A unified strategy targeting the thiodiketopiperazine mycotoxins exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin a and aranotin

Article abstract of DOI:10.1002/chem.201001169

A unified synthetic strategy directed towards mycotoxins belonging to the thiodiketopiperazine family is reported. The building blocks for a number of natural products-including exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin A and aranotin-have been synthesised stereoselectively from a common precursor. This key intermediate was constructed through an efficient and highly diastereoselective[2+2] cycloaddition between a ketene and an enecarbamate derived from l-pyroglutamic acid. The annelation of the second ring was accomplished through ring-closing metathesis and enol ether-olefin ring-closing metathesis to provide both cis-and trans-annelated azabicyclic cyclohexenones, as well as an annelated sevenmembered cyclic enol ether. A Pd-catalysed elimination of allyl acetate gave rise to the cyclohexadienol structure of gliotoxin. Dimerisation of one building block to afford the diketopiperazine core was demonstrated.

Full text of DOI:10.1002/chem.201001169

DOI: 10.1002/chem.201001169
A Unified Strategy Targeting the Thiodiketopiperazine Mycotoxins
ExseroACTHNURTGNEUhGN ilone, Gliotoxin, the Epicoccins, the Epicorazines,
Rostratin A and Aranotin
Ulrike Gross,[a] Martin Nieger,[b] and Stefan Brꢀse*[a]
Abstract: A unified synthetic strategy
reoselective [2+2] cycloaddition be-
tween a ketene and an enecarbamate
derived from l-pyroglutamic acid. The
annelation of the second ring was ac-
complished through ring-closing meta-
thesis and enol ether–olefin ring-clos-
ing metathesis to provide both cis- and
trans-annelated azabicyclic cyclohex-
directed towards mycotoxins belonging
to the thiodiketopiperazine family is
reported. The building blocks for a
number of natural products—including
exserohilone, gliotoxin, the epicoccins,
the epicorazines, rostratin A and ara-
notin—have been synthesised stereose-
lectively from a common precursor.
This key intermediate was constructed
through an efficient and highly diaste-
AHCTUNGTRENNeGUN nones, as well as an annelated seven-
membered cyclic enol ether. A Pd-cat-
alysed elimination of allyl acetate gave
rise to the cyclohexadienol structure of
gliotoxin. Dimerisation of one building
block to afford the diketopiperazine
core was demonstrated.
Keywords: cycloaddition · epithio-
diketopiperazines
· metathesis ·
natural products · stereoselective
synthesis
Introduction
Most fungal toxins are secondary metabolites, so-called my-
cotoxins.[1] Well-known classes of these include polyketides,
cyclic peptides, alkaloids and sesquiterpenoids. Another
class, the thiodiketopiperazines, are diketopiperazines con-
taining thio functionality in bridged or open form. All of
these thiodiketopiperazines exhibit important biological
characteristics, attributed in many cases to the sulfur
moiety.[2]
Out of this vast class of thiodiketopiperazines we have in-
vestigated the synthesis of a variety of natural products, all
with the same absolute configurations at their C2, C8 and
C9 carbon atoms (Scheme 1 and Scheme 2, below). They
[a] Dipl.-Chem. U. Gross, Prof. Dr. S. Brꢀse
Institut fꢁr Organische Chemie
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax : (+49)721-698-8581
Scheme 1. Structures of the mycotoxins gliotoxin (1), the aranotins (2),
apoaranotin (3) and the epicoccins (4).
E-mail: braese@kit.edu
[b] Dr. M. Nieger
differ in the sulfur functionality, which can be either bridged
or open, incorporating one, two or more sulfur atoms, and/
or in the positions of these functionalities. The A/B (and D/
E) ring systems are cis- or trans-annelated, thus differing in
their configurations at C4 (and C4’) (Scheme 2, see number-
ing scheme A). In most of the natural products the A and E
Laboratory of Inorganic Chemistry
Department of Chemistry
University of Helsinki, P.O. Box 55
00014 University of Helsinki (Finland)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001169.
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FULL PAPER
Exserohilone (5, Scheme 2), with trans fusion of the A,B
and D,E ring systems, isolated from Exserohilum holmii, ex-
hibits phytotoxic activity.[16] The 2,2’-disulfide derivatives the
epicorazines (6, again isolated from Epicoccum nigrum)
show antibacterial activity against Staphylococcus aureus.[17]
Closely related is rostratin A (7),[18] the only member of the
rostratin family with this specific configuration. It was isolat-
ed from Exserohilum rostratum and shows in vitro cytotoxic-
ity against the human colon carcinoma cell-line HCT-116.
The complex structures and important biological activities
of these thiodiketopiperazines clearly mark them as interest-
ing synthetic targets. To the best of our knowledge, however,
only gliotoxin has so far been produced by total synthesis,[19]
although other synthetic strategies directed towards some of
the thiodiketopiperazines, including rostratin C,[20] the epi-
Scheme 2. Structures of the mycotoxins exserohilone (5), epicorazine A
(6a), epicorazine B (6b) and rostratin A (7), together with the number-
ing scheme (A).
coccins A,
C
and
D
(3a–c),[21] gliotoxin (1)[22] and
MPC1001,[23] have been reported. Our results in the con-
struction of C2-symmetrical and unsymmetrical diketopiper-
azines in a one-step procedure from proline-type amino
acids,[24] as well as the impressive thiolation results of Mo-
vassaghi and co-workers,[25] prompted us to target the syn-
thesis of these thiodiketopiperazines. Our preliminary re-
sults relating to the construction of the scaffold of epicoc-
rings are substituted six-membered cyclohexane units, al-
though aranotin (2a) features an oxygen-containing seven-
membered heterocycle, a dihydrooxepine moiety.
Gliotoxin (1, Scheme 1) was the first thiodiketopiperazine
to be reported and is the best characterised. It was isolated
from culture broths of Gliocladium fimbriatum[3] and later
also from other microorganisms such as Trichoderma, Asper-
gillus and Penicillium. It shows strong antibacterial and anti-
viral activity,[4] is immunosuppressive[5] and causes apoptotic
and necrotic cell death.[6]
cins A, C and D were published earlier.[21] We now wish to
ACHTUNGTRENNUNG
report our overall strategy directed towards gliotoxin (1),
the aranotins (2), the epicoccins (4), exserohilone (5), the
epicorazines (6) and rostratin A (7).
Results and Discussion
Aranotin (2a) and acetylaranotin (2b) are biosyntheti-
cally closely related to gliotoxin.[7] They have been isolated
from Arachniotus aureus and Aspergillus terreus[7,8] and
show in vitro and in vivo activities against polio (types 1, 2
and 3), Coxsackie (A21) and rhino- and parainfluenza
(types 1 and 3) viruses.[7–9] The antiviral properties of the
metabolites are of particular interest because of their ability
to inhibit virus multiplication in tissue culture, with relative-
ly low toxicities against mammalian cells.
Other members of the aranotin family, such as apoarano-
tin (3), are hybrids of gliotoxin (AB rings) and aranotin
(DE rings) or are their 2,2’-(SMe)2 forms.[7,10] The emethalli-
cins, the phenylacetic ester and mandelic ester derivatives of
aranotin and apoaranotin, show potent inhibitory activity of
compound 48/80-induced histamine release from mast
cells.[11] SCH 64874, another ester derivative, is the first ex-
ample of a thiodiketopiperazine as an epidermal growth
factor receptor antagonist. Other examples of thiodiketopi-
perazines with dihydrooxepine cores are emestrin and its
methyl derivative MPC1001, exhibiting anti-cancer activi-
ty.[12,13]
Retrosynthetic analysis: We envisaged a versatile and ste-
reoselective synthesis of the building blocks of gliotoxin (1),
the aranotins (2), the epicoccins (4), exserohilone (5), the
epicorazines (6) and rostratin A (7) and others starting from
one common precursor: the azabicyclic lactone 17
(Scheme 3). The lactone 17 was to be synthesised through a
[2+2] cycloaddition between a ketene and an enecarbamate
derived from l-pyroglutamic acid (16). The cis-annelated
series, the cyclohexane 11 and the bisalcohol 10, as well as
the gliotoxin monomer 8, were to be obtained from the cis-
annelated cyclohexenone 14.
Retrosynthetically, 14 was to be constructed from the aza-
bicyclic lactone 17 in a three-step sequence involving a ring-
closing metathesis (RCM) of the intermediate lactol 20, gen-
erated by isomerisation of the terminal double bond and
subsequent vinylation (Scheme 4). It was thought that the
trans-fused series (the cyclohexenone 13 and the bisalcohol
9) should be accessible either by epimerisation of the cis-an-
nelated cyclohexenone 14 or by epimerisation of the alde-
hyde 21. The key steps of the construction of the six-mem-
bered ring involve isomerisation of the double bond in 15
(Scheme 3), 1,2-addition of a vinyl Grignard to the aldehyde
21 and RCM (Scheme 4).
The epicoccins (4, Scheme 1), which are all cis-annelated
and contain the quite unusual sulfur bridge between C2 and
C7, have only recently been isolated from a Cordyceps-colo-
nising isolate of Epicoccum nigrum.[14,15] Epicoccin A (4a)
shows modest antimicrobial activities, whereas epicoccin G
(4 f) effectively inhibits HIV-1 replication in C8166 cells.
The aldehyde 21 is also an intermediate in our synthetic
strategy for aranotin (2a). The key step of this approach is
an enol ether–olefin RCM, providing a seven-membered tet-
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S. Brꢀse et al.
five steps starting from l-pyro-
glutamic acid (16, Scheme 5).[21]
The key step for the stereose-
lective construction of the aza-
bicyclic lactone core was
a
highly diastereoselective [2+2]
cycloaddition between a ketene,
generated in situ from pent-4-
enoyl chloride, and the enecar-
bamate 22.[26–28] The azabicyclic
cyclobutanone 23 was isolated
as a single diastereoisomer in
good yield.[29] A proposed ex-
planation of the obtained dia-
stereoselectivity is shown in
Scheme 5(B).[27b,30] Baeyer–Vil-
liger oxidation of 23 with com-
plete regio- and chemoselectivi-
ty gave the azabicyclic lactone
17 in good yield.
The terminal double bond
was subsequently isomerised in
the presence of the second-gen-
eration Grubbs catalyst[31] and
vinyloxytrimethylsilane, giving
Scheme 3. Retrosynthetic analysis of the building blocks for gliotoxin (1), the epicoccins (4), the aranotins (2),
exserohilone (5), the epicorazines (6) and rostratin A (7). PG=protecting group.
Scheme 5. Synthesis of the key intermediate azabicyclic lactone 17:
a) tBuOAc, HClO4, RT; b) Boc2O, DMAP (14 mol%), CH3CN, 08C!
RT, 61% (two steps); c) LiBHEt3, toluene, ꢀ788C; DMAP (10 mol%),
trifluoroacetic anhydride (TFAA), Hꢁnig base (DIPEA), ꢀ788C!RT,
77%; d) pent-4-enoyl chloride, NEt3, cyclohexane, reflux, 75%;
e) mCPBA, NaHCO3, CH2Cl2, RT, 78%. Boc=tert-butoxycarbonyl,
DMAP=4-dimethylaminopyridine, DIPEA=diisopropylethylamine.
rise to the corresponding product, exclusively in the E con-
figuration (Scheme 6). This isomerisation method, employ-
ing a ruthenium hydride as the active species, has been
widely used in syntheses, in which the introduction of allyl
groups proved to be more efficient compared with the intro-
duction of vinyl or propenyl groups.[32] This was also the
case in our synthetic strategy, because the [2+2] cycloaddi-
tion with but-3-enoyl chloride (instead of the utilised pent-
4-enoyl chloride) did not give any cycloaddition product. In
contrast with other catalytic systems, isomerisation occurs
reliably only to the adjacent position. A 1,2-addition of
Scheme 4. Retrosynthetic approach to the cis- and trans-annelated cyclo-
hexenonenes 14 and 13, as well as to the annelated dihydrooxepine 12.
rahydrooxepine ring. The second double bond of the arano-
tin building block 12 would have to be installed through an
elimination reaction.
Synthesis: We achieved the synthesis of the azabicyclic lac-
tone 17, the key intermediate of our synthetic strategy, in
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A Unified Strategy Targeting Thiodiketopiperazine Mycotoxins
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Scheme 6. Synthesis of the cis-annelated cyclohexenone 14: a) vinyloxy-
trimethylsilane, second-generation Grubbs catalyst (3 mol%), toluene,
reflux, 88% (99% based on recovered starting material (brsm)); b) vinyl
Grignard, THF, ꢀ788C, 80%; c) second-generation Grubbs catalyst
(3 mol%), toluene, reflux, 72%.
Scheme 8. NOE correlations in epi-25 and 25 (R=OTBS).
vinyl Grignard reagent to the lactone gave the lactol 20 as a
single diastereoisomer (of unknown configuration at C4).
We were pleased that 20 underwent RCM in the presence of
the second-generation Grubbs catalyst[31] to afford the cis-
annelated cyclohexenone 14 as the building block for the
epicoccins A, C and D (4a–c). The absolute configuration
could be confirmed by crystal structure analysis.[21]
tert-Butyldimethylsilyl (TBS) protection of the hydroxy
function in 14 and subsequent reduction (Scheme 7) gave
Scheme 9. Synthesis of the building blocks 8 (for gliotoxin (1)) and 11
(for epicoccin G (4 f)): a) Pd(OAc)2 (20 mol%), PPh3, NEt3, toluene,
AHCTUNGTRENNUNG
1108C, 58% (81% brsm); b) H2, Pd/C (10 mol%), EtOAc, RT, 82%.
toxin (1) could thus be synthesised effectively in 12 steps
and 7.7% overall yield from l-pyroglutamic acid (16).[35]
Hydrogenation of the cis-annelated cyclohexenone 14 with
hydrogen on Pd/C gave rise to the building block 11 for epi-
coccin G (4 f).
To give access to the trans-annelated series based on the
azabicyclic cyclohexenone 13 (present in even more natural
products than that based on the cis-annelated 14) we per-
formed epimerisation experiments with the cis-annelated
TBS-protected cyclohexenone 14 and various bases and sol-
vents. In all cases, however, only the starting material could
be recovered, which is probably due to the cis-annelated cy-
clohexenone 14 being the thermally more stable epimer.
This could later be demonstrated with the partial epimerisa-
tion of the trans isomer 13 to its cis isomer 14 under meta-
thesis and basic conditions. We reasoned that epimerisation
might be possible with a proline derivative such as 29
(Scheme 10), without an annelated second ring, with which
the thermodynamically more stable product should be the
one with its substituents at C4 and C5 in an anti relation-
ship.
Initial experiments to synthesise the aldehyde 29 in a two-
step procedure,[36] involving opening of the lactone 17 to
give the corresponding amides or thioesters and subsequent
reduction, failed as a result of the low reactivity of 17. We
therefore decided to reduce the lactone completely to the
bisalcohol 27, in a stepwise protocol via the lactol 26. A
crystal structure of 26 verified the assigned configuration of
our compounds (Figure 1).
Scheme 7. Synthesis of the acetate 25 and the epicoccin F building block
epi-25 (4d): a) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 73%; b) NaBH4,
CeCl3·7H2O, MeOH, 08C, quant (24/epi-24 9:1); c) Ac2O, DMAP,
CH2Cl2, RT, 65% (25) and 18% (25/epi-25 1:1); d) DIAD, PPh3, p-nitro-
benzoic acid, THF, 08C ! RT, 65% (9:1); e) K2CO3, MeOH, RT, 82%
(epi-24/24 9:1); f) Ac2O, DMAP, CH2Cl2, RT, 81% (epi-25) and 11%
(epi-25 and 25). DIAD=diisopropyl azodicarboxylate.
the alcohol 24 with good diastereoselectivity (9:1), with the
hydride nucleophile attacking from the convex side of the
molecule. Mitsunobu inversion[33] and subsequent hydrolysis
of the benzoic ester gave rise to a 9:1 mixture of epi-24 and
24. The epimers could be separated as the acetates epi-25
and 25. The relative configurations of 25 and epi-25 could
be established by NOESY experiments (Scheme 8). The epi-
coccin F (4d) building block epi-25 was thus synthesised ste-
reoselectively in 13 steps.
A 9:1 mixture of the allylic acetates 25 and epi-25 was
subjected to the Pd0-catalysed elimination conditions of
Tsuji and Trost (Scheme 9).[34] The building block 8 for glio-
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S. Brꢀse et al.
Both hydroxy functions were subsequently protected as
triethylsilyl (TES) ethers. The primary TES-protected alco-
hol in 28 was then chemoselectively oxidised under Swern
conditions to afford the corresponding aldehyde 29, without
oxidisation
of
the
protected
secondary
alcohol
(Scheme 10).[37] Sometimes, epimerisation of the aldehyde
29 (!epi-29) to a small degree (up to 20%) was already ob-
servable under the Swern conditions. Complete epimerisa-
tion occurred upon treatment with 1,8-diazabicyclo-
AHCTUNGTREG[NNNU 5.4.0]undec-7-ene (DBU) in THF at room temperature, to
give epi-29 as a single diastereoisomer. The 1,2-addition of
vinyl Grignard reagent to the aldehyde function and subse-
quent oxidation to the vinyl ketone 30 was accomplished in
good yields. Unfortunately, subsequent isomerisation of the
terminal double bond proved difficult with this system. The
allylic TES-alcohol 31 could be obtained only in low to
moderate yield and with major impurities, which could not
be separated. We reasoned that the Michael system of 30
could be responsible for the encountered problems and so
we decided to perform the isomerisation on an earlier pre-
cursor.
Isomerisation of the double bond proceeded smoothly
with the bistriethylsilyl ether 28, to give the corresponding
product as a mixture of E and Z isomers in a ratio of 8:2
(Scheme 11). Again, use of Swern conditions resulted in the
Scheme 10. Attempted synthesis of the trans-annelated cyclohexenone
13: a) DIBAL, THF, ꢀ788C, 99%; b) NaBH4, MeOH, RT, 91%;
c) TESOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 98%; d) DMSO, (COCl)2,
ꢀ788C!ꢀ408C; NEt3, ꢀ788C!08C; e) DBU, THF, RT, 76% (2 steps);
f) vinyl Grignard, THF, ꢀ788C, 84%; g) Dess–Martin periodinane,
CH2Cl2, RT, 96%; h) vinyloxytrimethylsilane, second-generation Grubbs
catalyst (5 mol%), toluene, 1108C, 36–47% with impurities of unknown
structures. DIBAL=diisobutylaluminium hydride.
Scheme 11. Successful synthesis of the trans-annelated cyclohexenone 13:
a) vinyloxytrimethylsilane, second-generation Grubbs catalyst (5 mol%),
toluene, reflux, quant. (E/Z 8:2); b) DMSO, (COCl)2, ꢀ788C ! ꢀ408C;
NEt3, ꢀ788C!08C; c) DBU, THF, RT, 87% (2 steps, E/Z 8:2); d) vinyl
Grignard, THF, ꢀ788C, 79% (2 epimers 8:2, E/Z 8:2); e) Dess–Martin
periodinane, CH2Cl2, RT, 92% (E/Z 8:2); f) PPTS, CH2Cl2, RT, 80% (E/
Z 9:1); g) second-generation Grubbs catalyst (5 mol%), toluene, reflux,
56% (13) and 29% (14/13 3:1).
selective oxidation of the primary TES-protected alcohol in
the presence of the secondary one. Epimerisation of the al-
dehyde, 1,2-addition and oxidation were accomplished in
good to excellent yields as before. Unfortunately, we ob-
served no conversion of the allylic TES-alcohol 31 in our at-
tempted RCM reaction in the presence either of the second-
generation Grubbs catalyst[31] or of the second-generation
Grubbs–Hoveyda catalyst.[38] We reasoned that carbene for-
mation next to the bulky triethylsilyl group might be too
sterically hindered and indeed, after removal of the protect-
Figure 1. Crystal structure of lactol 26 (one independent molecule is
shown, displacement parameters are drawn at 50% probability level).
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A Unified Strategy Targeting Thiodiketopiperazine Mycotoxins
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ing group on the allylic alcohol with pyridinium para-tolu-
ACHTUNGTRENNUNGenesulfonate (PPTS), RCM could be accomplished in good
yields. We have thus been able to synthesise the trans-anne-
lated cyclohexenone 13, representing the building block of
epicorazines A (6a) and B (6b), as well as exserohilone (5),
stereoselectively in 15 steps. We observed slow epimerisa-
tion under the RCM conditions, resulting in the additional
isolation of the cis isomer 14 (22%).
Protection of the hydroxy function[39] and subsequent re-
duction with NaBH4 and CeCl3·7H2O gave the allylic alco-
hol 33 with perfect diastereoselectivity (Scheme 12). To
Scheme 12. Diastereoselective reduction of the trans-annelated cyclohex-
enone 13: a) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 33 (70%) and 33/epi-
33 1:1 (20%); b) NaBH4, CeCl3·7H2O, MeOH, 08C, 73%; c) DIAD,
PPh3, p-nitrobenzoic acid, THF, 08C!RT, 98 %.
Scheme 13. Synthesis of the precursors 38 and 39 for enol ether–olefin
RCM: a) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 95%; b) vinyloxytrime-
thylsilane, second-generation Grubbs catalyst (5 mol%), toluene, reflux,
quant (E/Z 8:2); c) HF/pyridine, THF, 08C, 91% (E/Z 8:2); d) [Ir-
assign the configuration at the newly established stereogenic
centre, we also synthesised the epimer 34 through a Mitsu-
nobu inversion. The coupling constants and NOESY data
clearly verified the attributed configuration of 33, which
therefore represents the building block for rostratin A (7).
To assess the feasibility of enol ether–olefin RCM for the
construction of our annelated oxepines (19!12, Scheme 4),
we opted first to carry out the synthesis on an elaborated
model substrate, lacking the leaving group for the construc-
tion of the second double bond. The bisalcohol 26 was
doubly TBS-protected (!35) and the terminal double bond
could again efficiently be isomerised (Scheme 13, left).
After extensive screening for selective deprotection of the
primary alcohol function, we identified HF/pyridine as the
reagent of choice,[40] giving the monoprotected bisalcohol 36
in excellent yield. The hydroxy function was vinylated in the
presence of an iridium catalyst, as reported by Okimoto
et al.[41] Treatment of 36 with vinyl acetate in the presence
AHCTUNGRTEN(GUNN cod)Cl]2 (10 mol%), Na2CO3, vinyl acetate, toluene, 1008C, 95% (E/Z
8:2); e) HF/pyridine, THF, 08C, 93%; f) allyl bromide, NaH, DMF,
08C!RT, 70%; g) vinyloxytrimethylsilane, second-generation Grubbs
catalyst (10 mol%), toluene, reflux, 62%.
Fisher-type carbene. It has been reported that the formation
of the Fisher-type carbene is critically detrimental, because
it has proved to be significantly less reactive or even unreac-
tive for further metathesis reaction in some cases.[42a,44b,45]
Decreased accessibility of the vinyl ether should therefore
favour cyclisation. To reduce this accessibility of the enol
ether we opted for the installation of a propenyl substituent
instead of the vinyl one (Scheme 13, right). The previously
synthesised bis-TBS-ether 35 was therefore selectively
mono
N
of [Ir
N
group was installed through isomerisation of the corre-
sponding allyl ether. Guided by recent reports that a ruthe-
nium hydride catalyst, generated from the second-genera-
tion Grubbs catalyst and vinyloxytrimethylsilane, also effi-
ciently isomerises allyl ethers to their enol ether ana-
logues,[46] we decided to carry out both allyl isomerisation
and the isomerisation of the terminal double bond in one-
pot fashion, and were indeed able to synthesise the doubly
isomerised product 39 in good yield. Unfortunately, subse-
quent RCM in the presence of ruthenium and molybdenum
catalysts was again unsuccessful. We then moved on to facil-
itate access to the olefin part by removal of the TBS pro-
tecting group on the allylic alcohol in 38 (Scheme 14). Grati-
fyingly the enol ether–olefin RCM proceeded smoothly with
vided the enol ether 38. We then attempted the enol ether–
olefin RCM for the preparation of the oxepine ring in 40.
Our approach was guided by the success of RCM for the
preparation of seven-membered cyclic enol ethers.[42] Un-
fortunately though, we observed no conversion either with
the second-generation Grubbs catalyst[31] or with the
second-generation Grubbs–Hoveyda[38] catalyst (25 mol%).
Use of the Schrock catalyst,[43] reported to be more active
and more successful than the ruthenium catalysts for enol
ether–olefin RCM,[42a,44] led to decomposition.
In the proposed mechanism for enol ether–olefin RCM
the Grubbs catalyst can react first either with the olefinic
moiety or alternatively with the enol ether, forming a
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The completion of the dihydrooxepine building block 10,
present in aranotin (2a), as well as thiolation on advanced
model diketopiperazines, are currently being pursued in our
laboratories and will be reported in due course.
Scheme 14. Enol ether–olefin RCM to afford the tetrahydrooxepine 42:
a) TBAF, THF, RT, 87% (E/Z 8:2); b) second-generation Grubbs catalyst
(20 mol%), toluene, 1108C, quant. TBAF=tetra n-butylammonium fluo-
ride.
Experimental Section
For full experimental details see the Supporting Information.
Crystal structure determination of 26: The single-crystal X-ray diffraction
study was carried out with a Bruker–Nonius Kappa-CCD diffractometer
at 123(2) K with use of MoKa radiation (l=0.71073 ꢃ). Direct Methods
(SHELXS-97) were used for structure solution and refinement was car-
ried out by use of SHELXL-97[47] (full-matrix, least-squares on F2). Non-
hydrogen atoms were refined anisotropically; hydrogen atoms were local-
ised by difference electron density determination and refined with the
aid of a riding model (H(O) free). The absolute configuration could not
be determined reliably by refinement of Flackꢄs x-parameter (x=
0.0(10)).[48] The absolute configuration was assigned by reference to the
unchanging chiral centre of l-pyroglutamic acid (16) in the synthetic pro-
cedure. Refinement of Hooftꢄs FLEQ parameter[49] confirmed the as-
signed absolute configuration (FLEQ=ꢀ0.01(24)). In one of the two in-
dependent molecules the allyl group and one tert-butyl carboxylate group
were disordered. The crystals were pseudo-merohedral twins.
the allylic alcohol 41 in the presence of the second-genera-
tion Grubbs[31] catalyst to afford the oxepine 42, represent-
ing the dihydro building block for aranotin (2a) and related
natural products. The second double bond of the oxepine
moiety is to be incorporated through an elimination of a
leaving group, to be installed on an earlier precursor such as
aldehyde 21 (Scheme 4).
As proof of principle we had already tested our reported
dimerisation conditions[24] on one of the synthesised building
blocks. The cis-annelated cyclohexenone 14 was therefore
protected as an acetate and the free amino acid 43 was ob-
tained in neat trifluoroacetic acid (TFA) (Scheme 15). With
methyl dichlorophosphite and triethylamine the diketopiper-
azine 44 could be isolated in modest yield over two steps as
a single diastereoisomer. It represents the dethio analogue
of the epicoccins A, C and D (4a–c).
Compound 26: colourless crystals, (C19H31NO6), M=369.45, crystal size
0.35ꢅ0.25ꢅ0.15 mm, orthorhombic, space group P212121 (No. 19), a=
10.157(1), b=10.186(1), c=40.645(4) ꢃ, V=4205.1(7) ꢃ3, Z=8, 1calcd
=
ACTHNUTRGNEUNG
1.167 Mgmꢀ3, F(000)=1600, m=0.086 mmꢀ1, 40207 reflections (2qmax
=
558), 9168 unique [Rint =0.047], 457 parameters, 214 restraints, R1 (I>
2s(I))=0.051, wR2 (all data)=0.120, S=1.03, largest diff. peak and hole
0.425 and ꢀ0.420 eꢃꢀ3
.
CCDC-773914 (26) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Acknowledgements
Scheme 15. Final assembly of the core 44 in epicoccins A, C and D (4a–
c): a) Ac2O, DMAP, CH2Cl2, RT, 92%; b) TFA, RT; c) MeOPCl2, NEt3,
toluene, 408C!1108C, 18% (2 steps).
We thank the Deutsche Forschungsgemeinschaft (DFG BR 1750/17-1)
and the Studienstiftung des deutschen Volkes (fellowship to U. Gross)
for financial support. We gratefully acknowledge the valuable experimen-
tal assistance of Simone Grꢀssle.
Conclusion
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Received: May 1, 2010
Published online: August 31, 2010
Chem. Eur. J. 2010, 16, 11624 – 11631
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11631