Synthesis and aromatisation of cyclic enediyne-containing amino acids

Article abstract of DOI:10.1039/b815176h

A series of cyclic enediyne-containing amino acids with ring sizes varying from 10 to 12 atoms have been prepared starting from propargylglycine and homopropargylglycine. Their reactivity towards Bergman cyclisation under elevated temperatures has been ex

Full text of DOI:10.1039/b815176h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and aromatisation of cyclic enediyne-containing amino acids†
Jasper Kaiser,a Bart C. J. van Esseveldt,a Margot J. A. Segers,a Floris L. van Delft,a Jan M. M. Smits,a
Sam Butterworthb and Floris P. J. T. Rutjes*a
Received 1st September 2008, Accepted 5th November 2008
First published as an Advance Article on the web 10th December 2008
DOI: 10.1039/b815176h
A series of cyclic enediyne-containing amino acids with ring sizes varying from 10 to 12 atoms have
been prepared starting from propargylglycine and homopropargylglycine. Their reactivity towards
Bergman cyclisation under elevated temperatures has been explored. The enediynes displayed marked
differences in cyclisation half-lives depending on the olefinic substituent and the ring size. A potential
candidate for incorporation into peptides has been identified.
Introduction
Enediyne cytotoxins rank among Nature’s most powerful antitu-
mour and antibiotic agents. First discovered in the mid 1980’s,1
they triggered a considerable interest in the enediyne chemistry
and biology. Upon thermal activation, the enediyne ((Z)-3-
ene-1,5-diyne) moiety (coined “warhead”)2 contained in these
compounds undergoes a symmetry-allowed rearrangement, the
so-called Bergman cyclisation reaction (BC), causing conversion
into the corresponding benzene derivative.3 The intermediate
benzenoid s,s-1,4-diradical (sometimes called para-benzyne) is
capable of abstracting hydrogen radicals from nearby DNA,
ultimately resulting in single and double strand cleavage.1
All natural enediynes have their “warhead” pre-activated by
being incorporated in a strained ring system thereby increasing
the reactivity towards cycloaromatisation. A few enediynes have
been approved for chemotherapeutic use, the first ever being
Fig. 1 The Bergman cyclisation and some N-heterocyclic enediynes.
R
neocarzinostatin (Japan, 1996).4 Mylotargꢀ, a conjugate of a
I
monoclonal antibody and the natural enediyne calicheamicin g1 ,
conducted research into this compound class.10 Du et al. reported
has been approved by the FDA in 2006 for the treatment of acute
myeloid leukemia.5 Due to the complexity and toxicity of the
naturally occurring enediynes, the design and synthesis of readily
accessible model systems mimicking their chemical and biological
function has become an important research target.6 Examples of
some model enediynes related to the current study are shown in
Fig. 1. The group of Basak prepared the cyclic nitrogen-containing
enediyne 1 and conducted kinetic studies.7 Banfi et al. addressed
the general problem of selectively triggering the BC by fusing a
cyclic enediyne to a b-lactam moiety (2) which serves as a locking
device that can be opened in a slightly basic environment.8
the synthesis of a series of 10-membered benzofused enediynes
(3) and studied their half-lives. Additionally, the tosyl-protected
variant 4 was shown to be capable of cleaving supercoiled DNA
(U-X DNA) upon incubation at 37 ◦C for 24 h at concentrations
of 10 mM and higher.
Owing to the powerful DNA cleaving and thus potential
antitumour activities of the enediynes, expanding the series of
readily accessible enediyne-containing amino acids could be of
general interest, especially in combination with suitable DNA
targeting probes. The versatile and well-described chemistry of
amino acids would ensure multiple possibilities for incorporation
of the amino acids in peptides or other targeting devices. In
this report, we disclose the synthesis and evaluation of a series
of 10-, 11- and 12-membered cyclic enediyne-containing amino
acids 5 (Scheme 1) as well as their cycloaromatisation products.
Furthermore, we report the unexpected racemisation of the title
compounds (specifically 4) occurring in the final step of their
syntheses even under mild conditions.
The first cyclic enediyne-containing amino acids published in
literature were assembled by Du et al.,9 but our group has also
aInstitute for Molecules and Materials, Radboud University Nijmegen,
Heyendaalseweg 135, 6525, AJ Nijmegen, The Netherlands. E-mail:
F.Rutjes@science.ru.nl; Fax: +31 24 365 3393; Tel: +31 24 365 3202
bAstraZeneca R & D, Alderley Park, Macclesfield, Cheshire, SK10 4TG,
United Kingdom
Retrosynthetically, the target compounds 5 should be accessible
via intramolecular C–N bond formation from the open chain
enediynes 6.9 We envisaged to assemble these cyclisation pre-
cursors by means of Sonogashira coupling11 of the appropriate
acetylenic amino acids 712 with enynes 8. The latter compounds,
† Electronic supplementary information (ESI) available: NMR spectra
of compounds 14–19, 23–26, 28, 29, 31–36; crystal data and structure
refinements for compounds 4, 19, 29 and 34. CCDC reference numbers
237705 (4), 698982 (29), 698983 (19) and CCDC 698984 (34). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b815176h
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a clean conversion of the starting materials into products within 3 h
according to TLC. In case of n = 1, the desired 10-membered cyclic
enediyne 4 could be isolated as a crystalline solid. Its 11-membered
homologue, however, could not be prepared using the latter
reaction since elimination rather than ring closure took place,
and the linear dienediyne 17 was produced instead. Interestingly,
neither 4 nor 17 showed optical activity in the polarimeter as
opposed to their respective parent compounds.
The racemic nature of product 4 was confirmed by its crystal
structure (see Fig. 2), showing both enantiomers in the unit cell.
Supposedly, the racemisation takes place after cyclisation during
which the sulfonamide proton is substituted. Due to the lack of
a more acidic NH, the a-proton of the now cyclic structure is
prone to deprotonation by a relatively mild base such as potassium
carbonate. Following this reasoning, the racemisation of 17 can
best be explained by assuming initial formation of the desired 11-
membered ring, followed by racemisation and finally ring strain-
promoted eliminative ring fission17 to give the acyclic expanded
conjugated system.
Scheme 1 Retrosynthesis of the title compounds.
in turn, would be constructed by Sonogashira reactions starting
from (Z)-configured vicinal vinyl dihalides.
Results and discussion
Initially, we studied the ring closure via intramolecular mesylate
displacement (Scheme 2).13
Fig. 2 Both enantiomers of enediyne 4 are present in its unit cell.18
Clearly, the racemisation and elimination problems in the
cyclisation step called for conditions as gentle as possible to
promote this transformation in the desired sense.19 The Mitsunobu
reaction20 has been recognised as a mild and efficient way to
N-alkylate sulfonamides or sulfonamide-protected amino acids,
especially when applied for intramolecular bond formation.21 This
strategy has also been applied by Du et al. in the synthesis of the
cyclic enediyne-containing amino acids 3.9 Following this concept,
acyclic enediynes 13 and 14 were treated with DEAD and PPh3
under high dilution (~5 mM) in THF (Scheme 3). To our dismay,
the outcome very much resembled the mesylate displacement
approach. Starting from (R)-13 (>98% ee), the 10-membered
enediyne (R)-4 was obtained with a substantially diminished
enantiomeric excess (76% ee). Surprisingly, even under the mild
conditions applied, elimination and also partial racemisation
took place with homopropargylic enynol (R)-14 (>98% ee). The
ee of the elimination product (R)-17 was determined to be as
low as 42%. It has to be assumed that racemisation proceeds
Scheme 2 Mesylate displacement strategy. Reagents and conditions:
(a) Haloenynol 10 (n = 1) or 11 (n = 2), PdCl2(PPh3)2 (cat.), CuI (cat.),
Et2NH, Et2O, rt; (b) MsCl, Et3N, CH2Cl2, 0 ◦C; (c) K2CO3, DMF, (high
dilution), rt.
Aryliodides 10 and 11 were prepared from 1,2-diiodobenzene
and propargyl alcohol or homopropargyl alcohol under Sono-
gashira conditions.14 Coupling of these enynes with enantiopure
N-tosyl-protected propargylglycine methyl ester15 (R)-9 proved
to be straightforward leading to the acyclic enediynes (R)-13
and (R)-14 in 89% and 71% yield, respectively.16 Reaction with
methanesulfonyl chloride (MsCl) afforded the corresponding
mesylates 15 and 16, setting the stage for base-induced cyclisation
reactions. Treatment of highly diluted solutions (6 mM) of these
mesylates in DMF with potassium carbonate (5 equiv.) resulted in
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and haloenynols 20–2214 proceeded via Sonogashira coupling
as anticipated, giving rise to enediynols 23–25. Subjection of
precursor 23 to Mitsunobu conditions led to the consumption
of starting material with concomitant appearance of a single new
spot on TLC which, however, had disappeared after work-up.
No enediyne could be isolated, instead the tetrahydroisoquinoline
derivative 26 was obtained, showing a different retention factor
on TLC.
Supposedly, the enediyne 27 had been formed, but underwent
Bergman cyclisation at ambient temperature within 30 minutes
under work-up conditions. In contrast to this behaviour, its
benzofused counterpart 4 was stable in crystalline form at room
temperature for months and could be kept in a chloroform solution
for several days without deterioration.22 The higher homologues
reacted like their benzofused counterparts: the homopropargylic
alcohol 24 led to the elimination product 28 in 34%, while 25 was
transformed into the 12-membered cycle 29 in a reasonable yield
(61%).
Scheme 3 Synthesis via Mitsunobu-type reaction. Reagents and condi-
tions: (a) PPh3, DEAD, THF (high dilution), rt.
In order to gain access to the thus far elusive 11-membered
cyclic enediynes, it was decided to start from protected (S)-
homopropargylglycine15 30. In this strategy, b-elimination of
the amine is no longer possible in the cyclisation step. Acyclic
enediynes 31 and 32 were readily formed by Sonogashira
couplings. Their intramolecular condensation under high dilu-
tion Mitsunobu conditions furnished the cyclic 11-membered
enediynes 33 and 34 in 70% and 80% yield, respectively, with both
products displaying optical activity (Scheme 5).23
via the cyclic enediyne as in the mesylate approach. These
observations, once more, clearly show the acidic nature of the a-
proton of the cyclic amino acids. Finally, the racemic homologue
( )-18 was cyclised under identical conditions, furnishing the
corresponding cyclic 12-membered enediyne 19 in a good yield
of 88%. These results emphasise the more general applicability of
the Mitsunobu reaction for preparing cyclic enediynes, although
the previously unaddressed9 issue of racemisation could not be
fully circumvented.
Along the same line, we set out to assemble an analogous
series of non-benzofused enediynes (Scheme 4). Synthesis of
the cyclisation substrates from racemic propargylglycine ( )-9
Scheme 5 Assembly of 11-membered cyclic enediynes. Reagents and
conditions: (a) Haloenynol (10 or 20), PdCl2(PPh3)2, CuI (cat.), n-BuNH2,
Et2O, rt; (b) PPh3, DEAD, THF (high dilution), rt.
Crystals suitable for X-ray structural analysis could be obtained
from compounds 4, 19, 29, and 34 (Fig. 3).24
A number of parameters are relevant with respect to the rate of
the Bergman cyclisation of cyclic enediynes: It has been proposed
that the distance between the acetylene termini (c–d distance,
˚
viz. Fig. 1) should be in the range of 2.9–3.4 A in order for the
Scheme 4 Synthesis of olefinic cyclic enediynes. Reagents and conditions:
(a) Haloenynol (20, 21, or 22), PdCl2(PPh3)2 (cat.), CuI (cat.), n-BuNH2,
Et2O, rt; (b) PPh3, DEAD, THF (high dilution), rt.
reaction to proceed at physiological temperatures.25 More recent
studies attribute a greater role to the strain difference between
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The 10-membered olefinic enediyne 27 (entry 1) underwent
cycloaromatisation spontaneously (Scheme 4). Its benzofused
analogue 4 (entry 2) is the only structure with a confirmed
˚
c–d distance within the “reactive window” of 2.9–3.4 A, and
it displayed a half-life of 59 min at 80 ◦C under the applied
conditions. For the same compound, Du et al.9 reported a half-life
of 9.5 h at 55 ◦C under somewhat different conditions (c = 10-4
M
in DMF, 100 equiv. CHD).29 Significantly higher temperatures and
reaction times were required to induce BC of the 11-membered
rings (entries 3–7), which followed our expectations. From the
available crystal structure data of 34 it is apparent that its
c–d distance is well outside the proposed reactive range of 2.9–
˚
3.4 A. It is therefore safe to assume that this is also true for
its olefinic counterpart 33. Indeed, only a trace amount of the
cyclised product was detected (1H-NMR) after having subjected
33 to temperatures of 80 ◦C for 24 h. Increasing the temperature
to 90 ◦C caused the BC to proceed with a half-life of 26 h.
Even higher temperatures were needed for benzene-fused 34 to
aromatise efficiently: after 24 h at 90 ◦C only small amounts of the
corresponding product could be detected. Finally, at 120 ◦C a half-
life of 175 h was measured (entry 7). Both 12-membered species 19
and 29 with c–d distances of 3.77 A and 3.88 A, respectively, proved
to be thermally stable at a temperature of 90 ◦C as anticipated.
Upon subjecting samples to a temperature of 120 ◦C, a trace
amount of the cyclised 29 could be detected after 24 h while 19
remained unchanged (entries 9 and 10).
Fig. 3 X-ray crystal structures of cyclic enediynes 4, 19, 29, and 34.
˚
˚
the ground state and the transition state of the reaction.26 The
electronic influences on the BC are probably the least studied, but
it is known that benzannulation of the olefinic portion of cyclic
enediynes slows down the cyclisation process.27 Furthermore, for
some cyclic, benzannulated enediynes the rate-determining step is
the quenching of the benzenoid diradical, and the reaction rate
therefore can be dependent on the concentration of the radical
trap.28
With our series of enediynes in hand we set out to study
their behaviour in the BC. Enediynes 4, 19, 29, 33, and 34 were
dissolved in deuterated DMSO (c = 0.1 M), 1,4-cyclohexadiene
(CHD, 2 equiv.) and an internal standard were added, and the
samples were sealed under an argon atmosphere before being
subjected to elevated temperatures. The formation of product and
the consumption of starting material were monitored by 1H-NMR.
Table 1 summarises the results.
Scheme 6 Cycloaromatisation of 11-membered enediynes 33 and 34.
Table 1 Half-life determination of cyclic enediynes
T (◦C)
t1/2
a
˚
Entry
Enediyne
Benzo-fused
n, p
Ring size
c–d (A)
1
2
3
4
5
6
7
8
9
27
4
No
Yes
No
—
Yes
—
—
No
—
1, 1
—
1, 2
—
—
—
—
3, 1
—
10
—
11
—
—
—
—
12
—
—
n.d.
3.23
n.d.
—
3.76
—
—
3.88
—
rt–30b
80
80
90
80
90
120
90
120
120
<30 min
59 min
Tracec
26 h
33
—
34d
—
—
29
—
19
Stablee
Tracec
175 h
Stable
Tracec
Stablee
10
Yes
—
3.77
a Obtained by crystal structure elucidation. b Compound 27 cyclised during the work-up procedure. c A small amount of the aromatisation product
1
1
was observed by H-NMR after 24 h at the indicated temperature. d c = 0.05 M. e No product was observed by H-NMR after 24 h at the indicated
temperature.
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In order to fully characterise the novel aromatisation products
of 33 and 34,30 both enediynes were heated in the presence of 100
equivalents of 1,4-cyclohexadiene in proprionitrile (Scheme 6).
After 6 days at reflux temperature (97 ◦C), enediyne 33 had
been consumed completely and the tetrahydrobenzazepine 35 was
isolated in a mediocre yield of 31%. Similarly, the benzene-fused
derivative 34 was converted into the tetrahydronaphthoazepine 36
with a Perkin Elmer 241 polarimeter; concentrations (c) are given
in g/100 mL. The ee values were obtained by chiral HPLC on
a Shimadzu LC-2010C apparatus equipped with a Daicell AD-
H column (eluent: hexane/2-propanol). High resolution mass
spectra were recorded on a MAT900 (EI, CI and ESI).
3-(2-Iodophenyl)prop-2-yn-1-ol (10)
◦
in a yield of 60% upon heating at 150 C for 9 days in a sealed
1,2-Diiodobenzene (1.010 g, 3.062 mmol) was dissolved in Et2O
(10 mL). Pd(PPh3)4 (140 mg, 0.121 mmol) and CuI (53 mg,
0.280 mmol) were added to the stirred solution, followed by n-
BuNH2 (1.5 mL, 15.2 mmol). Once a clear, homogeneous solution
had been formed, prop-2-yn-1-ol (0.175 mL, 3.006 mmol) was
added via syringe and stirring was continued for 6 h. One aliquot
of a saturated solution of NH4Cl was poured into the reaction
flask, the phases were separated, and the aqueous layer was
extracted with EtOAc (3 ¥ 5 mL). The combined organic layers
were washed with brine, dried over mgSO4, and concentrated in
vacuo. The crude product was purified by flash chromatography
(EtOAc/heptane, 2:7) yielding 10 as a yellowish oil that solidified
on cooling (401 mg, 1.554 mmol, 52%). The characterisation data
were consistent with those in ref. 14a.
tube.
Conclusions
In summary, the synthesis of a series of 10-, 11-, and 12-
membered cyclic enediyne-containing amino acids has been
described, proceeding via readily available acetylene-containing
amino acid building blocks. During the cyclisation into the
targeted enediyne structures, in several instances an unexpected
(partial) racemisation took place, even under virtually neutral
Mitsunobu conditions. While the synthesis of 11-membered ring
systems failed starting from propargylglycine due to b-elimination
after ring closure, isomeric 11-membered ring enediynes could be
successfully synthesized starting from homopropargylglycine.
Half-life determination experiments of the cylic enediynes
showed that, in line with previous studies, all benzannulated
enediynes reacted significantly slower than their unsubstituted
counterparts. Moreover, it is evident that ring strain plays a major
role: An increase in ring size goes along with a distinct decrease
of the rate of cycloaromatisation, e.g. the discrepance in reactivity
between 11-membered cycle 34 and 12-membered cycle 19, both
showing almost equal c–d distances in the solid state, can best be
explained by the higher strain in the smaller ring.
4-(2-Iodophenyl)but-3-yn-1-ol (11)
The title compound was prepared following the same procedure
as described for 10 starting from 1,2-diiodobenzene (669 mg,
2.027 mmol) in Et2O (10 mL), PdCl2(PPh3)2 (70 mg, 0.010 mmol),
CuI (40 mg, 0.210 mmol), Et2NH (1.05 mL, 10 mmol), and
but-3-yn-1-ol (0.190 mL, 2.510 mmol). Flash chromatography
(EtOAc/heptane, 1:10 → 1:3) furnished 11 as a light brown
oil (318 mg, 1.169 mmol, 58%). The characterisation data were
consistent with those in ref. 14b.
Of the enediynes presented in this study, the 10-membered
benzannulated system 4 has the highest potential utility: it is stable
at room temperature but can be activated at modestly elevated
temperatures. Investigations concerning further structural opti-
misation and conjugation of 4 with peptides and targeting devices
are currently ongoing.
5-(2-Iodophenyl)pent-4-yn-1-ol (12)
The title compound was prepared following the same procedure as
described for 10 by letting react a solution of 1,2-diiodobenzene
(2.34 g, 7.09 mmol) in Et2O (20 mL) with Pd(PPh3)4 (218 mg,
0.188 mmol), CuI (61 mg, 0.320 mmol), n-BuNH2 (3.8 mL,
38.4 mmol), and pent-4-yn-1-ol (0.66 mL, 7.09 mmol) over a
period of 12 h. Work-up and purification by flash chromatography
(EtOAc/heptane, 1:10 → 2:3) gave 12 as a yellow oil (1.081 g,
3.78 mmol, 53%). The characterisation data were consistent with
those in ref. 14a.
Experimental
General information
Solvents were distilled from appropriate drying agents prior
to use and stored under nitrogen. Enantiopure propargyl- and
homopropargylglycine were purchased from Chiralix B.V. All
other chemicals were purchased from Sigma-Aldrich or Acros
and used as received, unless stated otherwise. Reactions were
carried out under an inert atmosphere of dry nitrogen or argon.
Reactions were followed and Rf values are obtained using thin
layer chromatography (TLC) on silica gel-coated plates (Merck
60 F254) with the indicated solvent mixture. IR spectra were
recorded on an ATI Mattson Genesis Series FTIR spectrometer,
or a Bruker Tensor 27 FTIR spectrometer. NMR spectra were
recorded on a Bruker DPX 200 (200 MHz), a Bruker DMX 300
(300 MHz), anda VarianInova400(400 MHz). Chemicalshifts are
given in ppm with respect to tetramethylsilane (TMS) as internal
standard. Coupling constants are reported as J-values in Hz. Flash
chromatography was carried out using ACROS silica gel (0.035–
0.070 mm, 6 nm pore diameter). Optical rotations were determined
(R)-5-[2-(3-Hydroxy-prop-1-ynyl)-phenyl]-2-(toluene-4-
sulfonylamino)-pent-4-ynoic acid methyl ester (13)
A stirred solution of 4-(2-iodophenyl)prop-3-yn-1-ol (10) (335 mg,
1.298 mmol) in Et2O (15 mL) was treated with PdCl2(PPh3)2
(40 mg, 0.057 mmol), CuI (22 mg, 0.116 mmol), and Et2NH
(0.57 mL, 5.5 mmol). Stirring was continued until a clear,
homogeneous solution had been formed and propargylglycine15
(R)-9 (309 mg, 1.098 mmol) was added. After 4 h at ambient
temperature, the reaction mixture was poured into an aliquot
of a saturated solution of NH4Cl, the phases were separated
and the aqueous layer was extracted with EtOAc (33 ¥ 8 mL).
The combined organic layers were washed with brine, dried
over mgSO4, and all volatiles were removed in vacuo. Purification
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by flash chromatography (EtOAc/heptane, 2:3) provided 13 as a
yellowish oil (401 mg, 0.975 mmol, 89%). Rf 0.48 (EtOAc/heptane,
1:1); ee = 98.5%; nmax (neat) 3483, 3276, 2952, 1737, 1635, 1592,
1477, 1439; 1H-NMR and 13C-NMR spectra were consistent with
those published in ref. 9; HRMS (EI) calcd. for C22H21NO5S (M+)
411.1140, found 411.1136.
d, J = 8.4 Hz), 7.38–7.35 (1 H, m), 7.29–7.14 (5 H, m), 6.12
(1 H, d, J = 8.7 Hz), 4.20–4.14 (1 H, m), 3.89–3.82 (2 H, m),
3.61 (3 H, s), 2.98 (2 H, dd, J = 5.0, 3.4 Hz), 2.86 (2 H, dt, J =
5.8, 2.7 Hz), 2.55 (1 H, t, J = 6.3 Hz), 2.34 (3 H, s); dC (75 MHz,
CHCl3) 169.9, 143.3, 136.8, 131.8, 131.6, 129.4, 127.7, 127.3, 126.9,
125.8, 125.0, 91.1, 86.5, 83.0, 81.3, 60.9, 54.3, 52.9, 25.2, 24.0,
21.7; HRMS (EI) calcd. for C23H23NO5S (M+) 425.1297, found
425.1309.
4-Tosyl-1,2,7,8-tetradehydro-3,4,5,6-tetrahydro-4-benzazecine-5-
carboxylic acid methyl ester (4)
i) via mesylate displacement. To a cooled solution (0 ◦C)
of alcohol (R)-13 (338 mg, 0.821 mmol) in CH2Cl2 (15 mL),
MsCl (0.13 mL, 1.67 mmol) and Et3N (0.23 mL, 1.66 mmol)
were added. The reaction mixture was allowed to reach room
temperature and was stirred for 4 h after which it was poured
into CH2Cl2/water (80 mL, 1:1). The layers were separated,
and the organic layer was washed with water (23 ¥ 40 mL),
dried over mgSO4 and concentrated in vacuo. Purification by
flash chromatography (EtOAc/heptane, 2:3) afforded the mesylate
(R)-15 as a yellow oil (347 mg, 0.709 mmol, 86%). Rf 0.22
(EtOAc/heptane, 2:3); dH (300 MHz, CDCl3) 7.75 (2 H, d, J =
8.2 Hz), 7.46–7.40 (1 H, m), 7.36–7.22 (5 H, m), 5.68 (1 H, d, J =
8.4 Hz), 5.22 (2 H, dd, J = 15.9, 17.4 Hz), 4.18–4.13 (1 H, m), 3.62
(3 H, s), 2.97 (2 H, d, J = 4.8 Hz), 2.38 (3 H, s).
5-(2-But-3-en-1-ynyl-phenyl)-2-(toluene-4-sulfonylamino)-pent-4-
ynoic acid methyl ester (17)
i) via mesylate displacement. Whilst stirring, a solution of
alcohol (R)-14 (460 mg, 1.081 mmol) in CH2Cl2 (20 mL) at
0
◦C was treated with MsCl (0.17 mL, 2.18 mmol) and Et3N
(0.30 mL, 2.16 mmol). The mixture was allowed to come to
room temperature and stirred for additional 3 h after which
time it was poured into CH2Cl2/water (100 mL, 1:1). The
layers were separated, and the organic layer was washed with
water (23 ¥ 50 mL), dried over mgSO4 and concentrated in
vacuo. Purification by flash chromatography (EtOAc/heptane, 2:3)
produced mesylate (R)-16 as a yellow oil (495 mg, 0.983 mmol,
93%). Rf 0.15 (EtOAc/heptane, 2:3); dH (300 MHz, CDCl3) 7.73
(2 H, d, J = 8.4 Hz), 7.40–7.37 (1 H, m), 7.31–7.16 (5 H, m), 5.60
(1 H, d, J = 9.0 Hz), 4.46 (2 H, t, J = 6.6 Hz), 4.20–4.13 (1 H, m),
3.62 (3 H, s), 3.08 (3 H, s), 3.02 (2 H, t, J = 6.6 Hz), 2.93 (2 H, t,
J = 4.5 Hz), 2.38 (3 H, s).
A dilute solution of the mesylate (R)-15 (334 mg, 0.682 mmol)
in DMF (115 mL; c = 6 mM) was treated with K2CO3 (470 mg,
3.40 mmol) and stirred for 2 h at room temperature. The mixture
was poured into EtOAc/water (600 mL, 1:1), and the layers were
separated. The organic layer was washed with water (33 ¥ 300 mL),
dried over mgSO4, and concentrated in vacuo at room temperature.
After flash chromatography (EtOAc/heptane, 1:4), enediyne ( )-4
was obtained as a white solid 201 mg, 0.511 mol, 75%). Crystals
suitable for X-ray analysis could be grown from EtOAc/heptane.
To a dilute solution of the mesylate (R)-16 (480 mg, 0.953 mmol)
in DMF (160 mL; c = 6 mM) was added K2CO3 (658 mg,
4.77 mmol) and the mixture was stirred for 2 h at room
temperature. The contents of the reaction vessel were poured
into EtOAc/water (800 mL, 1:1), and the phases were separated.
The organic layer was washed with water (33 ¥ 400 mL), dried
over mgSO4, and concentrated in vacuo. After flash chromatog-
raphy (EtOAc/heptane, 1:4), the title compound was obtained as
[a]22 = 0◦ (c 0.5, CH2Cl2).
D
ii) via Mitsunobu reaction. Triphenylphosphine (262 mg,
0.999 mmol) was dissolved in a dilute solution (c = 5 mM) of
alcohol (R)-13 (207 mg, 0.503 mmol) in THF (100 mL). DEAD
(40% in toluene; 0.150 mL, 0.953 mmol) was added, and the
reaction mixture was stirred for 80 min at ambient temperature
followed by removal of all volatiles in vacuo at room temperature.
Flash chromatography (EtOAc/heptane, 1:10 → 1:3) afforded
(R)-4 as a white solid (156 mg, 0.396 mmol, 79%). ee = 73%.
a colourless oil (295 mg, 0.724 mmol, 76%). [a]22 = 0◦ (c 0.5,
D
CH2Cl2).
ii) via Mitsunobu reaction. A stirred, dilute solution of
alcohol (R)-14 (115 mg, 0.270 mmol) in THF (75 mL; c = 4 mM)
was treated with PPh3 (71 mg, 0.271 mmol). As soon as it had been
dissolved, DEAD (40% in toluene; 0.043 mL, 0.273 mmol) was
added via syringe and stirring was continued for 2 h. The volatiles
were removed in vacuo, and the crude product was subjected to
flash chromatography (EtOAc/heptane, 1:10 → 1:3) yielding (R)-
17 as a slightly yellowish oil (66 mg, 0.162 mmol, 60%). ee =
42%.
General characterisation data. Rf 0.19 (EtOAc/heptane, 1:4);
n
max (neat) 2958, 1735, 1593, 1459, 1433; 1H-NMR and 13C-NMR
spectra were consistent with those published in ref.9; HRMS (EI)
calcd. for C22H19NO4S (M+) 393.1035, found 393.1038.
(R)-5-[2-(4-Hydroxy-but-1-ynyl)phenyl]-2-(toluene-4-
sulfonylamino)-pent-4-ynoic acid methyl ester (14)
General characterisation data. Rf 0.14 (EtOAc/heptane, 1:4);
max (neat) 3270, 2949, 2915, 1740, 1593, 1480, 1442; dH (300 MHz,
n
The title compound was synthesised following the same procedure
as described for 13 by allowing to react 4-(2-iodophenyl)but-
3-yn-1-ol (11) in Et2O (15 mL) with PdCl2(PPh3)2 (18 mg,
0.025 mmol), CuI (10 mg, 0.052 mmol), Et2NH (0.26 mL,
2.5 mmol), and propargylglycine (R)-9 over a period of 12 h. Work-
up and purification by flash chromatography (EtOAc/heptane,
2:3) afforded 14 as a light yellow oil (151 mg, 0.355 mmol, 71%).
Rf 0.15 (EtOAc/heptane, 2:3); ee > 99%; nmax (neat) 3495, 3266,
2955, 1736, 1584, 1473, 1438; dH (300 MHz, CDCl3) 7.74 (2 H,
CDCl3) 7.75 (2 H, d, J = 8.4 Hz), 7.44–7.41 (1 H, m), 7.35–7.19
(5 H, m), 6.13 (1 H, dd, J = 17.5, 11.2 Hz), 5.80 (1 H, dd, J =
17.6, 2.1 Hz), 5.60 (1 H, dd, J = 11.1, 2.1 Hz), 5.56 (1 H, d, J =
9.1 Hz), 4.22 (1 H, ddd, J = 9.1, 5.4, 4.6 Hz), 3.62 (3H, s), 2.99
(1 H, dd, 17, 4.6 Hz), 2.89 (1 H, dd, 17 Hz, 5.4 Hz), 2.38 (3 H,
s); dC (75 MHz, CHCl3) 169.9, 143.6, 136.9, 132.1, 131.9, 129.6,
127.9 (2 C), 127.6, 127.1, 125.6, 124.9, 117.2, 92.0, 88.7, 86.9, 83.0,
54.5, 53.1, 25.5, 21.8; HRMS (EI) calcd. for C23H21NO4S (M+)
407.1191, found 407.1193.
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5-[2-(5-Hydroxypent-1-ynyl)phenyl]-2-(toluene-4-
sulfonylamino)pent-4-ynoic acid methyl ester (18)
brine (13 ¥ 20 mL) followed by drying over mgSO4. Removal of
the volatiles and ◦purification of the crude product by bulb-to-bulb
distillation (110 C, 5.0 mbar) furnished 20 as a clear, colourless
liquid (463 mg, 3.97 mmol, 27%). The characterisation data were
consistent with those in ref.7a and ref.14d.
The title compound was synthesised analoguously to the prepa-
ration of 13. Thus, 5-(2-iodophenyl)pent-4-yn-1-ol (12) (377 mg,
1.318 mmol) was stirred with Pd(PPh3)4 (81 mg, 0.070 mmol),
CuI (30 mg, 0.158 mmol), and Et2NH (0.8 mL, 7.7 mmol) in
Et2O (25 mL) before propargylglycine ( )-9 (405 mg, 1.440 mmol)
was added, and stirring was continued over night. Work-up
and purification by flash chromatography (EtOAc/heptane, 1:1)
afforded 18 as an off-white solid (578 mg, 1.315 mmol, 99%).
Crystals suitable for X-ray analysis could be grown from a CHCl3
solution top-layered with heptane. Rf 0.32 (EtOAc/heptane, 1:1);
nmax (KBr) 3486, 3118, 2942, 2228, 1752; dH (300 MHz, CDCl3)
7.75 (2 H, d, J = 8.3 Hz), 7.40–7.37 (1 H, m), 7.30–7.16 (5 H,
m), 6.11 (1 H, d, J = 8.9 Hz), 4.18 (1 H, td, J = 9.0, 5.2 Hz),
3.89 (1 H, q, J = 5.8 Hz), 3.64 (3 H, s), 2.98 (1 H, dd, J = 17.0,
5.3 Hz), 2.90 (1 H, dd, J = 17.0, 5.1 Hz), 2.67 (1 H, dt, J = 6.6,
0.8 Hz), 2.34 (3 H, s), 2.30 (1 H, t, J = 5.6 Hz), 1.96–1.87 (2 H,
m); dC (75 MHz, CHCl3) 170.4, 143.6, 137.0, 132.1, 132.0, 128.0,
127.3, 127.2, 126.2, 124.9, 93.8, 86.5, 83.0, 80.1, 61.9, 54.3, 52.8,
31.1, 24.9, 21.5, 16.3; HRMS (CI) calcd. for C24H25NO5S (M+)
439.1453, found 439.1441.
(Z)-6-Chlorohex-5-en-3-yn-1-ol (21)
The title compound was prepared using the same methodology as
described for 20 by letting react (Z)-1,2-dichloroethene (0.395 mL,
5.232 mmol) in Et2O (10 mL) with PdCl2(PPh3)2 (130 mg,
0.112 mmol), CuI (77 mg, 0.404 mmol), Et2NH (2.00 mL,
19.33 mmol), and but-3-yn-1-ol (0.300 mL, 3.963 mmol) over
a period of 4 h. Work-up followed by bulb-to-bulb distillation
◦
(60 C, 0.13 mbar) gave 21 as a clear, colourless liquid (284 mg,
2.175 mmol, 55%). The characterisation data were consistent with
those in ref.7a.
(Z)-7-chlorohept-6-en-4-yn-1-ol (22)
The title compound was synthesised following the method
described for 20. Thus, (Z)-1,2-dichloroethene (0.500 mL,
6.622 mmol) in Et2O (10 mL) was allowed to react with Pd(PPh3)4
(217 mg, 0.188 mol), CuI (108 mg, 0.563 mmol), Et2NH (3.00 mL,
29.00 mmol), and pent-4-yn-1-ol (0.560 mL, 6.018 mmol) over
a period of 7 h. Work-up and purification by bulb-to-bulb
distillation (70 ◦C, 0.07 mbar) afforded 22 as a clear, colourless
liquid (785 mg, 5.429 mmol, 90%). The characterisation data were
consistent with those in ref.14c.
5-Tosyl-1,2,9,10-tetradehydro-3,4,5,6,7,8-hexahydro-5-
benzazacyclododecine-4-carboxylic acid methyl ester (19)
Triphenylphosphine (87 mg, 1.094 mmol) was dissolved in a
solution of enediynic alcohol 18 (401 mg, 0.912 mmol) in THF
(110 mL; c = 8 mM). DEAD was added (40% in toluene;
0.500 mL, 1.091 mmol), and the reaction mixture was stirred
for 30 min. The volatiles were removed in vacuo and the crude
product was subjected to flash chromatography (EtOAc/heptane,
1:3) to yield 19 as a colourless oil that solidified on standing
(339 mg, 0.804 mmol, 88%). Crystals suitable for X-ray analysis
could be grown by slow evaporation of a CHCl3 solution. Rf 0.58
(EtOAc/heptane, 1:1); nmax (KBr) 3442, 3069, 2951, 2920; 2230,
1752, 1598, 1484, 1348; dH (400 MHz, CDCl3) 7.68 (2 H, d, J =
8.4 Hz), 7.33–7.25 (4 H, m), 7.21–7.13 (2 H, m), 4.88 (1 H, dd,
J = 6.5, 2.4 Hz), 4.10 (1 H, ddd, J = 15.3, 12.6 Hz, 4.1 Hz), 3.73
(1 H, ddd, J = 15.0, 12.3, 4.9 Hz), 3.50 (3 H, s), 3.36 (1 H, dd,
J = 17.7, 6.5 Hz), 2.83 (1 H, dd, J = 17.7, 2.4 Hz), 2.56–2.42
(2 H, m), 2.40 (3 H, s), 2.38–2.30 (1 H, m), 2.08–1.97 (1 H, m); dC
(100 MHz, CHCl3) 169.1, 143.4, 136.2, 131.1, 129.5, 127.9, 127.2,
126.8, 126.7, 94.5, 88.2, 82.8, 81.4, 57.8, 52.1, 45.8, 30.9, 23.9, 21.4,
17.0; HRMS (CI) calcd. for C24H23NO4S (M+) 421.1348, found
421.1329.
(Z)-10-Hydroxy-2-(toluene-4-sulfonylamino)dec-6-ene-4,8-diynoic
acid methyl ester (23)
The title compound was synthesised by a similar procedure
as described for 13. Thus, (Z)-5-chloro-pent-4-en-2-yn-1-ol (20)
(144 mg, 1.236 mmol) in Et2O (15 mL) was allowed to react
with n-BuNH2 (0.6 mL, 6.1 mmol), CuI (23 mg, 0.121 mmol),
PdCl2(PPh3)2 (42 mg, 0.060 mmol) and propargylglycine ( )-9
(396 mg, 1.408 mmol) over a period of 5 h. Work-up and pu-
rification by flash chromatography (EtOAc/heptane, 2:3) yielded
23 as a yellowish solid (175 mg, 0.484 mmol, 39%). Rf 0.30
(EtOAc/heptane, 1:1); nmax (ATR) 3494, 3274, 2950, 1740, 1329;
d
H (300 MHz, CDCl3) 7.77 (2 H, d, J = 8.3 Hz), 7.29 (2 H, d, J =
8.3 Hz), 5.93 (1 H, d, J = 7.8 Hz), 5.85 (1 H, td, J = 10.8, 1.9 Hz),
5.74 (1 H, td, J = 10.8, 1.9 Hz), 5.51 (2 H, d, J = 6.5 Hz), 4.17
(1 H, td, J = 4.5, 9.0 Hz), 3.64 (3 H, s), 3.03 (1 H, t, J = 6.5 Hz),
2.96–2.81 (2 H, m), 2.42 (3 H, s); dC (75 MHz, CHCl3) 170.2,
143.8, 136.9, 129.7, 127.1, 119.9, 119.3, 95.8, 90.4, 82.5, 82.0, 53.9,
53.1, 51.4, 25.3, 21.5; HRMS (EI) calcd. for C18H19NO5S (M+)
361.0984, found 361.0991.
(Z)-5-Chloropent-4-en-2-yn-1-ol (20)
A
stirred solution of (Z)-1,2-dichloroethene (1.10 mL,
14.57 mmol) in Et2O (15 mL) was treated with Pd(PPh3)4 (386 mg,
0.335 mmol), CuI (206 mg, 1.082 mmol), and Et2NH (7.20 mL,
69.60 mmol). Once a clear, homogeneous solution had been
formed, prop-2-yn-1-ol (0.77 mL, 14.57 mmol) was added and
stirring was continued for 3 h at ambient temperature. The reaction
mixture was poured into two aliquots of a saturated aqueous
solution of NH4Cl and the phases were separated. The organic
layer was extracted with EtOAc (33 ¥ 10 mL), the combined
organic phases were washed with 1M KHSO4 (13 ¥ 20 mL) and
(Z)-11-Hydroxy-2-(toluene-4-sulfonylamino)-undec-6-ene-4,8-
diynoic acid methyl ester (24)
The title compound was prepared following a similar procedure
as described for 13 by letting react (Z)-6-chlorohex-5-en-3-yn-1-
ol (21) (134 mg, 1.026 mmol) in Et2O (15 mL) with n-BuNH2
(0.51 mL, 5.2 mmol), PdCl2(PPh3)2 (38 mg, 0.054 mmol), CuI
(0.104 mmol), and propargylglycine ( )-9 (311 mg, 1.106 mmol)
over a period of 4 h. Work-up and flash chromatography
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(EtOAc/heptane, 1:10 → 1:1) afforded 24 as a yellow oil (298 mg,
0.794 mmol, 77%). Rf 0.20 (EtOAc/heptane, 1:1); nmax (KBr) 3444,
3265, 2953, 2215, 1753, 1160; dH (300 MHz, CDCl3) 7.76 (1 H, d,
J = 8.3 Hz), 7.28 (1 H, d, J = 8.3 Hz), 6.18 (1 H, bs), 5.79 (1 H,
td, J = 10.8, 2.1 Hz), 5.68 (1 H, td, J = 10.8, 1.8 Hz), 4.15 (1 H,
t, J = 4.7 Hz), 3.80 (1 H, t, J = 6.2 Hz), 3.60 (1 H, s), 2.94–2.78
(2 H, m), 2.71 (2 H, dt, J = 6.2, 1.5 Hz), 2.40 (1 H, s); dC (75 MHz,
CHCl3) 169.9, 143.5, 136.8, 129.5, 126.9, 120.1, 118.3, 95.3, 90.1,
81.5, 79.5, 60.6, 54.0, 52.6, 24.8, 23.7, 21.3; HRMS (CI) calcd. for
C19H22NO5S (M++H) 376.1219, found 376.1206.
Flash chromatography (EtOAc/heptane, 1:10 → 1:3) of the crude
product furnished 28 as a yellowish oil (44 mg, 0.123 mmol, 34%).
Rf 0.56 (EtOAc/heptane, 1:1); nmax (KBr) 3470, 3278, 2955, 2208,
1744; dH (300 MHz, CDCl3) 7.74 (2 H, d, J = 8.4 Hz), 7.28
(2 H, d, J = 8.4 Hz), 6.04 (1 H, ddd, J = 17.5, 11.1, 2.3 Hz),
5.91 (1 H, dd, J = 10.8, 2.2 Hz), 5.77–5.69 (2 H, m), 5.56 (1 H,
dd, J = 11.1, 2.1 Hz), 5.47 (1 H, d, J = 9.2 Hz), 4.15 (1 H,
ddd, J = 9.2, 5.4, 4.3 Hz), 3.61 (3 H, s), 2.92 (1 H, ddd, J =
17.6, 4.3, 2.2 Hz), 2.83 (1 H, ddd, J = 17.6, 5.41, 2.2 Hz), 2.41
(3 H, s); dC (75 MHz, CHCl3) 170.0, 143.7, 136.9, 129.7, 128.0,
127.1, 119.8, 118.8, 117.1, 95.7, 90.9, 87.2, 81.6, 54.1, 52.8, 25.3,
21.5; HRMS (CI) calcd. for C19H20NO4S (M++H) 358.1113, found
358.1103.
(Z)-12-Hydroxy-2-(toluene-4-sulfonylamino)-dodec-6-ene-4,8-
diynoic acid methyl ester (25)
The title compound was assembled similar to the prepara-
tion of 13. Thus, (Z)-7-chlorohept-6-en-4-yn-1-ol (22) (88 mg,
0.609 mmol) in Et2O (15 mL) was coupled to ( )-9 employing
PdCl2(PPh3)2 (20 mg, 0.028 mmol), CuI (12 mg, 0.063 mmol),
and n-BuNH2 (0.30 mL, 3.04 mmol). After stirring over night,
work-up and flash chromatography (EtOAc/heptane, 1:10 → 1:1)
yielded 25 as a yellowish oil (179 mg, 0.460 mmol, 75%). Rf 0.31
(EtOAc/heptane, 1:1); nmax (ATR) 3525, 3274, 3049, 2950, 2876,
2215, 1744, 1161; dH (300 MHz, CDCl3) 7.76 (2 H, d, J = 8.3 Hz),
7.28 (2 H, d, J = 8.3 Hz), 6.21 (1 H, d, J = 9.0 Hz), 5.78 (1 H, td,
J = 10.8, 2.2 Hz), 5.65 (1 H, td, J = 10.8, 2.1 Hz), 4.13 (1 H, td,
J = 9.1, 5.2 Hz), 3.81 (2 H, t, J = 6.1 Hz), 3.60 (3 H, s), 2.95–2.78
(2 H, m), 2.70 (1 H, bs), 2.56 (2 H, dt, J = 6.7, 2.2 Hz), 2.40 (3 H,
s), 1.88–1.79 (2 H, m); dC (75 MHz, CHCl3) 170.1, 143.5, 136.8,
129.5, 126.9, 120.3, 117.9, 97.9, 89.9, 81.4, 78.5, 61.3, 54.0, 52.6,
30.8, 24.8, 21.3, 16.2; HRMS (CI) calcd. for C20H23NO5S (M+)
390.1375, found 390.1378.
(Z)-1-Tosyl-azacyclododec-6-ene-4,8-diyne-2-carboxylic acid
methyl ester (29)
Triphenylphosphine (164 mg, 0.624 mmol) was dissolved in a
stirred, dilute solution (c = 5 mM) of enediynic alcohol 25 (161 mg,
0.413 mmol) in THF (90 mL). DEAD (40% in toluene; 0.280 mL,
0.612 mmol) was added and stirring was continued for 30 min
at room temperature. Removal of the volatiles followed by flash
chromatography (EtOAc/heptane, 1:10 → 1:4) afforded 29 as
white, waxy solid (90 mg, 0.252 mmol, 61%). Crystals suitable
for X-ray analysis could be grown from a CHCl3 solution top-
layered with MeOH. Rf 0.60 (EtOAc/heptane, 1:1); nmax (ATR)
3023, 2949, 2193, 1748, 1333; dH (300 MHz, CDCl3) 7.67 (2 H, d,
J = 8.4 Hz), 7.30 (2 H, d, J = 8.4 Hz), 5.72 (2 H, d, J = 1.5 Hz),
4.84 (1 H, dd, J = 6.4, 2.4 Hz), 4.05–3.94 (1 H, m), 3.84–3.73
(1 H, m), 3.56 (3 H, s), 3.25 (1 H, tdd, J = 17.6, 6.4, 1.6 Hz),
2.73 (1 H, dd, J = 17.6, 2.4 Hz), 2.51–2.21 (3 H, m), 2.43 (3 H,
s), 2.07–1.93 (1 H, m); dC (75 MHz, CHCl3) 169.1, 143.5, 136.2,
129.5, 127.2, 121.9, 120.6, 98.4, 91.8, 82.1, 81.2, 57.6, 52.2, 45.6,
30.7, 23.8, 21.4, 17.3; HRMS (EI) calcd. for C20H21NO4S (M+)
371.1191, found 371.1181.
2-Tosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl
ester (26)
Enediynic alcohol 23 (112 mg, 0.310 mmol) and PPh3 (121 mg,
0.461 mmol) were dissolved in THF (75 mL). Whilst stirring,
DEAD (0.075 mL, 0.476 mmol) was added via syringe and stirring
was continued for 2 h at ambient temperature. All volatiles were
removed in vacuo (T > 30 ◦C) and the crude product was purified
by flash chromatography (EtOAc/heptane, 1:3 → 1:1) providing
26 as a clear colourless oil (17 mg, 0.049 mmol, 16%). Rf 0.78
(EtOAc/heptane, 1:1); nmax (ATR) 3032, 2950, 2915, 1740, 1459,
1160; dH (300 MHz, CDCl3) 7.72 (2 H, d, J = 8.3 Hz), 7.28 (2 H,
d, J = 8.3 Hz), 7.19–7.02 (4 H, m), 5.01 (1 H, t, J = 4.5 Hz), 4.70
(1 H, d, J = 15.5 Hz), 4.49 (1 H, d, J = 15.5 Hz), 3.45 (3 H, s),
3.18 (2 H, d, J = 4.5 Hz), 2.41 (3 H, s); dC (75 MHz, CHCl3) 170.7,
143.5, 136.0, 131.4, 130.7, 129.5, 128.7, 127.3, 126.8 (2 C), 126.1,
53.8, 52.2, 44.4, 31.9, 21.5; HRMS (EI) calcd. for C18H19NO4S
(M+) 345.1035, found 345.0985.
(Z)-(S)-11-Hydroxy-2-(toluene-4-sulfonylamino)undec-7-ene-5,9-
diynoic acid methyl ester (31)
The title compound was prepared using a similar procedure as
described for 13: Protected (S)-homopropargylglycine 30 (247 mg,
0.836 mmol) was coupled to (Z)-5-chloropent-4-en-2-yn-1-ol (20)
(100 mg, 0.858 mmol) by the action of Pd(PPh3)4 950 mg,
0.043 mmol), CuI (18 mg, 0.095 mmol), and n-BuNH2 (0.50 mL,
5.1 mmol) in Et2O (40 mL) over a period of 5 h. Work-up and
flash chromatography (EtOAc/heptane, 1:2 → 1:1) gave access
to 31 as a yellowish solid (265 mg, 0.706 mmol, 84%). Rf 0.23
(EtOAc/heptane, 1:1); [a]22 = +50.0◦ (c 0.11, CH2Cl2); nmax
D
(ATR) 3511, 3270, 2949, 1744, 1433, 1338; dH (300 MHz, CDCl3)
7.76 (2 H, d, J = 8.4 Hz), 7.29 (2 H, d, J = 8.4 Hz), 5.82 (1 H,
td, J = 10.9, 1.8 Hz), 5.76 (1 H, td, J = 10.9, 2.0 Hz), 5.34
(1 H, d, J = 9.2 Hz), 4.46 (1 H, dd, J = 6.5, 1.8 Hz), 4.19–4.11
(1 H, m), 3.59 (3 H, s), 2.58 (1 H, t, J = 6.5 Hz), 2.49 (2 H,
dt, J = 6.6, 2.0 Hz), 2.42 (3 H, s), 2.08–1.97 (1 H, m), 1.94–1.82
(1 H, m); dC (75 MHz, CHCl3) 172.0, 143.8, 136.5, 129.7, 127.3,
120.0, 118.7, 95.9, 95.2, 82.6, 79.5, 54.9, 52.8, 51.5, 31.8, 21.6, 15.9;
HRMS (ESI) calcd. for C19H21NNaO5S (M++Na) 398.1038, found
398.1045.
(Z)-2-(Toluene-4-sulfonylamino)undeca-6,10-diene-4,8-diynoic
acid methyl ester (28)
Enediynic alcohol 24 (134 mg, 0.357 mmol) was dissolved in
THF (70 mL; c = 5 mM). PPh3 (142 mg, 0.541 mmol) was
added to the stirred solution and once it had dissolved, DEAD
(40% in toluene; 0.250 mL, 0.545 mmol) was transferred into
the reaction vessel via syringe. Stirring was continued for 1 h at
ambient temperature followed by removal of all volatiles in vacuo.
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(S)-6-[2-(3-Hydroxy-prop-1-ynyl)phenyl]-2-(toluene-4-
sulfonylamino)-hex-5-ynoic acid methyl ester (32)
4.44 (1 H, d, J = 17.5 Hz), 3.65 (3 H, s), 2.76–2.66 (1 H, m),
2.64–2.59 (2 H, m), 2.40 (3 H, s), 2.21–2.11 (1 H, m); dC (50 MHz,
CHCl3) 171.6, 143.6, 137.7, 129.7, 129.4, 129.3, 128.2, 127.5, 127.1,
126.9, 126.0, 95.1, 87.5, 86.9, 82.0, 57.6, 52.2, 41.7, 32.0, 21.4, 18.5;
HRMS (ESI) calcd. for C23H21NNaO4S (M++Na) 430.1089, found
430.1092.
The title compound was synthesised following a similar pro-
cedure as used for 13. Thus, 3-(2-iodophenyl)prop-2-yn-1-ol
(10) (130 mg, 0.504 mmol) in Et2O (25 mL) was allowed
to react with PdCl2(PPh3)2 (18 mg, 0.026 mol), CuI (10 mg,
0.053 mmol), n-BuNH2 (0.26 mL, 2.63 mmol) and protected
(S)-homopropargylglycine 30 (146 mg, 0.494 mmol) over a
period of 5.5 h. Work-up followed by flash chromatography
(EtOAc/heptane, 1:10 → 1:1) furnished 32 as a yellow solid
(139 mg, 0.327 mmol, 66%). Rf 0.20 (EtOAc/heptane, 1:1);
(S)-2-Tosyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine-3-carboxylic
acid methyl ester (35)
Cyclic enediyne 33 (78 mg, 0.218 mmol) was dissolved in EtCN
(10 mL), 1,4-cyclohexadiene (2.06 mL, 21.8 mmol, 100 equiv.)
was added, and the reaction mixture was heated to reflux under
a protective atmosphere of nitrogen for 6 d. All volatiles were
removed and the crude product was purified by flash chromatog-
raphy (EtOAc/heptane, 1:4) to give 35 as a white solid (24 mg,
[a]22 = +26.9◦ (c 1.0, CH2Cl2); nmax (ATR) 3499, 3261, 2950,
D
1735, 1432, 1337; dH (300 MHz, CDCl3) 7.74 (2 H, d, J = 8.4 Hz),
7.45–7.39 (1 H, m), 7.36–7.30 (1 H, m), 7.26–7.20 (2 H, m), 7.16
(2 H, d, J = 8.4 Hz), 5.80 (1 H, d, J = 9.1 Hz), 4.55 (2 H, d, J =
6.0 Hz), 4.19 (1 H, dt, J = 8.6, 5.0 Hz), 3.56 (3 H, s), 3.11 (1 H, t,
J = 6.0 Hz), 2.54 (2 H, t, J = 6.6 Hz), 2.30 (3 H, s), 2.13–2.02 (1 H,
m), 1.99–1.87 (1 H, m); dC (75 MHz, CHCl3) 172.1, 143.6, 136.4,
132.1, 131.7, 129.5, 127.9, 127.5, 127.2, 125.8, 125.1, 91.8, 91.6,
83.9, 80.6, 54.9, 52.7, 51.3, 31.6, 21.4, 15.7; HRMS (ESI) calcd.
for C23H23NNaO5S (M++Na) 448.1195, found 448.1194.
0.067 mmol, 31%). Rf 0.60 (EtOAc/heptane, 1:1); [a]22 = 58.1◦
D
(c = 0.42, CH2Cl2); nmax (ATR) 3031, 2950, 1740, 1437, 1333; dH
(400 MHz, CDCl3) 7.49 (2 H, d, J = 8.4 Hz), 7.21–7.18 (1 H,
m), 7.16–7.11 (4 H, m), 7.00–6.96 (1 H, m), 4.81–4.73 (2 H, m),
4.64 (1 H, d, J = 16.5 Hz), 3.67 (3 H, s), 2.90 (1 H, dd, J = 15.8,
10.1 Hz), 2.59 (1 H, dd, J = 15.8, 9.3 Hz), 2.36 (3 H, s), 2.34–2.26
(1 H, m), 2.00–1.92 (1 H, m); dC (75 MHz, CHCl3) 171.4, 143.0,
139.9, 137.2, 136.7, 129.4, 129.2, 128.7, 127.6, 127.1, 126.3, 59.2,
52.3, 48.6, 31.4, 29.3, 21.4; HRMS (ESI) calcd. for C19H21NNaO4S
(M++Na) 382.1089, found 382.1082.
(Z)-(S)-1-Tosyl-azacycloundec-7-en-5,9-diyne-2-carboxylic acid
methyl ester (33)
In a stirred solution of enediynic alcohol 31 (103 mg, 0.274 mmol)
in THF (55 mL; c = 5 mM) was dissolved PPh3 (86 mg,
0.380 mmol) followed by the addition of DEAD (40% in toluene;
0.150 mL, 0.327 mmol). Stirring was continued for 15 min at
ambient temperature, then all volatiles were removed in vacuo
at room temperature. Purification of the crude product by
flash chromatography (EtOAc/heptane, 1:4) afforded the title
compound an off-white solid (69 mg, 0.193 mmol, 70%). Rf
(S)-2-Tosyl-2,3,4,5-tetrahydro-1H-naphtho[2,3-c]azepine-3-
carboxylic acid methyl ester (36)
Cyclic enediyne 34 (15 mg, 0.037 mmol), EtCN (3 mL), and 1,4-
cyclohexadiene (0.35 mL, 3.70 mmol, 100 equiv.) were enclosed
in a sealed tube under a protective atmosphere of nitrogen. The
reaction vessel was exposed to a temperature of 150 ◦C for 9 d
after which time the volatiles were removed and the crude product
was subjected to preparative TLC (0.5% MeOH in CH2Cl2)
resulting in 36 as a white solid (9 mg, 0.022 mmol, 60%). Rf
0.62 (EtOAc/heptane, 1:1); [a]22 = +131.9◦ (c 0.72, CH2Cl2);
D
nmax (ATR) 3023, 2950, 2915, 2842, 2198, 1731, 1433, 1333; dH
(300 MHz, CDCl3) 7.69 (2 H, d, J = 8.4 Hz), 7.31 (2 H, d, J =
8.4 Hz), 5.83 (1 H, d, J = 10.4 Hz), 5.79 (1 H, d, J = 10.4 Hz), 5.25
(1 H, dd, J = 8.9, 2.5 Hz), 4.49 (1 H, d, J = 17.9 Hz), 4.38 (1 H,
d, J = 17.9 Hz), 3.64 (3 H, s), 2.79–2.69 (1 H, m), 2.63–2.55 (2 H,
m), 2.42 (3 H, s), 2.12–2.01 (1 H, m); dC (75 MHz, CHCl3) 171.7,
143.6, 137.8, 129.7, 127.0, 122.6, 120.1, 99.4, 91.0, 86.7, 81.8, 57.1,
52.2, 41.9, 33.0, 21.5, 19.1; HRMS (ESI) calcd. for C19H19NNaO4S
(M++Na) 380.0933, found 380.0960.
0.49 (EtOAc/heptane, 1:2); [a]22 = 1.1◦ (c = 0.45, CH2Cl2); nmax
D
(ATR) 2936, 1733, 1592, 1420, 1333; dH (400 MHz, CDCl3) 7.79–
7.75 (1 H, m), 7.73–7.69 (1 H, m), 7.67 (1 H, s), 7.51 (1 H, s), 7.48
(2 H, d, J = 2.3 Hz), 7.46–7.42 (2 H, m), 7.03 (2 H, d, J = 8.4 Hz),
4.94 (1 H, d, J = 16.3 Hz), 4.86 (1 H, t, J = 5.1 Hz), 4.72 (1 H,
d, J = 16.3 Hz), 3.70 (3 H, s), 3.07 (1 H, dd, J = 15.3, 11.2 Hz),
2.82 (1 H, dd, J = 15.3, 8.1 Hz), 2.48–2.41 (1 H, m), 2.28 (3 H,
s), 1.95–1.87 (1 H, m); dC (75 MHz, CHCl3) 171.3, 143.1, 138.2,
137.2, 135.1, 132.9, 132.0, 129.2, 127.7, 127.6, 127.5, 127.2, 127.0,
126.1, 125.7, 59.0, 52.4, 49.0, 31.6, 30.1, 21.4; HRMS (ESI) calcd.
for C23H24NO4S (M++H) 410.1426, found 410.1422.
(S)-4-Tosyl-1,2,8,9-tetradehydro-4,5,6,7-tetrahydro-3H-4-
benzazacycloundecine-5-carboxylic acid methyl ester (34)
Enediynic alcohol 32 (126 mg, 0.296 mmol) was dissolved in THF
(60 mL; c = 5 mM). Whilst stirring, PPh3 (93 mg, 0.355 mmol) and
DEAD (40% in toluene; 0.165 mL, 0.360 mmol) were added, and
stirring was continued for 15 min, then all volatiles were removed in
vacuo. The crude product was subjected to flash chromatography
(EtOAc/heptane, 1:10 → 1:4) to yield 34 as a white solid (96 mg,
0.236 mmol, 80%). Crystals suitable for X-ray analysis could
be grown from a CHCl3 solution top-layered with MeOH. Rf
Half-life determination of the cyclic enediynes
High temperature NMR experiments (T ≤ 80 ◦C). The NMR
probe was heated to a set temperature and allowed to equilibrate
until the internal temperature remained constant.31 A sealed NMR
tube containing an enediyne sample (vide infra) was inserted and
1H-NMR spectra were recorded at different points in time.
0.70 (EtOAc/heptane, 1:1); [a]22 = +37.0◦ (c 0.30, CH2Cl2);
D
nmax (ATR) 3062, 2950, 2915, 2846, 2228, 1735, 1445, 1329; dH
(300 MHz, CDCl3) 7.72 (2 H, d, J = 8.4 Hz), 7.34–7.18 (6 H,
m), 5.23 (1 H, dd, J = 8.2, 3.5 Hz), 4.58 (1 H, d, J = 17.5 Hz),
High temperature experiments (T > 80 ◦C). A sealed NMR
tube containing the enediyne sample (vide infra) was immersed
into an oil bath of constant temperature. In regular intervalls,
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the NMR tube was removed from the oil bath and immediately
cooled to room temperature by rinsing with heptane and acetone.
The conversion of the BC was then controlled by 1H-NMR.
105, 739; (b) A. L. Smith and K. C. Nicolaou, J. Med. Chem., 1996, 39,
2103.
2 K. C. Nicolaou, Y. Ogawa, G. Zuccarello and H. Kataoka, J. Am.
Chem. Soc., 1988, 110, 7247.
3 (a) R. R. Jones and R. G. Bergman, J. Am. Chem. Soc., 1972, 94, 660;
(b) R. G. Bergman, Acc. Chem. Res., 1973, 6, 25.
For enediyne 4. A NMR tube (ø = 5 mm) connected
to an argon/vacuum manifold was charged with enediyne 4
(20.3 mg, 0.052 mmol) and DMSO-d6 (450 mL). Of a solution
of 1,4-cyclohexadiene in DMSO-d6 (10% v/v) was added 97 mL
(0.103 mmol, 2 equiv.). Cyclohexane was added as internal stan-
dard as a solution in DMSO-d6 (10% v/v) (14 mL, 0.013 mmol).
The resulting solution was degassed by three freeze-pump-thaw
cycles and the NMR tube was tipped-off by flame under partial
vacuum. The concentration of 4 in the thus prepared sample
was 0.093 M. Decay of the starting material and formation of
product were monitored by high temperature NMR experiments
4 “Endiine”, in Ro¨mpp kompakt Basislexikon der Chemie, Georg Thieme
Verlag, Stuttgart, 1st edition, 1998, vol. 1, p. 661.
5 P. F. Bross, J. Beitz, G. Chen, X. H. Chen, E. Duffy, L. Kieffer, S. Roy,
R. Sridhara, A. Rahman, G. Williams and R. Pazdur, Clin. Cancer
Res., 2001, 7, 1490.
6 For reviews, see: (a) M. Kar and A. Basak, Chem. Rev., 2007, 107, 2861;
(b) D. S. Rawat and J. M. Zaleski, Synlett, 2004, 393; (c) A. Basak, S.
Mandal and S. S. Bag, Chem. Rev., 2003, 103, 4077.
7 (a) A. Basak, J. C. Shain, U. K. Khamrai, K. R. Rudra and A. Basak,
J. Chem. Soc. Perkin Trans. 1, 2000, 1955; (b) A. Basak, S. Mandal, A.
K. Das and V. Bertolasi, Bioorg. Med. Chem. Lett., 2002, 12, 873.
8 L. Banfi and G. Guanti, Eur. J. Org. Chem., 2002, 3745.
9 Y. M. Du, C. J. Creighton, Z. Y. Yan, D. A. Gauthier, J. P. Dahl, B.
Zhao, S. M. Belkowski and A. B. Reitz, Bioorg. Med. Chem., 2005, 13,
5936.
10 B. C. J. van Esseveldt, Synthesis of Multi-Functional Building Blocks
from Acetylene-Containing a-Amino Acids, Ph.D. Thesis, Radboud
University Nijmegen, 2004.
11 (a) R. D. Stephens and C. E. Castro, J. Org. Chem., 1963, 28, 3313;
(b) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
1975, 4467.
12 For a review on unsaturated a-H-a-amino acids see: J. Kaiser, S. S.
Kinderman, B. C. J. van Esseveldt, F. L. van Delft, H. E. Schoemaker,
R. H. Blaauw and F. P. J. T. Rutjes, Org. Biomol. Chem., 2005, 3, 3435.
13 Intramolecular displacement of a mesylate has been successfully used
in the preparation of enediynes 1, see ref. 7.
◦
(T = 80 C). The decay of 4 displayed first-order behaviour. t1/2
(80 ◦C) = 59 min.
For enediyne 19. A sample was prepared as described for 4
from enediyne 19 (21.8 mg, 0.052 mmol) in DMSO-d6 (450 mL),
1,4-cyclohexadiene in DMSO-d6 (10% v/v) (98 mL, 0.104 mmol,
2 equiv.), and cyclohexane in DMSO-d6 (10% v/v) (14 mL,
0.013 mmol) as internal standard. The concentration of 19 in the
final solution was 0.093 M. No decay of 19 could be observed up
to temperatures of 120 ◦C.
For enediyne 29. A sample was prepared as described for 4
from enediyne 29 (19.3 mg, 0.052 mmol) in DMSO-d6 (450 mL),
1,4-cyclohexadiene in DMSO-d6 (10% v/v) (98 mL, 0.104 mmol,
2 equiv.), and cyclohexane in DMSO-d6 (10% v/v) (14 mL,
0.013 mmol) as internal standard. The resulting concentration
of 29 was 0.093 M. No decay of the enediyne was observed at
temperatures of 90 ◦C. After being subjected to 120 ◦C for 24 h, a
trace amount of a decay product appeared in the 1H-NMR spectra.
14 (a) J. W. Grissom, D. Klingberg, D. H. Huang and B. J. Slattery, J. Org.
Chem., 1997, 62, 603; (b) J. W. Grissom, D. Klingberg, S. Meyenburg
and B. L. Stallman, J. Org. Chem., 1994, 59, 7876; (c) J. W. Grissom, T.
L. Calkins and H. A. McMillen, J. Org. Chem., 1993, 58, 6556; (d) A.
Hamze, O. Provot, J. D. Brion and M. Alami, J. Org. Chem., 2007, 72,
3868; see also ref.7.
15 Fully protected propargylglycine and homopropargylglycine were
prepared according to L. B. Wolf, K. C. M. F. Tjen, H. T. ten Brink, R.
H. Blaauw, H. Hiemstra, H. E. Schoemaker and F. P. J. T. Rutjes, Adv.
Synth. Catal., 2002, 344, 70.
16 For an early report of Sonogashira couplings on propargylglycine, see:
G. T. Crisp and P. T. Glink, Tetrahedron Lett., 1992, 33, 4649.
17 (a) C. J. M. Stirling, Chem. Rev., 1978, 78, 517; (b) R. J. Palmer and C.
J. M. Stirling, J. Am. Chem. Soc., 1980, 102, 7888.
18 Drawing generated by PLATON: A. L. Spek, PLATON, A Mul-
tipurpose Crystallographic Tool, Utrecht University, Utrecht, The
Netherlands, 2002.
19 In order to attenuate the a-H acidity of the 10-membered cyclic
enediyne, the mesylated cyclisation precursor was assembled with a
Boc instead of a Ts protecting group. This compound required long
reaction times and strong bases (NaH or KHMDS in THF) to give the
cyclic enediynes in very low yields.
For enediyne 33. A sample was prepared as described for 4
from enediyne 33 (17.8 mg, 0.050 mmol) in DMSO-d6 (500 mL),
1,4-cyclohexadiene (9.5 mL, 0.100 mmol), and a solution of
dimethyl oxalate in DMSO-d6 (2.5 M) (10 mL, 0.025 mmol) as
internal standard. The concentration of 33 in the sample was 0.096
M. Decay of 33 and formation of 35 were followed at 90 ◦C. The
decay of 33 displayed first-order behaviour. t1/2 (90 ◦C) = 26 h.
For enediyne 34. A sample was prepared as described for 4
from enediyne 34 (12.3 mg, 0.030 mmol) in DMSO-d6 (550 mL),
1,4-cyclohexadiene (5.7 mL, 0.060 mmol, 2 equiv.), and MeCN in
DMSO-d6 (10% v/v) (16 mL, 0.031 mmol) as internal standard.
The final concentration of 34 was 0.053 M. Decay of 34 and
formation of 36 were followed at 120 ◦C. The decay of 34 displayed
first-order behaviour. t1/2 (120 ◦C) = 175 h.
20 O. Mitsunobu and M. Yamada, Bull. Chem. Soc. Jpn., 1967, 40, 2380.
21 (a) J. R. Henry, L. R. Marcin, M. C. McIntosh, P. M. Scola, G. D.
Harris and S. M. Weinreb, Tetrahedron Lett., 1989, 30, 5709; (b) D.
Papaioannou, C. Athanassopoulos, V. Magafa, N. Karamanos, G.
Stavropoulos, A. Napoli, G. Sindona, D. W. Aksnes and G. W. Francis,
Acta Chem. Scand., 1994, 48, 324; (c) K. Wisniewski, A. S. Koldziejczyk
and B. Falkiewicz, J. Pept. Sci., 1998, 4, 1.
22 Similar stability was reported by Du et al. (ref. 9).
23 The extent of optical purity has not been determined.
24 Supplementary crystallographic data for this paper has been deposited
with The Cambridge Crystallographic Data Centre as CCDC 237705
(compound 4), CCDC 698982 (compound 29), CCDC 698983 (com-
pound 19) and CCDC 698984 (compound 34). These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif†.
25 (a) K. C. Nicolaou, G. Zuccarello, Y. Ogawa, E. J. Schweiger and T.
Kumazawa, J. Am. Chem. Soc., 1988, 110, 4866; (b) P. R. Schreiner, J.
Am. Chem. Soc., 1998, 120, 4184.
Acknowledgements
AstraZeneca (Macclesfield, UK) is kindly acknowledged for
financial support. Paul Schlebos (Institute for Molecules and
Materials, Radboud University Nijmegen, NL) is kindly thanked
for assistance with NMR experiments.
26 (a) P. Magnus, S. Fortt, T. Pitterna and J. P. Snyder, J. Am. Chem. Soc.,
1990, 112, 4986; (b) J. P. Snyder, J. Am. Chem. Soc., 1990, 112, 5367.
27 See for example:(a) K. C. Nicolaou, W. M. Dai, Y. P. Hong, S. C. Tsay,
K. K. Baldridge and J. S. Siegel, J. Am. Chem. Soc., 1993, 115, 7944;
Notes and references
1 For general reviews of natural enediynes see: (a) U. Galm, M. H. Hager,
S. G. Van Lanen, J. H. Ju, J. S. Thorson and B. Shen, Chem. Rev., 2005,
704 | Org. Biomol. Chem., 2009, 7, 695–705
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(b) M. F. Semmelhack, T. Neu and F. Foubelo, J. Org. Chem., 1994,
59, 5038; (c) S. Bhattacharyya, M. Pink, M. H. Baik and J. M. Zaleski,
Angew. Chem. Int. Ed., 2005, 44, 592.
by Du et al. (ref. 9) and in this report. Other factors, however, cannot
be excluded such as solvent effects (DMF vs. DMSO-d6) and also,
even though the reaction followed (pseudo) first order kinetics, the
concentration of the enediyne (10-4 M vs. 10-1 M) and the amount of
CHD (100 equiv. vs. 2 equiv.).
28 The dependence of the BC rate on the radical trap concentration in
some cases was first reported in: (a) M. F. Semmelhack, T. Neu and
F. Foubelo, Tetrahedron Lett., 1992, 33, 3277. For studies concerning
this matter, see: T. Kaneko, M. Takahashi and M. Hirama, Tetrahedron
Lett., 1999, 40, 2015; (b) S. Koseki, Y. Fujimura and M. Hirama, J.
Phys. Chem. A, 1999, 103, 7672; (c) G. B. Jones and P. M. Warner, J.
Am. Chem. Soc., 2001, 123, 2134.
30 The cycloaromatisation product of
ref. 9.
4 has been described in
31 The internal temperature was determined by observing the peak
separation of 1,2-ethanediol (80% in DMSO-d6) and computing the
formula: T[K] = -108.33Dd + 460.41 according to S. Berger and S.
Braun, in 200 and More NMR Experiments, Wiley-VCH, Weinheim,
3rd ed., 2004, pp. 145–148.
29 The temperature difference presumably is the main reason for the
pronounced difference between the half lives of enediyne 4 as measured
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©