for the preparation of pentaamine
spidertoxins was recently reportedby Bienz andco-workers.11c
Scheme 3. Reagents and conditions: (a) 14, PMe3, ADDP, CH2Cl2–THF 1:1; (b) TBAF, DMF, 50 8C; (c) NsCl, iPr2EtN, CH2Cl2; (d) TFA, CH2Cl2 1:1; (e) 16,
PMe3, ADDP, CH2Cl2–THF 1:1; (f) indol-3-ylacetic acid, DIC, HOBt; (g) DBU, 2-mercaptoethanol; (h) 17, PMe3, ADDP, CH2Cl2–THF 1:1; (i) 15, PMe3,
ADDP, CH2Cl2–THF 1:1.

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C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
In their case, the polyamine was constructed from the center
by bromide displacement reactions. In the present work,
however, the aim was to test the efficiency of the
Fukuyama–Mitsunobu SPS method for preparation of
long-chain polyamines. The sequence shown in Scheme 3
was carried out starting with 500 mg of resin 19. After the
initial Fukuyama–Mitsunobu alkylation with 14 under
modified Tsunoda conditions (PMe3, ADDP),22e removal
of the Teoc group, and subsequent treatment with NsCl,
resin 20 was obtained, which was extensively washed and
dried in vacuo.
One-fifth of resin 20 was then treated with TFA–CH2Cl2
(1:1) to give the dinosylated spermidine derivative 1a in
order to determine the yield after a single alkylation step.
The isolated yield of 1a was 67% after this 6-step reaction
sequence (including the resin loading and cleavage),
corresponding to an average yield per step of O93%.
Scheme 4. Reagents and conditions (a) 18, PPh3, DEAD, CH2Cl2–THF 1:1;
(b) TBAF, DMF, 50 8C; (c) 14, PPh3, DEAD, CH2Cl2–THF 1:1; (d) indol-
3-ylacetic acid, DIC, HOBt; (e) DBU, 2-mercaptoethanol; (f) TFA–CH2Cl2
1:1.
Another one-fifth of the original resin was elongated with
the N-Teoc-protected aminoalcohol (16), and the Teoc
group was removed to give resin 21. The terminal primary
amino group was acylated with indol-3-ylacetic acid under
activation with DIC and HOBt, the Ns groups were
removed, and the resin was treated with TFA–CH2Cl2 to
furnish 3a (12% isolated yield).
The optimized conditions developed for alkylation with
secondary alcohols were applied in order to prepare di-C-
methyl branched curtatoxin analog 30 (Scheme 4). Initially,
resin 2722e was elongated with the mono protected diol (18)
using PPh3 and DEAD in CH2Cl2–THF (1:1), and the Teoc
group was removed to give resin 28. The diamine building
block 14 was then introduced employing the same
Mitsunobu conditions, designed to give resin 29.
The remaining three fifths of the original resin were
elongated with mono-protected diol 17 to give resin 22,
which was further elongated with the building block 15 to
give 23. Resin 23 was then divided into three equal portions
for the acylation to give 4, and for chain elongations to give
24 and 25, respectively, as shown in Scheme 3. Thus, the
theoretical yields of 1a, 3a, 4, 5, and 26 represented the
same molar amounts, as they were designed to arise from
one fifth each of the starting resin 19. The Ns groups in the
fully protected resin-bound products were removed by two
treatments with DBU and 2-mercaptoethanol in DMF,18 for
24 h16 and for 1 h, respectively, in order to complete the
deprotection as indicated by a colorless drain [the absence
of the yellow 2-(2-nitrophenylthio)ethanol].18 The products
(4, 5, and 26) were released from the solid support with
TFA–CH2Cl2 (1:1) and purified by reversed-phase vacuum
liquid chromatography (VLC), a method previously
reported to be appropriate for isolation of acylpolyamines.31
Neither the yields nor the purities were satisfactory after the
RP-VLC purification, however, and 1H NMR spectra
demonstrated the presence of relatively complex mixtures,
with only minor resonances from the indole moiety present.
The samples were therefore analyzed by reversed-phase
HPLC and LC–MS.
The remaining sequence aimed towards 30 was performed
as described above, but no well-defined product could be
isolated by RP-VLC. Furthermore, LC–MS analysis of the
obtained fractions revealed no traces of 30, while the most
polar fraction contained the diamino alcohol 31, which
indicated that the first alkylation had taken place partially.
Thus, the decrease in yield as observed in consecutive
alkylations with primary alcohols appears to be even more
pronounced when using secondary alcohols.
As shown in Table 3, good isolated yields were obtained
after a single alkylation reaction with both primary and
secondary alcohols. However, in both cases the isolated
yields dropped significantly after the second consecutive
alkylation step. We hypothesize that the low yield generally
observed in the second SPS Fukuyama–Mitsunobu alkyl-
ation step may arise from interference of deposited
byproducts and/or excess reagents in the resin pores. This
Table 3. Isolated yields obtained in polyamine solid-phase synthesis using
polystyrene trityl resin as shown in Table 1, Schemes 3 and 4
For compound 4, the LC–MS analysis was satisfactory. This
was not the case for compound 5, however, and the
polyamine 26 was apparently not formed in appreciable
amounts after five Fukuyama–Mitsunobu coupling steps
(see Supporting Information for chromatograms and MS
spectra). The same negative result was obtained when
performing five consecutive elongations using the
Strømgaard approach (N-Teoc protected amino alcohols
and ADDP–PBu3).22c
1st Alkylation
2nd Alkylation
3rd Alkylation
Primary alcohol
Secondary
alcohol
67%a
59%b
12%a
0%c
Trace
n.p.d
a Isolated yields obtained in the experiments shown in Scheme 3.
b Isolated yield of compound 9 (Table 1).
c Yield of 30 (Scheme 4).
d Not performed.

C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
6051
explanation seems plausible when considering the problems
often encountered with isolation of products from Mitsu-
nobu reactions in general, a subject very recently reviewed
by Dembinski32 as well as by Dandapani and Curran.33
detector, and a CTO-10AC VP column oven, using a
Phenomenex Luna C18(2) 3 mm column (150!4.6 mm)
eluted at a rate of 0.8 mL/min. The system was controlled by
Class VP 6 software, and elution was performed with eluent
A (MeCN–H2O–TFA 10:90:0.1) containing 0% of eluent B
(MeCN–H2O–TFA 90:10:0.1) at tZ0–5 min, rising linearly
to 40% of B during tZ5–35 min, and rising linearly to
100% of B during tZ35–40 min. LC–MS was performed
using a ThermoFinnigan TSQ Quantum Ultra instrument.
The preparative HPLC system consisted of a Waters
model 590 pump, a Waters Lambda-Max model 481
spectrophotometric detector operating at 215 nm, and a
Phenomenex Luna C18(2) 5 mm column (250!21.2 mm).
The chromatograph operated isocratically at a flow-rate of
9 mL/min, using water–acetonitrile–TFA 85:15:0.1 as the
mobile phase. High-resolution mass spectrometry (HRMS)
measurements for exact mass determination were performed
on a Bruker APEX Qe Fourier transform mass spectrometer
equipped with a 7-tesla superconducting magnet and an
external electrospray ion source (Apollo source). The
spectra were externally calibrated with a CID (collision
induced dissociation) spectrum of LHRH (luteinizing
hormone releasing hormone) free acid. The samples were
introduced into the electrospray ion source using a 250 mL
syringe with a syringe pump flow of 2 mL/min.
3. Conclusions
The experiments described in the present paper show that
the Fukuyama–Mitsunobu amination reaction is a versatile
but also a limited method for SPS of secondary amines.
Superior reagent combinations for Fukuyama–Mitsunobu
alkylation of resin-bound 2-nitrobenzenesulfonamides with
secondary alcohols have been established by examining a
combinatorial array of selected phosphine-reagents and azo
reagents, with or without addition of a base. Also, resin-
bound Ns-activated glycine was successfully alkylated with
a secondary alcohol (cyclopentanol) in good yield, which
shows that these results may find extended use in the
synthesis of novel peptide analogs. Furthermore, systematic
elongation sequences targeting long-chain polyamines (up
to a heptaamine), showed that the Fukuyama–Mitsunobu
amination method employing primary alcohols is practi-
cally limited to two chain elongation steps in SPS, if
acceptable yields are to be obtained. However, when using a
secondary alcohol, only one alkylation step was feasible
under the conditions employed in the present work. Sharply
dropping yields in successive alkylation steps are thus the
most serious limitation of the use of the Fukuyama–
Mitsunobu reaction in SPS of polyamines.
4.2. General procedures
4.2.1. SPS Fukuyama–Mitsunobu alkylation of resin-
bound 2-nitrobenzenesulfonamides (Tables 1 and 2,
Schemes 1, 3, and 4). The vacuum dried N-nosyl-
functionalized resin (typically w0.1 mmol) was suspended
in THF (0.5 mL), and then a secondary alcohol or a
monoprotected diol (5 equiv) in CH2Cl2 (0.5 mL), a
phosphine (6 equiv, w0.6 mL, 1.0 M in THF) and an azo
reagent (5 equiv) in CH2Cl2 (0.5 mL) were added. The
mixture was shaken at room temperature under N2 for 3 h.
The resin was drained and washed with DMF, MeOH and
CH2Cl2 (3!5 mL, 5 min each time) and flushed with N2
for 15 min, after which the procedure was repeated twice.
In the final repetition the reaction time was 16 h.
4. Experimental
4.1. Chemicals and instruments
Unless otherwise stated, starting materials were obtained
from commercial suppliers and used without further
purification. Trityl resins (100–200 mesh, 1% divinyl-
¨
benzene) were obtained from Novabiochem (Laufelingen,
Switzerland) and IRIS Biotech (Marktredwitz, Germany).
The Rink amide resin was from IRIS Biotech (Marktred-
witz, Germany). Indol-3-ylacetic acid was purchased from
Lancaster (Morecambe, England). Tetrahydrofuran (THF)
was distilled under N2 from sodium/benzophenone prior to
use. Dry dichloromethane was distilled from P2O5 and kept
4.2.2. SPS Fukuyama–Mitsunobu alkylation of resin-
bound amino alcohols (Schemes 3 and 4). A vacuum-dried
resin-bound alcohol (typically w0.1 mmol) was suspended
in THF (0.5 mL), and then N-nosyl activated primary amine
(5 equiv) in CH2Cl2 (0.5 mL), phosphine (6 equiv,
w0.6 mL, 1.0 M in THF) and an azo reagent (5 equiv) in
CH2Cl2 (0.5 mL) were added. The mixture was shaken at
room temperature under N2 for 3 h. The resin was drained
and washed with DMF, MeOH and CH2Cl2 (3!5 mL,
5 min each time) and flushed with N2 for 15 min, after
which the procedure was repeated twice. In the final
repetition the reaction time was 16 h.
˚
over 4 A molecular sieves. Water for reversed-phase high-
performance liquid chromatography (HPLC) was filtered
through a 0.22 mm membrane filter (Millipore, Millipak40).
1H NMR spectra were recorded at 400.14 or 600.13 MHz
on a Bruker Avance 400 or Avance 600 spectrometer,
respectively, and 13C NMR spectra were recorded at
100.6 MHz on a Bruker Avance 400 spectrometer, using
CDCl3 or CD3OD as solvents and TMS as internal standard.
Coupling constants (J values) are given in hertz (Hz).
Multiplicities of 1H NMR signals are reported as follows: s,
singlet; d, doublet; t, triplet; p, pentet; m, multiplet; br,
broad signal. VLC was performed using Merck silica gel
60H, 5–40 mm (average size 15 mm), or Merck LiChroprep
RP-18 (40–63 mm) stationary phase. Analytical HPLC was
performed on a Shimadzu HPLC-system consisting of an
SCL-10A VP controller, an SIL-10AD VP autoinjector, an
LC-10AT VP Pump, an SPD-M10A VP diode array
4.2.3. Nosylation of resin-bound amines (Schemes 1 and
3). The resin was dried in vacuo and NsCl (5 equiv) in
CH2Cl2 was added under a stream of N2. iPr2EtN (7 equiv)
was added, and the mixture was shaken at room temperature
for 15 h. Then the resin was washed with DMF, MeOH and
CH2Cl2 (3!5 mL, 5 min each time) and dried in vacuo
before the next chain-elongation step.

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C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
4.2.4. Removal of TBDPS or Teoc groups (Schemes 3 and
4). The resin was treated with TBAF$3H2O (5 equiv) in
DMF (3 mL) for 30 min at 50 8C, and washed with DMF,
MeOH and CH2Cl2 (3!5 mL, 5 min each time).
131.9, 125.2, 55.3, 44.3, 41.7, 38.7, 30.4, 30.0, 20.7, 19.5,
14.1. HRMS: m/z calcd for [C15H26N3O2S]C 344.1639,
found 344.1640, DM 0.32 ppm.
Compound 13. Yield: 21 mg (78%) of a yellow oil. 1H NMR
(400 MHz, CDCl3): d 8.10 (d, JZ7.3 Hz, 1H, Ns), 7.76–
7.66 (br m, 3H, Ns), 6.53 (br s, 1H, NHCO), 5.73 (br s, 1H,
NHCO), 4.33 (m, 1H, CHN), 3.93 (br s, 2H, H-a), 1.91–1.22
(br m, 8H). 13C NMR (100 MHz, CDCl3): d 148.1, 134.3,
132.5, 132.1, 131.4, 124.5, 59.6, 46.7, 29.0 (2C), 23.2 (2C).
HRMS: m/z calcd for [C13H17N3O5SNa]C 350.0781, found
350.0782, DM 0.37 ppm.
4.2.5. Introduction of the indol-3-ylacetic acid residue
(Schemes 3 and 4). The resin was suspended in dry DMF
(1 mL). DIC (5 equiv), HOBt (5 equiv), and indol-3-
ylacetic acid (5 equiv) in dry DMF (1 mL) were added
and the mixture was shaken at room temperature under N2
for 4 h. The resulting resin was drained and washed with
DMF, CH2Cl2 and DMF (3!5 mL, 5 min each time).
4.2.9. N-[(2-Nitrophenyl)sulfonyl]-N1-[(2-trimethylsilyl)-
ethoxycarbonyl]-1,4-butanediamine (14). (2-Trimethyl-
silyl)ethyl p-nitrophenyl carbonate (4.83 g, 17.05 mmol)
in CH2Cl2 (25 mL) was added to a stirred solution of 1,4-
butanediamine (3.97 g, 45 mmol, 2.6 equiv) in MeOH
(25 mL), and the mixture was stirred for 16 h at room
temperature. The methanol was removed in vacuo and then
EtOAc (250 mL) was added. The organic phase was washed
with 2 M aq NaOH (4!100 mL) and brine (2!100 mL),
dried (Na2SO4), filtered, concentrated, and dried in vacuo to
4.2.6. Removal of Ns groups on solid phase (Schemes 3
and 4). The resin was treated twice with DBU (10 equiv) in
DMF (1 mL) and 2-mercaptoethanol (20 equiv) in DMF
(1 mL) for 20 and 1 h, respectively. The resin was drained
and washed with MeOH between each repetition until a final
colorless drain confirmed complete deprotection. The resin
was washed with DMF, MeOH and CH2Cl2 (3!5 mL,
5 min each time).
4.2.7. Cleavage from the resins (Tables 1 and 2, Schemes
1, 3, and 4). The products were cleaved by treatment with
TFA–CH2Cl2 (4 mL, 1:1 for trityl linkers and 95:5 for Rink
linker) at room temperature for 2 h. The drained solvent was
combined with washings (MeOH (2!5 mL) and CH2Cl2
(2!5 mL) and concentrated in vacuo. The products were
purified by reversed-phase VLC [H2O–MeCN–TFA
(95:5:0.1, 90:10:0.1, 85:15:0.1 and 80:20:0.1)] or prepara-
tive RP-HPLC.
1
give a sufficiently pure product (2.89 g; 73%). H NMR
(400 MHz, CD3OD): d 4.11 (t, JZ8.3 Hz, 2H, CH2O), 3.10
(t, JZ6.4 Hz, 2H, CH2NHCO), 2.64 (t, JZ6.4 Hz, 2H,
CH2NH2), 1.49 (m, 4H, 2!CH2), 0.98 (t, JZ8.3 Hz, 2H,
CH2Si), K0.05 (br s, 9H, (CH3)3Si). 13C NMR (100 MHz,
CD3OD): d 159.8, 64.2, 42.7, 41.9, 31.4, 28.8, 19.2, K0.9
(3C). The crude material, iPr2EtN (2.80 mL), and NsCl
(3.30 g) were dissolved in CH2Cl2 (40 mL) and the solution
was stirred at room temperature. After 16 h the mixture was
concentrated, the residue was loaded onto a VLC column
(7!7 cm), and the column eluted with hexane–EtOAc
(10:1, 6:1, 4:1, 2:1, and 1:1) to furnish 14 (4.39 g; 62%
overall) as a pale yellow syrup. 1H NMR (400 MHz,
CDCl3): d 8.13 (m, 1H, Ns), 7.86 (m, 1H, Ns), 7.74 (m, 2H,
Ns), 5.38 (br t, 1H, NHSO2), 4.57 (br t, 1H, NHCO), 4.13
(m, 2H, CH2O), 3.12 (m, 4H, 2!CH2N), 1.55 (m, 4H, 2!
CH2), 0.96 (t, JZ7.2 Hz, 2H, CH2Si), 0.02 [br s, 9H,
(CH3)3Si]. 13C NMR (100 MHz, CDCl3): d 156.9, 148.0,
133.7, 133.6, 132.8, 125.4, 63.0, 43.4, 40.2, 27.1, 26.8, 17.8,
K1.5 (3C).26
4.2.8. Characterization of compounds 1a, 3a, 9, and 13.
Compound 1a. Yield: 44 mg (67%) of a yellow syrup. H
1
NMR (400 MHz, CDCl3): d 8.04 (m, 2H, Ns), 7.83–7.76 (br
m, 6H, Ns), 3.40 (t, JZ7.2 Hz, 2H), 3.30 (t, JZ6.6 Hz, 2H),
3.02 (t, JZ6.6 Hz, 2H), 2.86 (t, JZ7.2 Hz, 2H), 1.87 (p,
JZ7.2 Hz, 2H), 1.58 (m, 2H), 1.47 (m, 2H). 13C NMR
(100 MHz, CDCl3): d 149.6, 135.5, 135.0 (2C), 134.8,
133.7, 133.6, 133.3, 131.5 (2C), 125.9, 125.6, 49.3, 46.2,
43.7, 38.6, 28.9, 27.8, 26.2. HRMS: m/z calcd for
[C19H26N5O8S2]C 516.1217, found 516.1217, DM
0.14 ppm.
4.2.10. N-[(2-Nitrophenyl)sulfonyl]-N1-[(2-trimethyl-
silyl)ethoxycarbonyl]-1,3-propanediamine (15). The pro-
cedure was as described above using 1,3-propanediamine as
the starting material, to give 15 (2.15 g; 68% overall) as a
pale yellow syrup. 1H NMR (400 MHz, CDCl3): d 8.12 (m,
1H, Ns), 7.84 (m, 1H, Ns), 7.74 (m, 2H, Ns), 5.95 (br s, 1H,
NHSO2), 4.99 (br s, 1H, NHCO), 4.13 (br t, JZ8.2 Hz, 2H,
CH2O), 3.25 (q, JZ6.4 Hz, 2H), 3.16 (q, JZ6.4 Hz, 2H),
1.71 (p, JZ6.4 Hz, 2H, CH2), 0.96 (br t, JZ8.2 Hz, 2H,
CH2Si), 0.02 [br s, 9H, (CH3)3Si]. 13C NMR (100 MHz,
CDCl3): d 157.2, 147.9, 133.8, 133.5, 132.7, 125.2, 63.0,
40.7, 37.3, 30.2, 17.6, K1.6 (3C). HRMS: m/z calcd for
[C15H24N3O6SSiNa]C 426.1126, found 426.1127, DM
0.40 ppm.
1
Compound 3a. Yield: 11 mg (12%) of a colorless oil. H
NMR (600 MHz, CDCl3): d 7.56 (d, JZ7.9 Hz, 1H), 7.37
(d, JZ8.1 Hz, 1H), 7.13 (dd, JZ8.1 and 7.9 Hz, 1H), 7.04
(dd, JZ8.1 and 7.9 Hz, 1H), 3.69 (s, 2H, CH2CO), 3.11–
3.03 (br m, 6H, 3!CH2N), 2.98 (t, JZ7.6 Hz, 2H, CH2N),
2.81 (m, 4H, 2!CH2N), 2.08 (m, 2H), 1.82 (p, JZ6.6 Hz,
2H), 1.63 (m, 2H), 1.36 (m, 2H). 13C NMR (100 MHz,
CDCl3): d 176.5, 138.2, 128.4, 125.2, 122.8, 120.1, 119.3,
112.6, 109.4, 48.2, 48.0, 46.0 (2C), 37.8 (2C), 36.7, 33.9,
27.6, 25.3 (2C). HRMS: m/z calcd for [C20H34N5O]C
360.2758, found 360.2759, DM 0.39 ppm.
Compound 9. Yield: 12 mg (59%) of a yellow oil after RP-
1
VLC. H NMR (400 MHz, CDCl3): d 8.05 (d, JZ7.3 Hz,
1H, Ns), 7.80–7.72 (br m, 3H, Ns), 3.91 (m, 1H, CHNNs),
3.39 (t, JZ7.8 Hz, 2H, CH2NNs), 2.72 (t, JZ7.3 Hz, 2H,
CH2NH2), 1.65–1.26 (br m, 8H, 4!CH2), 1.10 (d, JZ
C
NMR (100 MHz, CDCl3): d 157.2, 147.9, 135.1, 132.9,
4.2.11. N-[(2-Trimethylsilyl)ethoxycarbonyl]-3-amino-1-
propanol (16). 3-Amino-1-propanol (552 mL, 2.4 mmol,
1.2 equiv) was dissolved in MeOH (20 mL), (2-trimethyl-
silyl)ethyl p-nitrophenyl carbonate (567 mg, 2.0 mmol) in
6.1 Hz, 3H, CH3CH), 0.84 (t, JZ7.3 Hz, 3H, CH3CH2). 13

C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
6053
CH2Cl2 (20 mL) was added, and the mixture was stirred at
room temperature for 16 h. Methanol was removed in
vacuo, EtOAc (150 mL) was added, and the organic phase
was washed with 2 M aq NaOH (4!75 mL), and brine (2!
75 mL), dried (Na2SO4), filtered and concentrated. Drying
in vacuo afforded compound 16 (1.23 g; 79%) as a colorless
30 min to cap unreacted trityl chloride functionalities. The
resin was washed with DMF, MeOH and CH2Cl2 (3!
5 mL), and then it was treated with TBAF (426 mg,
6.75 mmol, 5 equiv) in DMF (10 mL) at room temperature
for 2 h. Finally the resin was drained, washed with DMF,
MeOH and CH2Cl2 (3!5 mL), and freeze-dried to give the
functionalized resin (19, 1.25 g, 1.283 mmol/g assuming
that complete conversions had been achieved).
1
syrup. H NMR (400 MHz, CD3OD): d 4.13 (t, JZ8.3 Hz,
2H, CH2O), 3.59 (t, JZ6.3 Hz, 2H, CH2OH), 3.18 (t, JZ
6.9 Hz, 2H, CH2N), 1.69 (br p, Jz6.7 Hz, 2H, CH2), 0.98 (t,
JZ8.3 Hz, 2H, CH2Si), 0.05 [br s, 9H, (CH3)3Si]. 13C NMR
(100 MHz, CD3OD): d 159.4, 63.7, 60.4, 38.6, 33.7, 18.6,
K1.6 (3C).34
Acknowledgements
The authors gratefully acknowledge financial support to
C. A. O. through the Novo Nordisk PhD Plus Prize and from
the Danish Technical Research Council (Grant No. 26-00-
0312). We also thank Ms. Maja Lambert and Dr. Cailean
Clarkson for help with LC–MS, and Ms. Uraiwan
Ngamrabiab Adamsen and Ms. Birgitte Simonsen for
technical assistance. The Lundbeck Foundation and the
Danish Medical Research Council (Grant No. 22-02-0340)
are thanked for financial support to S. H. H. NMR
equipment used in this work was acquired through grants
from Apotekerfonden af 1991 (Copenhagen).
4.2.12. 3-(tert-Butyldiphenylsilyloxy)-1-propanol (17). A
mixture of 1,3-propanediol (1.66 mL, 23.0 mmol) and NaH
(920 mg, 23 mmol; 60% suspension in oil) in dry THF
(20 mL) was stirred at room temperature under N2 for
30 min.
tert-Butyldiphenylsilylchloride
(5.98 mL,
23.0 mmol) was added during 1 h, and stirring was
continued for 16 h. The mixture was then diluted with
EtOAc (200 mL), and washed with water (3!100 mL) and
brine (2!100 mL). The organic layer was dried (Na2SO4),
filtered and concentrated. The residue was purified by VLC
(hexane–EtOAc 15:1, 8:1, and 6:1) to give 17 (5.58 g; 77%)
1
as a clear syrup. H NMR (400 MHz, CDCl3): d 7.69 (m,
4H, Ph), 7.41 (m, 6H, Ph), 3.85 (br t, JZ7.2 Hz, 4H, 2!
CH2O), 1.82 (p, JZ7.2 Hz, 2H, CH2), 1.06 [br s, 9H,
CH3)3C]. 13C NMR (100 MHz, CDCl3): d 135.6 (4C), 133.3
(2C), 129.8 (2C), 127.8 (4C), 63.2, 61.8, 34.4, 26.9 (3C),
19.1. HRMS: m/z calcd for [C19H26O2SiNa]C 337.1594,
found 337.1595, DM 0.27 ppm.
Supplementary data
Supplementary data associated with this article can be found
at 10.1016/j.tet.2005.04.027
4.2.13. 5-(tert-Butyldiphenylsilyloxy)-2-hexanol (18). A
mixture of 2,5-hexanediol (809 mg, 6.9 mmol) and NaH
(280 mg, 6.9 mmol; 60% suspension in oil) in dry THF
(10 mL) was stirred at room temperature under N2 for
References and notes
30 min.
tert-Butyldiphenylsilylchloride
(1.78 mL,
6.9 mmol) was added during 30 min, and stirring was
continued for 16 h. The mixture was then diluted with
EtOAc (100 mL), and washed with water (3!75 mL) and
brine (2!75 mL). The organic layer was dried (Na2SO4),
filtered and concentrated. The residue was purified by VLC
(hexane–EtOAc 15:1, 8:1, and 6:1) to give 18 (1.78 g; 73%)
1. Cohen, S. S. A guide to polyamines; Oxford University Press:
New York, 1998.
2. (a) Bergeron, R. J.; McManis, J. S.; Liu, C. Z.; Feng, Y.;
Weimar, W. R.; Luchetta, G. R.; Wu, Q.; Ortiz-Ocasio, J.;
Vinson, T. J. R.; Kramer, D.; Porter, C. J. Med. Chem. 1994,
37, 3464–3476. (b) Reddy, V. K.; Valasinas, A.; Sarkar, A.;
Basu, H. S.; Marton, L. J.; Frydman, B. J. Med. Chem. 1998,
41, 4723–4732. (c) Casero, R. A.; Woster, P. M. J. Med. Chem.
2001, 44, 1–26. (d) Valasinas, A.; Sarkar, A.; Reddy, V. K.;
Marton, L. J.; Basu, H. S.; Frydman, B. J. Med. Chem. 2001,
44, 390–403.
1
as a clear syrup. H NMR (400 MHz, CDCl3): d 7.67 (m,
4H, Ph), 7.39 (m, 6H, Ph), 3.88 (m, 1H, CHOH), 3.69 (m,
1H, CHOSi), 1.65–1.44 (br m, 4H, 2!CH2), 1.14–1.04 (br
m, 15H, 5!CH3). 13C NMR (100 MHz, CDCl3): d 136.0
(2C), 135.9 (4C), 129.6 (2C), 127.5 (4C), 69.5/69.4* (1C),
68.3/68.0* (1C), 35.5/35.1* (1C), 34.7/34.5* (1C), 27.1
(3C), 23.4, 23.1/22.8* (1C), 19.2 (diastereoisomers).
HRMS: m/z calcd for [C22H32O2Si]C 357.2244, found
357.2244, DM 0.03 ppm.
3. (a) Byk, G.; Dubertret, C.; Escriou, V.; Frederic, G.; Jaslin, G.;
Rangara, R.; Pitard, B.; Crouzet, J.; Wils, P.; Schwartz, B.;
Scherman, D. J. Med. Chem. 1998, 41, 224–235.
(b) Yingyongnarongkul, B.-e.; Howarth, M.; Elliott, T.;
Bradley, M. Chem. Eur. J. 2004, 10, 463–473.
(c) Yingyongnarongkul, B.-e.; Howarth, M.; Elliott, T.;
Bradley, M. J. Comb. Chem. 2004, 6, 753–760.
4.2.14. Preparation of N-resin-bound 3-amino-1-propa-
nol (19). 3-Amino-1-propanol (1.03 mL, 13.5 mmol,
10 equiv) was dissolved in dry CH2Cl2 (20 mL) and TMS-
Cl (1.71 mL, 13.5 mmol, 10 equiv) was added. The mixture
was stirred at 40 8C under N2 for 1.5 h, and Et3N (3 mL,
16 equiv) was added upon cooling to room temperature,
followed by trityl chloride resin (1.0 g, 1.35 mmol/g,
1.35 mmol). The mixture was stirred at room temperature
under N2 overnight. The resin was drained, washed with
MeOH and treated with 20% iPr2EtN in MeOH (30 mL) for
4. (a) Scott, R. H.; Sutton, K. G.; Dolphin, A. C. Trends Neurosci.
1993, 16, 153–160. (b) Williams, K. Biochem. J. 1997, 325,
289–297. (c) Igarashi, K.; Kashiwagi, K. Biochem. Biophys.
Res. Commun. 2000, 271, 559–564.
5. For recent reviews, see: (a) Strømgaard, K.; Andersen, K.;
Krogsgaard-Larsen, P.; Jaroszewski, J. W. Mini Rev. Med.
Chem. 2001, 1, 317–338. (b) Strømgaard, K.; Mellor, I. R.

6054
C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
Med. Res. Rev. 2004, 24, 589–620. (c) Mellor, I. R.;
Usherwood, P. N. R. Toxicon 2004, 43, 493–508.
Tzouros, M.; Chesnov, S.; Bigler, L.; Bienz, S. Helv. Chim.
Acta 2002, 85, 2827–2846. (d) Olsen, C. A.; Witt, M.;
Jaroszewski, J. W.; Franzyk, H. Org. Lett. 2003, 5, 4183–4185.
(e) Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H.
Org. Lett. 2004, 6, 1935–1938. (f) Picard, S.; Le Roch, M.;
Renault, J.; Uriac, P. Org. Lett. 2004, 6, 4711–4714.
6. Quistad, G. B.; Reuter, C. C.; Skinner, W. S.; Dennis, P. A.;
Suwanrumpha, S.; Fu, E. W. Toxicon 1991, 29, 329–336.
7. (a) Jasys, V. J.; Kelbaugh, P. R.; Nason, D. M.; Philips, D.;
Rosnack, K. J.; Saccomano, N. A.; Stroh, J. G.; Volkmann,
R. A. J. Am. Chem. Soc. 1990, 112, 6696–6704. (b) Jasys,
V. J.; Kelbaugh, P. R.; Nason, D. M.; Phillips, D.; Rosnack,
K. J.; Forman, J. T.; Saccomano, N. A.; Stroh, J. G.;
Volkmann, R. A. J. Org. Chem. 1992, 57, 1814–1820.
(c) Adams, M. E. Toxicon 2004, 43, 509–525.
12. (a) Chhabra, S. R.; Khan, A. N.; Bycroft, B. W. Tetrahedron
¨
Lett. 2000, 41, 1095–1098. (b) Jonsson, D. Tetrahedron Lett.
¨
2002, 43, 4793–4796. (c) Jonsson, D.; Unden, A. Tetrahedron
Lett. 2002, 43, 3125–3128.
13. (a) Paikoff, S. J.; Wilson, T. E.; Cho, C. Y.; Schultz, P. G.
Tetrahedron Lett. 1996, 37, 5653–5656. (b) Nefvi, A.; Ostresh,
J. M.; Meyer, J.-P.; Houghten, R. A. Tetrahedron Lett. 1997,
38, 931–934. (c) Ostresh, J. M.; Schoner, C. G.; Hamashin,
V. T.; Nefvi, A.; Meyer, J.-P.; Houghten, R. A. J. Org. Chem.
1998, 63, 8622–8623. (d) Yu, Y.; Ostresh, J. M.; Houghten,
R. A. Org. Lett. 2001, 3, 2797–2799. (e) Hall, D. G.; Laplante,
C.; Manku, S.; Nagendran, J. J. Org. Chem. 1999, 64,
698–699. (f) Wang, F.; Manku, S.; Hall, D. G. Org. Lett. 2000,
2, 1581–1583. (g) Manku, S.; Laplante, C.; Kopac, D.; Chan,
T.; Hall, D. G. J. Org. Chem. 2001, 66, 874–885. (h) Manku,
S.; Wang, F.; Hall, D. G. J. Comb. Chem. 2003, 5, 379–391.
(i) Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H.
J. Org. Chem. 2004, 69, 6149–6152.
8. (a) Eldefrawi, A. T.; Eldefrawi, M. E.; Konno, K.; Mansour,
N. A.; Nakanishi, K.; Eugene, O.; Usherwood, P. N. R. Proc.
Natl. Acad. Sci. U.S.A. 1988, 85, 4910–4913. (b) Piek, T.;
Fokkens, R. H.; Karst, H.; Kruk, C.; Lind, A.; van Marle, J.;
Tong, Y. C. In Neurotox 8: molecular basis of drug and
pesticide action; Lunt, G. G., Ed.; Elsevier: Amsterdam, 1988;
pp 61–76.
9. (a) Nakanishi, K.; Goodnow, R., Jr.; Konno, K.; Niwa, M.;
Bukownik, R.; Kallimopoulos, T.; Usherwood, P. N. R.;
Eldefrawi, A. T.; Eldefrawi, M. E. Pure Appl. Chem. 1990, 62,
1223–1230. (b) Bruce, M.; Bukownik, R.; Eldefrawi, A. T.;
Eldefrawi, M. E.; Goodnow, R., Jr.; Kallimopoulos, T.;
Konno, K.; Nakanishi, K.; Niwa, M.; Usherwood, P. N. R.
Toxicon 1990, 28, 1333–1346. (c) Goodnow, R., Jr.;
Bukownik, R.; Nakanishi, K.; Usherwood, P. N. R.; Eldefrawi,
A. T.; Anis, N. A.; Eldefrawi, M. E. J. Med. Chem. 1991, 34,
2389–2394. (d) Nakanishi, K.; Choi, S.-K.; Hwang, D.; Lerro,
K.; Orlando, M.; Kalivretenos, A. G.; Eldefrawi, A. T.;
Eldefrawi, M. E.; Usherwood, P. N. R. Pure Appl. Chem. 1994,
66, 671–678. (e) Choi, S.-K.; Kalivretenos, A. G.; Usherwood,
P.; Nakanishi, K. Chem. Biol. 1995, 2, 23–32. (f) Nakanishi,
K.; Huang, X.; Jiang, H.; Liu, Y.; Fang, K.; Huang, D.; Choi,
S.-K.; Katz, E.; Eldefrawi, M. E. Bioorg. Med. Chem. 1997, 5,
1969–1988. (g) Huang, D.; Jiang, H.; Nakanishi, K.;
Usherwood, P. N. R. Tetrahedron 1997, 53, 12391–12404.
(h) Strømgaard, K.; Brierley, M. J.; Andersen, K.; Sløk, F. A.;
Mellor, I. R.; Usherwood, P. N. R.; Krogsgaard-Larsen, P.;
Jaroszewski, J. W. J. Med. Chem. 1999, 42, 5224–5234.
(i) Bixel, M. G.; Krauss, M.; Liu, Y.; Bolognesi, M. L.; Rosini,
M.; Mellor, I. R.; Usherwood, P.; Melchiorre, C.; Nakanishi,
K.; Hucho, F. Eur. J. Biochem. 2000, 267, 110–120. (j) Bixel,
M. G.; Krauss, M.; Weise, C.; Bolognesi, M. L.; Rosini, M.;
Usherwood, P. N. R.; Melchiorre, C.; Hucho, F. Farmaco
2001, 56, 133–135. (k) Bixel, M. G.; Weise, C.; Bolognesi,
M. L.; Rosini, M.; Brierley, M. J.; Mellor, I. R.; Usherwood,
P.; Melchiorre, C.; Hucho, F. J. Biol. Chem. 2001, 276,
6151–6160. (l) Mellor, I. R.; Brier, T. J.; Pluteanu, F.;
Strømgaard, K.; Saghyan, A.; Eldursi, N.; Brierley, M. J.;
Andersen, K.; Jaroszewski, J. W.; Krogsgaard-Larsen, P.;
Usherwood, P. N. R. Neuropharmacology 2002, 44, 70–80.
(m) Brier, T. J.; Mellor, I. R.; Tikhonov, D.; Neagoe, I.; Shao,
Z.; Brierley, M. J.; Strømgaard, K.; Jaroszewski, J. W.;
Krogsgaard-Larsen, P.; Usherwood, P. N. R. Mol. Pharmacol.
2003, 64, 954–964. (n) Jørgensen, M. R.; Olsen, C. A.; Mellor,
I. R.; Usherwood, P. N. R.; Witt, M.; Franzyk, H.; Jaroszewski,
J. W. J. Med. Chem. 2005, 48, 56–70.
14. For reviews, see: (a) Kan, T.; Fukuyama, T. Chem. Commun.
2004, 353–359. (b) Fukuyama, T.; Jow, C.-K.; Cheung, M.
Tetrahedron Lett. 1995, 36, 6373–6374.
15. Mitsunobu, O. Synthesis 1981, 1–28.
16. (a) Hidai, Y.; Kan, T.; Fukuyama, T. Tetrahedron Lett. 1999,
40, 4711–4714. (b) Hidai, Y.; Kan, T.; Fukuyama, T. Chem.
Pharm. Bull. 2000, 48, 1570–1576.
17. (a) Kan, T.; Kobayashi, H.; Fukuyama, T. Synlett 2002,
1338–1340. (b) Andersen, T. F.; Strømgaard, K. Tetrahedron
Lett. 2004, 45, 7929–7933.
18. (a) Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119,
2301–2302. (b) Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc.
1998, 120, 2690–2691.
19. (a) Reichwein, J. F.; Liskamp, R. M. J. Tetrahedron Lett. 1998,
39, 1243–1246. (b) Reichwein, J. F.; Wels, B.; Kruitjzer,
J. A. W.; Versluis, C.; Liskamp, R. M. J. Angew. Chem., Int.
Ed. 1999, 38, 3684–3687. (c) Brouwer, A. J.; Liskamp,
R. M. J. J. Org. Chem. 2004, 69, 3662–3668. (d) Lin, X. D.;
Dorr, H.; Nuss, J. M. Tetrahedron Lett. 2000, 41, 3309–3313.
20. Viirre, R. D.; Hudson, R. H. E. Org. Lett. 2001, 3, 3931–3934.
21. Dankwarth, S. M.; Smith, D. B.; Porco, J. A., Jr.; Nguyen,
C. H. Synlett 1997, 854–856.
22. (a) Chhabra, S. R.; Khan, A. N.; Bycroft, B. W. Tetrahedron
Lett. 2000, 41, 1099–1102. (b) Hone, N. D.; Payne, L. J.
Tetrahedron Lett. 2000, 41, 6149–6152. (c) Strømgaard, K.;
Andersen, K.; Ruhland, T.; Krogsgaard-Larsen, P.;
Jaroszewski, J. W. Synthesis 2001, 877–884. (d) Kromann,
H.; Krikstolaityte, S.; Andersen, A. J.; Andersen, K.;
Krogsgaard-Larsen, P.; Jaroszewski, J. W.; Egebjerg, J.;
Strømgaard, K. J. Med. Chem. 2002, 45, 5745–5754.
(e) Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk, H.
Synlett 2004, 473–476.
23. Hughes, D. L. In Organic reactions; Paquette, L. A., Ed.;
Wiley: New York, 1992; Vol. 42, pp 335–656.
24. Valentine, D. H., Jr.; Hillhouse, J. H. Synthesis 2003, 317–334.
ˆ
25. (a) Tsunoda, T.; Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993,
34, 1639–1642. (b) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.;
10. For recent reviews, see: (a) Karigiannis, G.; Papaioannou, D.
Eur. J. Org. Chem. 2000, 1841–1863. (b) Kuksa, V.; Buchan,
R.; Lin, P. K. T. Synthesis 2000, 1189–1207.
11. (a) Renault, J.; Lebranchu, M.; Lecat, A.; Uriac, P.
Tetrahedron Lett. 2001, 42, 6655–6658. (b) Manov, N.;
Bienz, S. Tetrahedron 2001, 57, 7893–7898. (c) Manov, N.;
ˆ
Ito, S. Chem. Lett. 1994, 539–542.
26. Olsen, C. A.; Jørgensen, M. R.; Witt, M.; Mellor, I. R.;

C. A. Olsen et al. / Tetrahedron 61 (2005) 6046–6055
6055
Usherwood, P. N. R.; Jaroszewski, J. W.; Franzyk, H. Eur.
J. Org. Chem. 2003, 3288–3299.
30. Barlos, P. Liebigs Ann. Chem. 1988, 1079–1081.
31. Wellendorph, P.; Jaroszewski, J. W.; Hansen, S. H.; Franzyk,
H. Eur. J. Med. Chem. 2003, 38, 117–122.
27. Hillier, M. C.; Desrosiers, J.-N.; Marcoux, J.-F.; Grabowski, J.
Org. Lett. 2004, 6, 573–576.
32. Dembinski, R. Eur. J. Org. Chem. 2004, 2763–2772.
33. Dandapani, S.; Curran, D. P. Chem. Eur. J. 2004, 10,
3130–3138.
28. Falck, J. R.; Lai, J.-Y.; Cho, S.-D.; Yu, J. Tetrahedron Lett.
1999, 40, 2903–2906.
29. Wacowich-Sgarbi, S. A.; Bundle, D. R. J. Org. Chem. 1999,
64, 9080–9089.
34. Kita, Y.; Haruta, J.-I.; Yasuda, H.; Fukunaga, K.; Shirouchi,
Y.; Tamura, Y. J. Org. Chem. 1982, 47, 2697–2700.