The cascade radical cyclisation approach to prenylated alkaloids: Synthesis of stephacidin A and notoamide B

Article abstract of DOI:10.1039/c3ob40979a

A strategy for the synthesis of members of the prenylated indole alkaloid family is described, which involves a radical cascade process of an appropriately substituted diketopiperazine (DKP) core structure. Several approaches to the generation of the initial radical were explored, with the most successful involving treatment of a sulfenyl substituted DKP under classical reductive conditions by heating with Bu₃SnH and a radical initiator. The required, fully substituted, radical precursor DKP structures were prepared using regio- and stereocontrolled enolate chemistry of simpler proline-tryptophan derived DKPs. The new approach allowed rapid access to a key polycyclic indoline structure, which was converted into either of the natural products stephacidin A or notoamide B.

Full text of DOI:10.1039/c3ob40979a

Organic &
Biomolecular Chemistry
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The cascade radical cyclisation approach to prenylated
alkaloids: synthesis of stephacidin A and notoamide B†
Cite this: Org. Biomol. Chem., 2013, 11,
4957
Nigel S. Simpkins,* Ilias Pavlakos, Michael D. Weller and Louise Male
A strategy for the synthesis of members of the prenylated indole alkaloid family is described, which
involves a radical cascade process of an appropriately substituted diketopiperazine (DKP) core structure.
Several approaches to the generation of the initial radical were explored, with the most successful invol-
ving treatment of a sulfenyl substituted DKP under classical reductive conditions by heating with Bu3SnH
and a radical initiator. The required, fully substituted, radical precursor DKP structures were prepared
using regio- and stereocontrolled enolate chemistry of simpler proline-tryptophan derived DKPs. The new
approach allowed rapid access to a key polycyclic indoline structure, which was converted into either of
the natural products stephacidin A or notoamide B.
Received 8th May 2013,
Accepted 13th June 2013
DOI: 10.1039/c3ob40979a
www.rsc.org/obc
these systems, and their potent biological activities, served to
generate immediate synthetic interest in these targets,4 and
Introduction
Stephacidins A (1) and B (2) are members of the prenylated total syntheses of the stephacidins soon emerged from the
indole alkaloid family and were isolated from the mitosporic groups of Myers,5 Baran,6 and Williams.7
fungus Aspergillus ochraceus WC76466 by Qian-Cutrone and co-
The details of the dimerisation of synthetic avrainvillamide
workers in 2002.1 The gross structure of stephacidin A was to give stephacidin B were elucidated initially by Myers.5 The
assigned following detailed NMR studies, the polycyclic indole same group subsequently provided evidence of the dis-
system, fused to a proline-derived bridged diketopiperazine sociation of stephacidin B in cell culture to provide the highly
(DKP) resembling known structures such as paraherquamides electrophilic avrainvillamide, the two alkaloids being demon-
and brevianamides. However, the structure of the much more strated to be equivalent in their ability to inhibit certain
complex stephacidin B proved more difficult to solve. Although cancer cell lines.8 Further studies implicated the nuclear cha-
NMR, MS and other data indicated that stephacidin B approxi- perone protein nucleophosmin as the probable target for
mated a dimeric structure with respect to stephacidin A, the avrainvillamide, the antiproliferative effects of the alkaloid see-
unique, complex, and beautiful architecture (2) of this alkaloid mingly deriving from its reaction with a cysteine residue on
was only fully assigned following single crystal X-ray analysis this protein.9
(Fig. 1).1a
Extensive and pioneering synthetic work from Baran’s
At this point, these researchers recognised that stephacidin group established the first access to stephacidin A, and sub-
B could be formed biosynthetically by dimerisation of avrain- sequently clarified aspects of the absolute stereochemistry of
villamide (3), an alkaloid described in an earlier patent from these compounds.6a,c The synthesis of potent model systems
the Fenical group,2 and also reported by workers at Pfizer, who further elucidated the requirements for cytotoxicity.
had named it CJ-17665.3
The Williams group, which has been responsible for the
Alkaloids 1 and 2 were found to have potent tumour inhibi- vast majority of research in this area, has achieved syntheses
tory properties, especially stephacidin B, which displayed an of many of these targets, including 1–4, has delineated numer-
IC50 of 0.06 μM against a testosterone-sensitive prostate cancer ous biosynthetic pathways for this family, and has established
cell line, LNCaP.1
a biomimetic Diels–Alder approach as perhaps the most direct
The fascinating and complex molecular architectures of the and powerful method for the synthesis of the bridged DKP
stephacidins, the interesting biogenetic interrelationships in system at the core of these natural products.10
Our own interest in the stephacidins stemmed from earlier
work in which we had explored the regio- and stereocontrol
School of Chemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT,
available in enolate reactions of various proline-containing
UK. E-mail: n.simpkins@bham.ac.uk
†Electronic supplementary information (ESI) available. CCDC 848586, 936851
DKP systems.11 This enabled rapid access to sulfenylated DKPs
capable of cationic substitution, and led subsequently to the
design of a cationic ‘cascade’ approach using hydroxy-DKPs
and 936852. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3ob40979a
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Fig. 1 Structures of selected prenylated indole alkaloids.
Scheme 1 A cationic double cyclisation step in the synthesis of ent-malbrancheamide B.
that provided a concise synthesis of ent-malbrancheamide B
(5), Scheme 1.12
In this approach, the key reaction involved treatment of
hydroxy-DKP 6 with TMSOTf, to provide 7 as the result of a dia-
stereoselective tandem cationic cyclisation sequence. Two
further steps provided ent-malbrancheamide (5) as the un-
natural enantiomer.
Scheme 2 Proposed double radical cyclisation to give key polycyclic indolines.
Unfortunately, we failed in our efforts to synthesise stepha-
cidin A this way, since the pyrano-substituted indole corres-
ponding to 6 did not undergo productive double cyclisation
under any of the acidic or Lewis acidic conditions explored.
However, this previous work provided a platform for tackling
the synthesis of the stephacidins by a radical mediated cascade
process somewhat analogous to that shown in Scheme 1. We
recently described our preliminary results in this area,13 and
herein we show how this strategy has furnished new syntheses
of both stephacidin A (1) and notoamide B (4).
captodative radicals derived from amino acids,16 and (iii) cycli-
sation of radicals onto indoles (mainly at C-2).17 However, this
particular type of cascade had no close precedent and pre-
sented obvious challenges in terms of harnessing two less
common modes of cyclisation for two sequential 6-membered
ring formations. Our earlier work appeared to support the idea
that the required stereochemical outcome at C-6 should pre-
dominate, whilst the relative stereochemical outcome at the (cis)
indoline ring junction did not appear crucial (see later).
The idea of accessing the alkaloid framework of stephacidin
A via the corresponding indoline was especially attractive,
since exactly these systems were required to enter the stephaci-
Results and discussion
Based on earlier results, our attention focused on the key din B–avrainvillamide manifold by chemistry established by
double radical cyclisation outlined in Scheme 2. We envisaged the Baran group. Gribble reduction of stephacidin
A
that a precursor group X would provide access to a carbon- (NaBH3CN, AcOH) had given a corresponding indoline (of
centred radical on the DKP core and that the radical would unassigned relative stereochemistry), which could then be oxi-
undergo sequential 6-exo and 6-endo modes of cyclisation.
dised by SeO2–H2O2 to give avrainvillamide and thus stephaci-
Various aspects of this plan were reasonably well prece- din B in modest yield.6b,c This process has also been employed
dented, including: (i) radical generation on DKPs (mainly by the Williams group,7b and Baran also improved the efficiency
involving oxidation or bromination),14,15 (ii) cyclisation of of the oxidative step by switching to oxone as oxidant.18
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Thus, a rapid synthesis of a stephacidin A indoline would
be expected to facilitate direct access to avrainvillamide and
stephacidin B by avoiding the need for Gribble reduction and
also enable synthesis of stephacidin A itself by simple
dehydrogenation.
One option that we pursued was to generate a radical on a
DKP intermediate 8, without an obvious radical precursor
group, i.e. using X = H. Generation of an initial enolate at this
position followed by exposure to an appropriate oxidant, using
methods described by Baran for bis-enolate coupling,19 might
be expected to initiate a radical cascade. A brief exploration of
this concept, starting from DKP 10, revealed that only a single
cyclisation could be achieved, Scheme 3.
Treatment of DKP 10 with LDA followed by addition of
CuCl2 led cleanly to formation of monocyclised product 11,
which was isolated as a single diastereoisomer. This result is
well precedented, based on a large family of known metal
mediated cyclisations, including copper, iron, and especially
manganese.20 The stereochemical outcome mirrors that seen
in our earlier cationic cyclisation (Scheme 1), in which we
invoked minimisation of steric interactions between the prenyl
Fig. 2 Structure of sulfenylated DKP 14a with ellipsoids shown at the 50%
probability level. Solvent methanol and hydrogen atoms have been omitted for
clarity.
appendage undergoing cyclisation and the ring nitrogen pro- sulfenylation was expected to proceed with inversion of con-
tecting groups (PMB). figuration, and in this series of compounds this outcome was
Further studies in this area may be warranted but we have confirmed by a single crystal X-ray determination carried out
instead focused on the use of sulfenylated DKPs to generate on DKP 14a, Fig. 2.
radicals under conventional Bu3SnH reductive conditions. As
described in our communication, we initially explored this be effectively ‘telescoped’ into a one-pot procedure, giving
chemistry on model systems, Scheme 4.13
ready access to 14a. A problem identified previously is the
We discovered that the prenylation and sulfenylation could
The synthesis of sulfenylated DKPs 14 followed our previous reluctance of bridged DKPs bearing amide PMB groups to
reports in which we had established that mixed proline undergo effective deprotection. In our previous cationic chem-
derived DKPs undergo highly regio- and stereoselective prenyl- istry we turned to the use of O-benzyl hydroxamic acid deriva-
ation at the proline residue. A subsequent enolate mediated tives like 6/7, which facilitated late stage unveiling of the
lactam NH group through SmI2 mediated N–O bond clea-
vage.12 This tactic was less suitable for the modified radical
cascade approach and we instead employed Boc protection,
which was applied to the readily available DKP 13, leading in
turn to sulfenylated derivative 14b. Radical cyclisations of 14a
and 14b gave broadly similar results, but only the doubly Boc
protected system allowed ultimate deprotection, Scheme 5.
When run on 0.5 g scale this reaction provided four iso-
Scheme 3 Enolate oxidation as a means of DKP cyclisation.
meric indolines 15a–d. The major compound 15a, along with a
second compound 15c, comprising about 75% of the total
product, were shown to have the same relative stereochemistry
at C-6 as seen in the stephacidins. Our stereochemical assign-
ments followed from a combination of NMR nOe analysis,
X-ray structure determinations, and correlation with a compound
described previously by Baran and co-workers.
The two major products 15a and 15b, which could not be
separated by column chromatography, were deprotected by
treatment with formic acid (92% yield) to give the corres-
ponding indolines 16a and 16b. In all of these compounds the
cis-fused nature of the indoline was evident from nOe studies,
as was the syn nature of the indoline junction protons to H-6
in the case of 16a.
When samples of pure indolines 16a and 16b were dis-
Scheme 4 Synthesis of sulfenylated DKPs.
solved in MeOH and allowed to slowly evaporate, crystals of
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Scheme 5 Radical cascade cyclisation to give indoline products.
each compound suitable for X-ray structure determination
were obtained, Fig. 3.21
In the same way, we deprotected indoline 15c by treatment
with formic acid to give 16c (87% yield). The Baran group had
The results from these structure determinations were fully previously mentioned an indoline with the C-6 configuration
in accord with our expectations from the NMR studies.
corresponding to stephacidin but of unspecified relative indo-
line stereochemistry. Comparison spectra forwarded to us
revealed that their indoline matched our compound 16c.22
With the structures of three of the cyclisation products
15/16 secured, the structure of 15d/16d could also be assigned
as shown, although the assignment of 16d is tentative since it
was not fully characterised due to its apparent poor stability.
Thus our radical cyclisation route provides a different
major indoline product compared to the indole Gribble
reduction. This result is not easily rationalized and was not a
concern at this stage, particularly since this stereochemical
feature had not been highlighted (or even assigned) in the pre-
vious sequences of Baran and Williams.
The synthesis of the more elaborate sulfenylated DKP inter-
mediate, corresponding to 14b, required for the synthesis of
the stephacidin natural products, was achieved starting from
N-Boc tryptophan acid 17. This was in turn prepared from
6-benzyloxyindole using the same nine-step sequence as that
reported by Williams (67% overall yield).7b Coupling of acid 17
with prenyl proline 18 was carried out using HATU and DIPEA
in MeCN to afford proline amide 19 (Scheme 6).
Initial studies to remove the Boc group from amide 19
under mild acidic conditions using formic acid, followed by
attempts at cyclisation by heating the crude materials in
2-butanol/toluene proved unsatisfactory; the desired DKP pro-
ducts 20 (isolated as 2 separable diastereoisomers) were
obtained in a low yield (<35% combined) and the experiment
was also very difficult to reproduce.
It appears that the presence of an acid-sensitive 2,2-
dimethyl pyran ring in the molecule is problematic to this
approach and we note that Williams described a one-pot
microwave heating of a substrate closely related to 19 (featur-
ing an allyl group rather than a prenyl group as the substitu-
ent) to achieve the same overall transformation.7b In our
hands, subjecting 19 to the same protocol of microwave
heating (MeCN, 150 °C, 30 min) did not lead to conversion.
Fig. 3 Structure of indolines 16a and 16b with ellipsoids drawn at the 50%
probability level. For 16b the methanol solvent molecule and the minor com-
ponent of the disordered group C(2)/C(2’) have been omitted for clarity.
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Scheme 6 Synthesis of Boc-protected tryptophan DKPs 21a and 21b.
We were delighted however to observe that changing the previously, we observed the formation of indoline products in
solvent to H2O for the microwave step gave a much improved a distribution that mirrored the result from the model system.
yield for the desired DKP products.23 Thus, heating the crude On the smaller scale employed here (ca. 0.1 g), only three iso-
product of the HATU coupling step in the microwave (H2O, meric indolines could be isolated, the minor compound
165 °C, 10 min) afforded the anti-DKP 20a and the syn-DKP corresponding to 15d was not observed.
20b in 21% and 28% yield, respectively. Both diastereoisomers
were each then subjected to a double Boc protection to afford together with a second compound 23b were obtained as an
the intermediates 21a and 21b. inseparable mixture in 77% yield. Comparison of the NMR
After column chromatography, the major compound 23a
Intermediates 21a and 21b were subsequently combined, spectra of the mixture 23a + 23b with those of 15a + 15b
since they were expected to generate the same enolate on revealed that these mixtures were clearly analogous. Thus, the
deprotonation. Treatment of a mixture of 21a + 21b (1 : 1.6 relative stereochemistry at C-6 in the major product is correct
ratio) with LDA at low temperature followed by electrophilic for synthesis of the stephacidins. The third isomeric indoline
quenching of the resulting enolate with phenyl disulfide 23c was also obtained in 13% yield.
indeed gave sulfenylated DKP 22 in acceptable yield (Scheme 7).
From this point only dehydrogenation and deprotection
With this key intermediate in hand, attention was focused steps were required to furnish stephacidin A. Dehydrogenation
on the crucial cascade radical cyclisation. Pleasingly, treatment of the mixture of 23a + 23b was accomplished in high yield by
of 22 under the reductive Bu3SnH conditions employed treatment with DDQ in ethyl acetate (Scheme 8).24
Scheme 7 Sulfenylation and radical cascade cyclisation to afford indoline products related to stephacidin.
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Scheme 8 Synthesis of (−)-1 (stephacidin A) and (+)-4 (notoamide B).
After chromatography on silica this afforded the separated first by dehydrogenation of the indoline to generate (−)-1,
indoles 24a and 24b in 72% and 22% yield, respectively. The which then rapidly converts to (+)-4 in the presence of excess
Boc groups of 24a were then removed using the same micro- oxidant.
wave protocol as previously described (H2O, 165 °C, 10 min) to
This unexpected result raises a question in respect of the
give (−)-1 (stephacidin A), which exhibited spectroscopic data ability of indoline stereoisomers derived from 23a and 23c to
in accord with those reported by Qian-Cutrone et al.,1 and the be usefully transformed into avrainvillamide and so on to ste-
groups of Baran6a,c and Williams.7 In agreement with the phacidin B. It appears possible that these two diastereomeric
observation by Williams,7b we found (−)-1 to be mostly insolu- series may behave differently, at least in reaction with SeO2–
ble in common organic solvents although it was sparingly H2O2. Unfortunately, at present we have made only small
soluble in either CDCl3–d4-MeOH (1 : 1) or d6-DMSO and this quantities of these compounds, and the particularly meagre
allowed for its NMR analysis.
amount of 23c available by our route has not allowed us to
As highlighted above, a key attraction of a direct entry to probe this possibility in more detail.
the stephacidin framework at the indoline oxidation state is
the pivotal role of these intermediates in previous syntheses of
avrainvillamide and stephacidin B, described by Williams and
Conclusions
Baran.6,7 Naturally we were interested to see if our indoline
intermediates could be transformed in the same fashion.
A radical cascade sequence allowed a synthesis of model indo-
In pursuit of this objective, a sample of 23a + 23b of slightly line compounds 15/16 related to the stephacidins. The struc-
lower diastereoselectivity than before (2.5 : 1) was subjected to tures of three diastereomeric indoline intermediates were fully
the microwave conditions for the removal of the Boc groups, to assigned, allowing us to identify the indoline series employed
give 25 (d.r. = 2.5 : 1). The major component 25 in this mixture in studies by Baran, which was generated by indole reduction.
of indolines is distinct from the intermediate generated by
Extension of this work then allowed us to complete a syn-
Gribble reduction by Williams and Baran to which we ascribe thesis of stephacidin A (1) starting from commercially available
the relative stereochemistry shown for 23c. However, we 6-benzyloxyindole in 16 steps and 6.0% overall yield. Key fea-
expected this feature not be of significance, and we anticipated tures of our strategy include (i) an enolate mediated sulfenyla-
that oxidation of our indoline would give access to avrainvilla- tion to prepare radical precursor 22 and (ii) the cascade radical
mide in modest yield (20–30%) based on precedent. In the cyclisation converting 22 to indolines 23a–c, which possess the
event, reaction of 25 with catalytic SeO2 and 30% H2O2 core structure of the stephacidins. With these indolines in
afforded a single product in 55% yield. Remarkably, and hand, just two operationally simple, routine steps (DDQ oxi-
unexpectedly, this product was neither avrainvillamide or dation and a microwave-promoted Boc deprotection) were
stephacidin B but was instead determined to be (+)-4 (noto- required to complete the synthesis of (−)-1.
amide B).25
A particularly attractive feature of our synthetic sequence is
Notoamide B is known to be a product of oxidation of ste- the rapid access to indoline intermediates closely related to
phacidin A, occurring via epoxidation of the 2,3-disubstituted the stephacidins. Unfortunately the indoline diastereomer vali-
indole followed by a pinacol-type rearrangement that leads dated as a precursor to both avrainvillamide and stephacidin B
to ring contraction.7a,b,26 We therefore assume that the is a minor component of our synthetic indoline mixture.
transformation of 25 to (+)-4 under these conditions proceeds Attempted oxidation of a diastereomeric indoline 25 instead
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provided unexpected access to notoamide B (+)-4. With the tert-Butyl 3-({(6′R,7′R,8a′R)-10-(4′′-methoxybenzyl)-5′,9′-dioxo-
limited material available it has not yet been possible to 7′-(prop-1′′′-en-2′′′-yl)hexahydro-1H-6′,8a′-(epiminomethano)-
clearly identify the product manifolds available from each dia- indolizin-6′-yl}methyl)-1H-indole-1-carboxylate (11)
stereomeric indoline series.
This new synthetic entry to the stephacidin and notoamide
natural products should be of significant utility, bearing in
mind the continued interest in synthetic, biosynthetic and bio-
chemical properties of these systems.27–31
A
condenser and an addition funnel containing CuCl2
(245 mg, 1.82 mmol) were connected to a three-neck round-
bottomed flask under argon atmosphere. A solution of DKP 10
(130 mg, 0.23 mmol) in dry THF (7 mL) was added to the flask
and the solution was cooled to −78 °C. Freshly prepared LDA
(0.40 mL of a 0.8 M solution in THF, 0.32 mmol) was added
Experimental section
General
Reactions were carried out under dry N2 using dry glassware. dropwise and the reaction mixture was stirred at −78 °C for
Tetrahydrofuran (THF) was distilled from sodium/benzophe- 10 min. The CuCl2 was added portion-wise over 10 min and
none. Acetonitrile, dichloromethane, methanol, and toluene the mixture immediately turned to dark blue-green. The
were dried using a Pure Solv-MD Solvent Purification System. cooling bath was removed and the mixture was stirred for
All other reagents and solvents were used as received from 15 min at room temperature and then gradually heated to
commercial suppliers unless otherwise indicated.
reflux. After 1 h the oil bath was removed and the crude
Liquid volumes less than 1 mL were measured and dis- mixture was allowed to cool to room temperature. EtOAc
pensed with Hamilton gastight syringes. Reaction tempera- (15 mL) was added and the mixture was washed with H2O
tures refer to the temperature measured in an external bath. (10 mL), saturated NH4Cl (2 × 10 mL), brine (10 mL) and dried
Progress of reactions was monitored by thin layer chromato- (MgSO4). The solvent was removed under reduced pressure
graphy (TLC) using Merck Silica Gel 60 F254 aluminium or and purification of the crude material by column chromato-
plastic backed plates that were visualized with UV light, graphy (petrol–EtOAc, 1 : 1) afforded bridged DKP 11 as a pale
p-anisaldehyde or potassium permanganate. Flash column yellow foam (103 mg, 79%); Rf = 0.25 (1 : 1 EtOAc–petrol);
chromatography was carried out using Davisil 60 Å Silica νmax(CHCl3)/cm−1 3007 m, 1728 m, 1690vs, 1612w, 1512 m,
Gel in the solvent systems indicated. Melting points were 1453 m, 1372 s, 1309 m, 1249 s, 1156 s, 1081 m, 810w, 754vs,
recorded using a Gallenkamp melting point apparatus and are 667 m; δH (400 MHz, CDCl3) 1.61 (3H, s), 1.67 (9H, s), 1.83
uncorrected.
(1H, dd, J 13.4, 5.4 Hz), 1.88–1.96 (1H, m), 2.04–2.11 (2H, m),
NMR data were recorded either on a Bruker AV300, 2.26 (1H, dd, J 13.4, 10.4 Hz), 2.88–2.95 (1H, m), 2.98 (1H, dd,
AVIII300, AV400, AVIII400 or DRX500 spectrometers in the J 10.4, 5.4 Hz), 3.19 (1H, d, J 17.6 Hz), 3.38 (1H, dd, J 17.6, 1.5
deuterated solvents indicated and the spectra were calibrated Hz), 3.62 (2H, app t, J 6.9 Hz), 3.75 (3H, s), 4.36 (1H, d, J 15.7
on residual solvent peaks. Chemical shifts (δ) are quoted in Hz), 4.61 (1H, br s), 4.63 (1H, d, J 15.7 Hz), 4.76 (1H, br s), 6.67
ppm and J values are quoted in Hz. In reporting spectral data, (2H, d, J 8.7 Hz), 6.75 (2H, d, J 8.7 Hz), 7.25–7.35 (2H, m), 7.45
the following abbreviations were used: s (singlet), d (doublet), (1H, br s), 7.52 (1H, d, J 7.2 Hz), 8.04 (1H, d, J 7.1 Hz); δC
t (triplet), q (quartet), dd (doublet of doublets), m (multiplet), (100 MHz, CDCl3) 18.9, 24.2, 24.8, 28.2, 29.9, 36.4, 44.4, 45.9,
br (broad). In the case of ambiguous assignments, 2-dimensional 52.1, 55.1, 66.1, 69.0, 83.7, 113.6, 114.7, 115.1, 116.3, 118.4,
homonuclear (1H–1H) and heteronuclear (1H–13C) NMR experi- 122.4, 124.4, 128.0, 130.0, 131.1, 134.7, 142.8, 149.7, 158.6,
ments were used. All NMR spectra were processed using 167.4, 173.5, one resonance (CH, Ar) not observed (resonance
MestReNova.
overlap); m/z (ES+) 592.4 ([M + Na]+, 100%); HRMS m/z (ES+)
Infrared spectra were recorded on a Perkin Elmer Spectrum Found (M + Na)+ 592.2776. C34H39N3O5Na requires 592.2787.
100 FTIR spectrometer as neat films or with CHCl3, wave-
lengths (ν) are quoted in cm−1. Optical rotations were recorded
tert-Butyl 3-({(3′S,8a′S)-2′-(4′′-methoxybenzyl)-octahydro-1′,4′-di-
as dilute solutions in the indicated solvent in a 25 mm glass
cell using a JASCO DIP370 digital polarimeter at 294 nm. The
microwave reactions were carried out in a CEM Discover-S
instrument with a fixed hold time. Mass spectra were acquired
on a Waters Micromass LCT TOF spectrometer using electro-
spray ionisation (ESI). Electron impact (EI) spectra were
recorded on a Waters Micromass Zabspec/Magnetic sector
mass spectrometer.
oxopyrrolo[1,2a]pyrazin-3′-yl}methyl)-1H-indole-1-carboxylate (12)
(i) N-(4-Methoxybenzyl)-L-tryptophan
Experimental procedures and compound data for com-
pounds 14a, 14b, 15a–c, and 16a–c can be found in our p-Anisaldehyde (7.2 mL, 60 mmol) was added to a suspension
communication.13
of L-tryptophan (4.0 g, 20 mmol) in MeOH (150 mL). After
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stirring the mixture for 1 h, sodium cyanoborohydride (3.8 g,
A
solution of N-(tert-butoxycarbonyl)-N-(4-methoxybenzyl)-
60 mmol) was added and the mixture was stirred for a further L-tryptophan (13 g, 31 mmol) and L-proline methyl ester hydro-
16 h. The resulting solid was collected on a sinter, washed chloride (5.1 g, 31 mmol) in CH2Cl2 (1.25 L) was cooled to
with MeOH (2 × 25 mL) and dried in vacuo, to yield N- 0 °C. HOBt (4.16 g, 31 mmol), triethylamine (4.3 mL,
(4-methoxybenzyl)-L-tryptophan as a colourless solid (6.13 g, 31 mmol) and EDCI (5.9 g, 31 mmol) were added and the solu-
98%); decomp. 245–250 °C; νmax(CHCl3)/cm−1 3476, 2830, tion was stirred for 16 h. The mixture was washed with 1 M
1645, 1593, 1512, 1399, 1251, 1182, 1033; δH (270 MHz, NaOH (200 mL), water (100 mL), 1 M HCl (200 mL), water
d6-DMSO, 90 °C) 3.06–3.20 (2H, m), 3.40 (2H, br s), 3.74 (100 mL), brine (200 mL), dried (MgSO4) and the solvent
(3H, s), 3.88 (1H, br s), 6.85 (2H, d, J 6.6 Hz), 6.98 (1H, app. was evaporated under reduced pressure. The crude product
t, J 6.5 Hz), 7.08 (1H, app. t, J 7.0 Hz), 7.18 (3H, br s), 7.35 was purified by column chromatography (33% EtOAc in petrol)
(1H, d, J 7.4 Hz), 7.52 (1H, d, J 6.5 Hz), 10.92 (1H, s); HRMS to yield the title compound as a colourless foam (16.0 g,
m/z (EI) Found (M + H)+ 324.1484. C19H20N2O3 requires 97%); [α]2D0 −32.5 (c, 1.055, CHCl3); νmax(CHCl3)/cm−1 3480 m,
324.1474.
(ii)
phan
2954w, 1743 s, 1681 s, 1649 s, 1612 m, 1456 m, 1399 m,
N-(tert-Butoxycarbonyl)-N-(4-methoxybenzyl)-L-trypto- 1367 m, 1159w, 1037w; δH (270 MHz, d6-DMSO, 70 °C) 1.25
(9H, s), 1.60–1.84 (3H, m), 3.03–3.06 (2H, br s), 3.25–3.41
(3H, m), 3.59 (3H, s), 3.75 (3H, s), 3.91 (1H, br s), 4.18 (1H, d,
J 15.8 Hz), 4.60 (1H, d, J 15.8 Hz), 5.09 (1H, br s), 6.87 (2H, d,
J 8.5 Hz), 6.98–7.11 (3H, m), 7.17 (2H, d, J 8.5 Hz), 7.35 (1H, d,
J 7.8 Hz), 7.54 (1H, d, J 7.6 Hz), 10.67 (1H, s); δC (125 MHz,
d6-DMSO) 24.6, 27.8, 28.6, 28.8, 44.9, 45.9, 52.2, 55.5,
57.2, 58.8, 79.5, 110.1, 111.7, 113.7, 118.5, 121.2, 124.5, 128.0,
128.9, 129.7, 131.3, 136.6, 155.2, 158.8, 168.2, 172.5; HRMS
Ethyldiisopropylamine (6.8 mL, 40 mmol) was added to a sus-
pension of N-(4-methoxybenzyl)-L-tryptophan (3.4 g, 11 mmol)
in water–1,4-dioxane (1 : 1, 150 mL). After stirring the mixture
for 80 min, di-tert-butyl dicarbonate (7.8 g, 36 mmol) was
added and the solution was stirred for a further 16 h. The
mixture was partitioned between 1 M NaOH (150 mL) and
CHCl3 (150 mL) and the phases were separated. The aqueous
phase was acidified to pH 4, by the addition of a saturated
solution of citric acid and was then extracted with CHCl3 (2 ×
150 mL). The combined organic extracts were washed with
brine (100 mL), dried (MgSO4) and the solvent was evaporated
under reduced pressure. The crude product was purified by
column chromatography (20% acetone in CH2Cl2) to yield the
title compound as a colourless solid (2.46 g, 54%); m.
p. 70–71 °C; [α]D20 −56.8 (c, 1.101, CHCl3); νmax(CHCl3)/cm−1
3477 m, 3124 m, 2952 m, 2859 m, 1748 m, 1714 s, 1692 s,
1613 m, 1456 m, 1368 m, 1304w, 1120 s; δH (270 MHz, d6-
DMSO, 90 °C) 1.38 (9H, s), 3.17 (1H, dd, J 14.7, 8.8 Hz), 3.37
(1H, dd, J 14.7, 5.6 Hz), 3.73 (3H, s), 3.93 (1H, d, J 15.5 Hz),
4.34 (1H, d, J 15.5 Hz), 4.42 (1H, m), 6.74 (2H, d, J 8.6 Hz),
6.97 (1H, s), 6.98 (1H, s), 7.04 (2H, d, J 8.6 Hz), 7.10 (1H, ddd,
J 7.8, 7.7, 1.0 Hz), 7.37 (1H, d, J 8.0 Hz), 7.43 (1H, d, J 7.7 Hz),
10.64 (1H, s); δC (67 MHz, d6-DMSO, 90 °C) 28.6, 50.7,
54.0, 55.6, 61.0, 79.9, 111.5, 111.9, 114.0, 114.2, 118.8, 121.4,
124.0, 128.0, 129.4, 130.1, 136.9, 155.5, 158.8, 173.1; HRMS
m/z (ES+) Found (M + Na)+ 447.1910. C24H28N2O5Na requires
447.1890.
m/z (ES+) Found (M + H)+ 536.2745. C30H38N3O6 requires
536.2761.
(iv) tert-Butyl 3-({(3′S,8a′S)-2′-(4′′-methoxybenzyl)-octahydro-
1′,4′-dioxopyrrolo[1,2a] pyrazin-3′-yl}methyl)-1H-indole-1-car-
boxylate (12)
A solution of N-(tert-butyloxycarbonyl)-N-(4-methoxybenzyl)-
L-tryptophanyl-L-proline methyl ester (3.0 g, 5.5 mmol) in
formic acid (150 mL) was stirred at room temperature for 16 h
and the formic acid was then evaporated under reduced
pressure. 2-Butanol (150 mL) and toluene (50 mL) were added
to the residual oil and the mixture was heated at reflux for
17 h. The solvent was evaporated under reduced pressure and
the crude material was purified by column chromatography
(20% acetone in CH2Cl2) to afford the intermediate proline-
tryptophan diketopiperazine as a colourless solid (1.67 g,
75%). A sample of this diketopiperazine (1.0 g, 2.5 mmol) was
dissolved in CH2Cl2 (100 mL), cooled to 0 °C, and triethyl-
amine (0.38 mL, 2.7 mmol) was added. After stirring the solu-
tion for 15 min, di-tert-butyl dicarbonate (1.6 g, 7.4 mmol) was
added and the solution was stirred for a further 16 h. The reac-
tion mixture was diluted with CH2Cl2 (100 mL) and poured
into water (200 mL). The phases were separated and the
aqueous phase was extracted with CH2Cl2 (2 × 100 mL). The
(iii)
N-(tert-Butoxycarbonyl)-N-(4-methoxybenzyl)-L-trypto-
phanyl-L-proline methyl ester
combined organic extracts were washed with
1 M HCl
(200 mL), water (200 mL), brine (200 mL), dried (MgSO4), and
the solvent was evaporated under reduced pressure. The crude
product was purified by column chromatography (5% acetone
4964 | Org. Biomol. Chem., 2013, 11, 4957–4970
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in CH2Cl2) to yield the Boc-protected diketopiperazine 12 as a 3.81 (1H, dt, J 12.3, 8.3 Hz), 4.34 (1H, dd, J 11.2, 3.5 Hz) 5.08
colourless solid (1.24 g, 99%); m.p. 81–83 °C; [α]2D0 −81.5 (1H, app t, J 7.8 Hz), 5.62 (1H, d, J 9.7 Hz), 5.78 (1H s), 6.62
(c, 0.985, CHCl3); νmax(CHCl3)/cm−1 2981w, 2936w, 2838w, (1H, d, J 9.7 Hz), 6.65 (1H, d, J 8.5 Hz), 6.90 (1H, d, J 1.9 Hz),
1730 s, 1658 s, 1455 m, 1371 s, 1154 m, 1083 m, 1036w; 7.27 (1H, d, J 8.5 Hz), 8.75 (1H, br s); δC (100 MHz, CDCl3)
δH (500 MHz, CDCl3) −0.54 (1H, app. p, J 10.8 Hz), 1.33 (1H, 17.7, 20.4, 26.0, 27.35, 27.44, 28.1, 34.5, 36.0, 45.0, 54.3, 68.5,
m), 1.55 (1H, m), 1.67 (9H, s), 2.01 (1H, m), 3.11 (1H, ddd, 75.8, 105.4, 110.3, 110.7, 116.9, 117.0, 118.5, 121.3, 122.2,
J 11.9, 10.3, 4.4 Hz), 3.30 (1H, dd, J 15.5, 5.5 Hz), 3.50–3.58 129.6, 133.4, 137.8, 149.2, 165.4, 171.5; HRMS m/z (ES+) Found
(2H, m), 3.81 (3H, s), 3.87 (1H, dd, J 11.2, 6.0 Hz), 3.95 (1H, d, (M + Na)+ 456.2257. C26H31N3O3 requires 456.2263. Diketopi-
J 14.7 Hz), 4.25 (1H, br s), 5.60 (1H, d, J 14.7 Hz), 6.89 (2H, d, J perazine 20b: Rf = 0.12 (100% EtOAc); νmax(CHCl3)/cm−1
8.5 Hz), 7.22 (1H, s), 7.23 (2H, d, J 8.5 Hz), 7.30 (1H, dd, J 8.3, 4211vw, 3286br m, 3016 m, 2972 m, 2932 m, 1677 s, 1626 s,
8.3 Hz), 7.31 (1H, dd, J 8.3, 8.3 Hz), 7.51 (1H, d, J 8.3 Hz), 8.10 1492w, 1445 m, 1378w, 1304w, 1215 s, 1193w, 1162w, 1121 m,
(1H, d, J 8.3 Hz); δC (125 MHz, CDCl3) 21.1, 25.8, 28.2, 29.0, 1046w, 898vw, 756 s, 668 m; δH (300 MHz, CDCl3) 1.42 (3H, s),
44.7, 45.5, 55.4, 58.8, 59.2, 83.9, 113.9, 114.4, 115.1, 119.5, 1.43 (3H, s), 1.65 (3H, s), 1.76 (3H, s), 1.91–2.06 (3H, m),
122.6, 124.76, 124.80, 127.5, 129.7, 130.3, 135.1, 149.4, 159.5, 2.13–2.22 (1H, m), 2.35 (1H, dd, J 14.2, 7.3 Hz), 2.56 (1H, dd,
164.2, 166.1; HRMS m/z (ES+) Found (M + H)+ 504.2465. J 14.2, 8.1 Hz), 2.91 (1H, dd, J 14.0, 11.5 Hz), 3.38–3.50 (1H, m),
C29H34N3O5 requires 504.2498.
3.56 (1H, dd, J 14.0, 2.2 Hz), 3.87–4.00 (1H, m), 4.03–4.13 (1H,
m), 5.20 (1H, t, J 7.8 Hz), 5.61 (1H, d, J 9.7 Hz), 6.09 (1H, br s),
6.62 (1H, d, J 9.7 Hz), 6.65 (1H, d, J 8.6 Hz), 6.87 (1H, d, J 1.9
Hz), 7.34 (1H, d, J 8.6 Hz), 8.89 (1H, br s); δC (100 MHz, CDCl3)
18.0, 19.6, 26.3, 27.3, 27.4, 31.8, 35.0, 36.2, 44.7, 57.7, 67.7,
75.7, 105.3, 110.7, 110.8, 117.0, 118.1, 118.7, 121.5, 122.0,
129.6, 133.2, 137.1, 149.1, 165.0, 169.9; m/z (ES+) 456.2 ([M +
Na]+, 100%); HRMS m/z (ES+) Found (M + Na)+ 456.2240.
C26H31N3O3Na requires 456.2263.
(3S,8aR)-8a-(3′,3′-Dimethylallyl)-3-{(7′′,7′′-dimethyl-1′′,7′′-dihydro-
pyrano[2,3-g]indol-3′′-yl)methyl}-hexahydropyrrolo[1,2-a]-
pyrazine-1,4-dione (20a) and (3R,8aR)-8a-(3′,3′-dimethylallyl)-
3-{(7′′,7′′-dimethyl-1′′,7′′-dihydropyrano-[2,3-g]indol-3′′-yl)methyl}-
hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (20b)
[It is not uncommon with repeated runs of this experiment
to observe the HATU derived by-product N,N,N′,N′-tetramethyl-
urea as an impurity in trace quantities, which occurs as a
1
singlet at δ = 2.7 ppm in the H NMR spectrum. Such samples
were carried forward to the next step (Boc protection) with no
Diisopropylethylamine (110 μL, 0.63 mmol) was added to a deleterious effect on the outcome of reaction.]
solution of proline ester hydrochloride salt 18 (69 mg,
0.30 mmol) and Boc-protected amino acid 17 (98 mg,
(3S,8aR)-1-tert-Butyloxycarbonyl-8a-(3′,3′-dimethylallyl)-3-{(1′′-
0.25 mmol) in MeCN (3 mL) at room temperature and the reac-
tion mixture was stirred for 5 min. HATU (112 mg, 0.30 mmol)
was added in one portion and the reaction mixture was stirred
at room temperature for 4 h. The reaction mixture was sub-
sequently transferred to a microwave reactor vessel and the
volatile organics were removed under reduced pressure. H2O
(12 mL) was added and the vessel was placed in a microwave
synthesizer (Discover-S, CEM). The heterogenous mixture was
heated with stirring in the microwave to 165 °C for
tert-butyloxycarbonyl-7′′,7′′-dimethyl-1′′,7′′-dihydropyrano[2,3-g]-
indol-3′′-yl)methyl}-hexahydropyrrolo[1,2-a]pyrazine-1,4-
dione (21a)
10 minutes. After cooling to room temperature, the resulting Di-tert-butyl dicarbonate (58 mg, 0.27 mmol) and 4-DMAP
cloudy white suspension was extracted with EtOAc (3 × 15 mL) (1.5 mg, 12 μmol) were added to a solution of diketopiperazine
and the combined organic layers were washed with brine (3 × 20a (48 mg, 0.11 mmol) in CH2Cl2 (1.5 mL) and the reaction
10 mL) and dried (MgSO4). The solvent was evaporated under mixture was stirred at room temperature for 2 h. The volatile
reduced pressure and purification of the crude material by organics were removed under reduced pressure and the crude
column chromatography (100% EtOAc → 2% MeOH in EtOAc) material was purified by column chromatography (petrol–
afforded the anti-diastereoisomer 20a as a colourless oil EtOAc, 1 : 1) to afford the double Boc-protected product 21a as
(27 mg, 21%) and the syn-diastereoisomer 20b as a white solid a colourless foam (51 mg, 73%); Rf = 0.72 (1 : 1 EtOAc–petrol);
(31 mg, 28%). Diketopiperazine 20a: Rf = 0.24 (100% EtOAc); νmax(film)/cm−1 2978 m, 2933w, 1774w, 1721 s, 1656 s, 1578w,
νmax(CHCl3)/cm−1 3296br m, 3008 m, 2976 m, 2930 m, 1644br 1455 m, 1393 m, 1368 s, 1317 m, 1275 s, 1253 s, 1149vs, 1115
s, 1492w, 1440 s, 1378w, 1320w, 1254w, 1215 s, 1190 m, s, 982 s, 940w, 846 m, 754 m, 665w; δH (300 MHz, CDCl3)
1163 m, 1120 m, 1047w, 899vw, 856vw, 804w, 753 s, 667 m; δH 0.56–0.71 (1H, m), 1.08–1.27 (1H, m), 1.43 (3H, s), 1.44 (3H, s),
(300 MHz, CDCl3) 1.44 (3H, s), 1.45 (3H, s), 1.55 (3H, s), 1.66 1.50 (3H, s), 1.54–1.66 {23H, m, including [1.55 (9H, s), 1.60
(3H, s), 1.89–2.16 (4H, m), 2.34–2.52 (2H, m), 2.77 (1H, dd, J (9H, s), 1.64 (3H, s)]}, 2.16 (1H, dd, J 14.1, 7.3 Hz), 2.28 (1H,
14.8, 11.2 Hz), 3.48–3.60 (1H, m), 3.70 (1H, dd, J 14.8, 3.5 Hz), dd, J 14.1, 8.5 Hz), 3.09–3.23 (1H, m), 3.35 (1H, dd, J 14.5, 4.9
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Hz), 3.42–3.62 (2H, m), 4.75–4.83 (1H, m), 4.86–4.96 (1H, m), diketopiperazines 21a and 21b (1 : 1.6 ratio, 160 mg,
5.58 (1H, d, J 9.9 Hz), 6.76 (1H, dd, J 8.5, 0.4 Hz), 6.95 (1H, d, 0.25 mmol) in THF (2 mL). The reaction mixture was stirred at
J 9.9 Hz), 7.07 (1H, s), 7.23 (1H, d, J 8.5 Hz); δC (100 MHz, this temperature and after 30 min, phenyl disulfide (275 mg,
CDCl3) 17.9, 19.1, 26.0, 26.7, 27.2, 27.96, 27.98, 29.0, 33.5, 1.26 mmol) was added. After 3 h, the reaction mixture was
37.5, 44.1, 59.9, 69.1, 74.7, 83.4, 83.6, 109.5, 113.4, 113.9, quenched at −78 °C by the addition of a saturated solution of
116.4, 120.0, 121.5, 125.5, 126.9, 127.3, 131.8, 137.3, 149.6, NH4Cl (15 mL). Upon warming to room temperature, the
150.8, 151.7, 163.8, 169.1; m/z (ES+) 656.8 ([M + Na]+, 100%); product was extracted with EtOAc (3 × 20 mL) and the com-
HRMS m/z (ES+) Found (M + Na)+ 656.3311. C36H47N3O7Na bined organic layers were washed with H2O (3 × 20 mL), brine
requires 656.3312.
(3 × 20 mL) and dried (MgSO4). The solvent was removed
under reduced pressure and purification of the crude material
by column chromatography (20% EtOAc in petrol) afforded
sulfenylated diketopiperazine 22 as a colourless foam (106 mg,
57%); Rf = 0.59 (1 : 1 EtOAc–petrol); νmax(CHCl3)/cm−1 3466vw,
3059w, 2977 m, 2932 m, 1742 s, 1660 s, 1577w, 1476 m,
1439 m, 1394 m, 1369 m, 1350 m, 1309w, 1274 m, 1255 m,
1218 m, 1152 s, 1120 m, 1068w, 1024vw, 983 m, 889vw, 847 m,
752 m, 693 m; δH (300 MHz, CDCl3) 0.78–0.91 (1H, m),
0.97–1.12 {4H, m, including [1.08 (3H, s)]}, 1.29–1.48 {12H, m,
including [1.43 (6H, s), 1.44 (3H, s)]}, 1.54–1.71 {19H, m,
including [1.57 (9H, s), 1.63 (9H, s)]}, 2.98–3.12 (1H, m),
3.16–3.30 (1H, m), 3.84 (1H, d, J 14.4 Hz), 3.99 (1H, d,
J 14.4 Hz), 4.44–4.56 (1H, m), 5.55 (1H, d, J 9.9 Hz), 6.77
(1H, dd, J 8.6, 0.3 Hz), 6.86 (1H, d, J 9.9 Hz), 7.26–7.38 (3H, m),
7.45 (1H, s), 7.48 (1H, d, J 8.6 Hz), 7.59–7.67 (2H, m);
δC (100 MHz, CDCl3) 17.2, 18.8, 25.8, 26.8, 27.2, 27.9,
28.0, 31.2, 32.1, 36.8, 45.0, 67.4, 74.7, 80.0, 83.7, 84.6,
109.6, 113.6, 114.5, 116.9, 120.9, 121.7, 125.5, 126.4,
127.5, 128.6, 130.0, 132.0, 134.8, 137.9, 149.6, 151.5,
151.6, 162.0, 169.1, one resonance (quat. C) not observed
(resonance overlap); m/z (ES+) 764.4 ([M + Na]+, 100%); HRMS
m/z (ES+) Found (M + Na)+ 764.3341. C42H51N3O7SNa requires
764.3345.
(3R,8aR)-1-tert-Butyloxycarbonyl-8a-(3′,3′-dimethylallyl)-3-
{(1′′-tert-butyloxycarbonyl-7′′,7′′-dimethyl-1′′,7′′-dihydropyrano-
[2,3-g]indol-3′′-yl)methyl}-hexahydropyrrolo[1,2-a]pyrazine-1,4-
dione (21b)
Di-tert-butyl dicarbonate (85 mg, 0.39 mmol) and 4-DMAP
(2 mg, 16 μmol) were added to a solution of diketopiperazine
20b (70 mg, 0.16 mmol) in CH2Cl2 (2 mL) and the reaction
mixture was stirred at room temperature for 2 h. The volatile
organics were then removed under reduced pressure and the
crude material was purified by column chromatography (40%
EtOAc in petrol) to afford the double Boc-protected product
21b as a colourless foam (84 mg, 83%); Rf = 0.51 (1 : 1 EtOAc–
petrol); νmax(film)/cm−1 2978 m, 2933w, 177w, 1728 s, 1656 s,
1456 m, 1369 s, 1329 m, 1274 s, 1256 s, 1218 m, 1147vs, 1119
s, 981 m, 1847 m, 751vs, 666w; δH (300 MHz, CDCl3) 1.23 (9H,
s), 1.43 (3H, s), 1.45 (3H, s), 1.56 (3H, s), 1.59 (9H, s), 1.67 (3H,
s), 1.81–2.21 (5H, m), 2.29 (1H, dd, J 14.6, 8.2 Hz), 3.21 (1H,
dd, J 14.7, 7.4 Hz), 3.27–3.44 (2H, m), 3.89 (1H, dt, J 12.4, 8.4
Hz), 4.94–5.10 (2H, m), 5.58 (1H, d, J 9.9 Hz), 6.82 (1H, d, J 8.5
Hz), 6.95 (1H, d, J 9.9 Hz), 7.24 (1H, s), 7.35 (1H, d, J 8.5 Hz);
δC (100 MHz, CDCl3) 17.9, 20.0, 26.0, 26.8, 27.1, 27.4,
28.0, 30.3, 35.0, 36.3, 45.2, 60.4, 68.8, 74.7, 83.6, 84.0,
109.9, 113.8, 115.3, 117.4, 119.4, 121.6, 125.5, 125.6, 126.7,
132.1, 136.4, 149.6, 150.5, 151.8, 164.6, 169.3; m/z (ES+) 656.5
([M + Na]+, 100%), 556.4 (25, [M − Boc + Na]+); HRMS m/z
(ES+) Found (M + Na)+ 656.3332. C36H47N3O7Na requires
656.3312.
Radical cyclisation affording a mixture of indolines 23a, 23b
and 23c
The toluene for the radical cyclisation was freshly degassed by
bubbling argon through the solvent for 45 min. The reaction
was performed in a two-neck round-bottomed flask fitted with
a reflux condenser, while a syringe pump was employed for the
reagent additions. Under an atmosphere of argon, 1,1′-azobis
(cyclohexanecarbonitrile) (1.4 mL of a 0.05 M solution in
toluene, 0.5 equiv.) and tributyltin hydride (1.4 mL of a 0.16 M
solution in toluene, 1.6 equiv.) were simultaneously added
dropwise over 2 h to a refluxing solution of sulfenylated
DKP 22 (106 mg, 0.14 mmol) in toluene (2 mL) at 150 °C.
(3S,8aR)-1-tert-Butyloxycarbonyl-8a-(3′,3′-dimethylallyl)-3-
{(1′′-tert-butyloxycarbonyl-7′′,7′′-dimethyl-1′′,7′′-dihydropyrano-
[2,3-g]indol-3′′-yl)methyl}-3-(phenylthio)-hexahydropyrrolo[1,2-a]-
pyrazine-1,4-dione (22)
A freshly prepared solution of LDA (1.4 mL of a 0.71 M solu- Upon complete addition of the initiator and tin hydride, the
tion in THF–hexane, 1.3 : 1, 1.0 mmol) at −78 °C was reaction mixture was stirred at reflux for 1 h followed by
transferred via syringe to a cooled (−78 °C) mixture of cooling to room temperature. The reaction mixture was
4966 | Org. Biomol. Chem., 2013, 11, 4957–4970
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concentrated under reduced pressure and purification of the Boc-protected stephacidin A (24a) and Boc-protected C6-epi-
residue by column chromatography (33% EtOAc in petrol → stephacidin A (24b)
100% EtOAc) afforded indoline products 23a and 23b* as an
inseparable mixture of diastereoisomers in a 3.3 : 1 ratio
(70 mg, 77%) along with indoline 23c as a colourless oil
(12 mg, 13%).
Indolines 23a and 23b*: Rf = 0.42 (1 : 1 EtOAc–petrol);
νmax(CHCl3)/cm−1 2976w, 1693 s, 1458w, 1392w, 1368 m,
1339 m, 1251 s, 1145vs, 1117 s, 847w, 749vs, 666w; δH
(300 MHz, CDCl3) 0.29 (3H, s, CH3), 0.94 (3H, s, CH3*), 1.01
(3H, s, CH3), 1.10 (3H, s, CH3*), 1.39 (3H, s, CH3*), 1.40 (3H, s,
CH3), 1.46 (3H, s, CH3), 1.495 (9H, s, (CH3)3), 1.503 (9H, s, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (15 mg, 66 μmol)
(CH3)3*), 1.51 (3H, s, CH3*), 1.54 (9H, s, (CH3)3*), 1.56 (9H, s, was added in one portion to a solution of indolines 23a and
(CH3)3), 1.64–1.81 (5H, m, H5a, H5a*, H3a, H3a*, H6*), 23b (3.3 : 1 ratio, 28 mg, 44 mmol) in EtOAc (2 mL) and the
1.86–1.98 (4H, m, H2, H2*), 2.07–2.20 (4H, m, H5b, H5b*, reaction mixture was stirred at room temperature for 20 min.
H21a, H21a*), 2.32 (1H, dd, J 10.2, 6.0 Hz, H6), 2.63–2.73 (1H, Complete consumption of the starting material was observed
m, H3b*), 2.71–2.81 (1H, m, H3b), 3.18–3.28 (2H, m, H1a, by TLC and the reaction mixture was diluted with EtOAc
H1a*), 3.39 (1H, dd, J 15.0, 1.9 Hz, H21b), 3.42–3.58 (3H, m, (10 mL) and quenched using 5% aq. NaHCO3 solution (8 mL).
H1b, H1b*, H21b*), 3.83–3.93 (2H, m, H20, H20*), 4.42 (1H, d, The layers were separated and the aqueous phase was extracted
J 7.9 Hz, H8), 4.51 (1H, d, J 8.7 Hz, H8*), 5.56 (1H, d, J 9.8 Hz, with EtOAc (3 × 5 mL). The combined organic phases were
H12), 5.59 (1H, d, J 9.7 Hz, H12*), 6.36 (1H, d, J 9.7 Hz, H13*), washed with H2O (3 × 5 mL), brine (3 × 5 mL) and dried
6.37 (1H, d, J 9.8 Hz, H13), 6.57 (1H, d, J 8.2 Hz, H17*), 6.63 (MgSO4). The solvent was removed under reduced pressure
(1H, d, J 8.2 Hz, H17), 7.22 (1H, dd, J 8.1, 1.2 Hz, H18), 7.29 and purification of the residue by column chromatography
(1H, dd, J 8.1, 1.1 Hz, H18*); δC (100 MHz, CDCl3) 15.6 (CH3), (2% EtOAc → 30% EtOAc in petrol) afforded Boc-protected ste-
22.2 (C21*), 23.8 (C21), 24.1 (C2), 24.3 (C2*), 24.6 (CH3*), phacidin A 24a as a colourless film (20 mg, 72%) and Boc-pro-
25.7 (CH3*), 26.4 (CH3), 27.7 (CH3), 27.8 (C(CH3)3, C(CH3)3*), tected C6-epi-stephacidin A 24b as a colourless oil (6 mg,
28.3 (C(CH3)3, C(CH3)3*, CH3*), 28.5 (CH3), 28.7 (CH3*), 22%). Boc-protected stephacidin A 24a: Rf = 0.69 (100%
29.7 (C3*), 29.9 (C3), 31.4 (C5, C5*), 35.7 (C7*), 37.5 (C20*), EtOAc); νmax(CHCl3)/cm−1 2978 m, 2932w, 1739vs, 1697 s,
37.8 (C20), 38.2 (C7), 41.4 (C6*), 44.2 (C1*), 44.3 (C1), 1394w, 1369 m, 1270 m, 1255 m, 1144vs, 1090w, 847w, 755 m;
48.2 (C6), 62.8 (quat. C*), 64.0 (quat. C), 65.6 (quat. C*), 66.1 δH (300 MHz, CDCl3) 1.25 (3H, s), 1.46 (3H, s), 1.47 (6H, s),
(quat. C), 69.1 (C8*), 71.1 (C8), 74.8 (quat. C, quat. C*), 1.54 (9H, s), 1.57 (9H, s), 1.84–1.95 (1H, m), 1.97–2.10 (3H, m),
81.3 (quat. C, quat. C*), 84.8 (quat. C*), 85.1 (quat. C), 111.7 2.28 (1H, dd, J 13.9, 10.3 Hz), 2.74 (1H, dd, J 10.3, 4.3 Hz),
(quat. C*), 112.0 (quat. C), 112.26 (C17*), 112.31 (C17), 2.78–2.89 {2H, m, including [2.84 (1H, d, J 16.0 Hz)]},
121.2 (C13), 121.7 (C13*), 123.7 (C18), 125.4 (C18*), 127.2 3.36–3.49 (1H, m), 3.53–3.65 (1H, m), 3.85 (1H, d, J 16.0 Hz),
(C12*), 127.5 (quat. C*), 127.7 (C12), 128.5 (quat. C), 5.60 (1H, d, J 9.7 Hz), 6.48 (1H, d, J 9.7 Hz), 6.77 (1H, d, J 8.4
139.1 (quat. C*), 139.2 (quat. C), 150.3 (quat. C*), 150.5 Hz), 7.21 (1H, d, J 8.4 Hz); δC (100 MHz, CDCl3) 19.4, 23.8,
(quat. C), 152.47 (quat. C), 152.52 (quat. C*), 154.3 (quat. C, 24.3, 26.7, 26.8, 26.9, 27.6, 27.8, 29.9, 30.9, 37.4, 44.3, 50.1,
quat. C*), 167.0 (quat. C), 168.2 (quat. C*), 170.8 (quat. C, 63.8, 66.1, 74.9, 84.7, 85.2, 109.1, 111.0, 112.4, 118.6, 120.8,
quat. C*); m/z (ES+) 656.4 ([M + Na]+, 100%); HRMS m/z 122.7, 127.2, 134.2, 139.4, 150.3, 150.9, 152.9, 166.5, 170.8; m/z
(ES+) Found (M + Na)+ 656.3305. C36H47N3O7Na requires (ES+) 654.3 ([M + Na]+, 100%); HRMS m/z (ES+) Found (M +
656.3312.
Indoline 23c: Rf = 0.26 (1 : 1 EtOAc–petrol); νmax(CHCl3)/ C6-epi-stephacidin A 24b: Rf
Na)+ 654.3147. C36H45N3O7Na requires 654.3155. Boc-protected
0.27 (1 : 1 EtOAc–petrol);
=
cm−1 2978w, 1725 m, 1688 s, 1457 m, 1393 m, 1368 m, 1251 s, νmax(CHCl3)/cm−1 2979w, 2930w, 1765 m, 1740 s, 1691 s,
1146 s, 1092 m, 847w, 748 s, 666 m; δH (300 MHz, CDCl3) 0.89 1479w, 1369 m, 1297 m, 1253 s, 1140vs, 1119 s, 1090 m, 846w,
(3H, s), 0.92 (3H, s), 1.39 (3H, s), 1.49 (9H, s), 1.52 (3H, s), 1.56 751vs, 666w; δH (300 MHz, CDCl3) 1.09 (9H, s), 1.45 (3H, s),
(9H, s), 1.67–1.74 (1H, m), 1.85–2.04 (4H, m), 2.16 (1H, t, J 9.3 1.46 (3H, s), 1.48 (3H, s), 1.49 (3H, s), 1.55 (9H, s), 1.80–1.92
Hz), 2.66–2.76 (1H, m), 3.17–3.22 (2H, m), 3.38–3.46 (1H, m), (1H, m), 1.97–2.26 (4H, m), 2.38 (1H, dd, J 10.4, 4.0 Hz),
3.61–3.70 (1H, m), 3.92–4.01 (1H, m), 4.43 (1H, d, J 8.9 Hz), 2.81–2.92 (1H, m), 3.49–3.67 (4H, m), 5.61 (1H, d, J 9.7 Hz),
5.60 (1H, d, J 9.8 Hz), 6.35 (1H, d, J 9.8 Hz), 6.54 (1H, d, 6.50 (1H, d, J 9.7 Hz), 6.76 (1H, d, J 8.3 Hz), 7.25 (1H, d, J 8.3
J 8.0 Hz), 6.81 (1H, dd, J 8.0, 1.1 Hz); δC (100 MHz, CDCl3) Hz); δC (100 MHz, CDCl3) 20.2, 22.8, 24.3, 26.5, 26.9, 27.1,
20.2, 23.1, 24.1, 25.0, 26.1, 28.0, 28.3, 28.7, 30.3, 32.6, 27.6, 28.2, 29.8, 32.4, 37.1, 44.4, 48.8, 64.8, 66.7, 74.9, 84.4,
36.5, 37.6, 44.5, 46.4, 64.6, 66.1, 69.2, 75.0, 77.2, 81.5, 84.6, 84.8, 108.8, 110.8, 112.4, 118.8, 120.6, 122.6, 127.4, 134.0,
112.2, 112.4, 121.5, 122.5, 127.7, 129.3, 139.3, 150.3, 152.8, 139.8, 149.2, 150.7, 153.3, 167.9, 170.0; m/z (ES+) 654.2
167.9, 170.7; m/z (ES+) 656.0 ([M + Na]+, 100%); HRMS m/z ([M + Na]+, 100%), 554.2 (18, [M − Boc + Na]+); HRMS m/z
(ES+) Found (M + Na)+ 656.3310. C36H47N3O7Na requires (ES+) Found (M + Na)+ 654.3120. C36H45N3O7Na requires
656.3312.
654.3155.
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(−)-Stephacidin A (1)
(3 mL) and EtOAc (3 mL). The layers were separated and the
aqueous phase was extracted with EtOAc (5 mL). The com-
bined organic layers were washed with brine (5 mL) and dried
(MgSO4). The solvent was removed under reduced pressure
and purification of the residue by column chromatography
(5% MeOH in CH2Cl2) afforded (+)-4 as a pale yellow film
(3.3 mg, 55%): Rf = 0.22 (5% MeOH in CH2Cl2); νmax(CHCl3)/
cm−1 3240br m, 2974w, 1681vs, 1643 s, 1594 m, 1457 m, 1397,
1334 m, 1214 m, 1183 m, 1119 m, 1057 m, 902vw, 750vs,
666 m; δH (300 MHz, CDCl3) 0.82 (3H, s), 0.85 (3H, s), 1.43
(3H, s), 1.45 (3H, s), 1.66–1.73 (1H, m), 1.78–1.87 (1H, m),
1.94–2.08 (3H, m), 2.15 (1H, d, J 14.8 Hz), 2.72–2.83 (1H, m),
3.21 (1H, d, J 14.8 Hz), 3.37–3.52 (2H, m), 3.56–3.68 (1H, m),
5.69 (1H, d, J 9.9 Hz), 6.33 (1H, d, J 9.9 Hz), 6.46 (1H, d, J 8.2
Hz), 6.91 (1H, br s), 7.13 (1H, d, J 8.2 Hz), 8.35 (1H, br s); δC
(100 MHz, CDCl3) 19.8, 23.3, 24.8, 27.8, 27.9, 29.7, 30.7, 34.4,
43.9, 46.1, 56.1, 62.3, 66.6, 68.8, 76.2, 77.2, 105.0, 109.9, 116.1,
121.9, 127.0, 131.0, 136.7, 152.9, 169.5, 184.2; m/z (ES+) 470.2
([M + Na]+, 88%), 486.2 (100, [M + K]+); HRMS m/z (ES+) Found
[M + Na]+ 470.2058. C26H29N3O4Na requires 470.2056.
Boc-protected 24a (20 mg, 32 μmol) was transferred to a micro-
wave reactor vessel and H2O (3 mL) was added. The vessel was
placed in a microwave synthesizer (Discover-S, CEM) and
heated with stirring to 165 °C for 10 minutes. Upon com-
pletion, the reaction mixture was allowed to cool to room
temperature and diluted with H2O (7 mL). The product was
extracted with EtOAc (3 × 15 mL) and the combined organic
fractions were washed with brine (3 × 10 mL) and dried
(MgSO4). The volatile organics were removed under vacuum
overnight to afford (−)-1 as a white solid (10 mg, 73%): Rf =
0.30 (100% EtOAc); νmax(CHCl3)/cm−1 3325 m, 2970w, 2929w,
1639 s, 1673vs, 1587w, 1439 m, 1375 m, 1261 m, 1190 m,
1121 m, 1055 m, 899w, 810 m, 730 m, 662w; δH (400 MHz, d6-
DMSO) 1.00 (3H, s), 1.28 (3H, s), 1.368 (3H, s), 1.373 (3H, s),
1.79–1.87 (2H, m), 1.95–2.08 (2H, m), 2.05 (1H, dd, J 13.7, 9.9
Hz), 2.42 (1H, dd, J 9.9, 5.0 Hz), 2.51–2.56 (1H, m), 2.63 (1H, d,
J 15.6 Hz), 3.21–3.28 (1H, m), 3.30–3.35 (1H, m), 3.36 (1H, d,
J 15.6 Hz), 5.72 (1H, d, J 9.8 Hz), 6.47 (1H, d, J 8.3 Hz), 6.93 (1H,
d, J 9.8 Hz), 7.09 (1H, d, J 8.3 Hz), 8.69 (1H, s), 10.44 (1H, s); δC
(100 MHz, CDCl3) 21.5, 23.8, 24.0, 27.0, 27.1, 28.0, 28.7, 30.1,
34.6, 43.5, 49.2, 59.6, 66.0, 75.0, 103.8, 104.8, 108.6, 117.5,
118.2, 121.5, 129.0, 132.8, 139.6, 147.5, 168.5, 173.0; m/z (ES+)
431.3 ([M]+, 100%); HRMS m/z (ES+) Found [M]+ 431.2212.
C26H29N3O3 requires 431.2209. Data were in agreement with
those reported previously in the literature.1,6a,c,7
The 1H and 13C NMR spectra of this product were also
recorded in d6-acetone, which showed data in agreement with
that reported previously.7a,b,25
X-Ray crystallography
Crystal data for 14a. C40H45N3O5S, CH4O, M = 711.89,
orthorhombic, a = 10.6567(3), b = 13.9156(4), c = 24.7451(6) Å,
U = 3669.56(17) Å3, T = 120(2) K, space group P212121, Z = 4,
28 682 reflections measured, 6618 unique (Rint = 0.0212) which
were used in all calculations. The final R1 was 0.0332 (I > 2σ(I))
and wR(F2) was 0.0925 (all data). Flack parameter = 0.020 (13).
CCDC 936852.
Crystal data for 16a.21 C21H25N3O2, M = 351.44, ortho-
rhombic, a = 11.2588(1), b = 11.7630(2), c = 12.8358(2) Å, U =
1699.94(4) Å3, T = 120(2) K, space group P212121, Z = 4, 10 076
reflections measured, 2910 unique (Rint = 0.0278) which were
used in all calculations. The final R1 was 0.0329 (I > 2σ(I)) and
wR(F2) was 0.0861 (all data). CCDC 848586.
(+)-Notoamide B (4)
Crystal data for 16b. C21H25N3O2, CH4O, M = 383.48, ortho-
A mixture of Boc-protected indolines 23a and 23b (2.5 : 1 ratio, rhombic, a = 8.0470(17), b = 10.678(3), c = 22.331(5) Å, U =
70 mg, 110 μmol) was transferred to a microwave reactor vessel 1918.8(8) Å3, T = 100(2) K, space group P212121, Z = 4, 14 736
and H2O (12 mL) was added. The vessel was placed in a micro- reflections measured, 2518 unique (Rint = 0.0754) which were
wave synthesizer (Discover-S, CEM) and heated with stirring to used in all calculations. The final R1 was 0.0628 (I > 2σ(I)) and
165 °C for 10 minutes. Upon completion, the reaction mixture wR(F2) was 0.1319 (all data). CCDC 936851.
was allowed to cool to room temperature and diluted with H2O
(8 mL). The product was extracted with EtOAc (3 × 20 mL) and group.13 Suitable crystals were selected and datasets were
the combined organic fractions were washed with brine (3 × measured on a Bruker SMART 6000 diffractometer (λCu-Kα
The structure of 16a has been reported previously by this
=
10 mL) and dried (MgSO4). The solvent was removed under 1.54184 Å) for 14a and 16a and by the EPSRC UK National
reduced pressure and purification of the residue by column Crystallography Service32 on a Rigaku AFC12 goniometer
chromatography (100% EtOAc) afforded 25 (d.r. = 2.5 : 1) as a equipped with an enhanced sensitivity (HG) Saturn724+ detec-
colourless oil (27 mg, 57%). A sample of these indolines tor mounted at the window of an FR-E+ SuperBright molyb-
(5.8 mg, 13.4 μmol) was dissolved in 1,4-dioxane (0.4 mL) and denum rotating anode generator (λMo-Kα = 0.71073 Å) with HF
30% aqueous H2O2 (15 μL, 10 equiv.) was added. Selenium(IV) Varimax optics for 16b. The data collections were driven by
dioxide (10 μL of a 0.23 M solution in H2O, 17 mol%) SMART33 and processed by SAINTPLUS34 for 14a and 16a
was added and the reaction mixture was stirred at room and was driven and processed by CrystalClear-SM Expert
temperature for 20 h. The mixture was diluted with H2O 2.0 r735 for 16b. Absorption corrections were applied using
4968 | Org. Biomol. Chem., 2013, 11, 4957–4970
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CrystalClear-SM Expert 2.0 r735 for 16b and using SADABS36
for 14a and 16a. The structures were all solved in SHELXS-9737
and were refined by a full-matrix least-squares procedure on F2
in SHELXL-97.37 All non-hydrogen atoms were refined with
anisotropic displacement parameters. The hydrogen atoms in
all structures were added at calculated positions and refined
by use of a riding model with isotropic displacement para-
meters based on the equivalent isotropic displacement para-
meter (Ueq) of the parent atom. Figures were produced using
OLEX2.38
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Acknowledgements
We acknowledge the University of Birmingham for support of
IP, and the Engineering and Physical Sciences Research
Council (EPSRC) for support of MDW.
The NMR instruments used in this research were obtained
through Birmingham Science City: Innovative Uses for
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