Total Synthesis of α- and β-Amanitin

Article abstract of DOI:10.1002/anie.201914935

α-Amanitin and related amatoxins have been studied for more than six decades mostly by isolation from death cap mushrooms. The total synthesis, however, remained challenging due to unique structural features. α-Amanitin is a potent inhibitor of RNA polyme

Full text of DOI:10.1002/anie.201914935

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Accepted Article
Title: Alpha- and Beta-Amanitin Total Synthesis
Authors: Christian Lutz, Werner Simon, Susanne Werner-Simon,
Andreas Pahl, and Christoph Müller
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10.1002/anie.201914935
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Alpha- and Beta-Amanitin Total Synthesis
Christian Lutz[a], Werner Simon[a], Susanne Werner-Simon[a], Andreas Pahl[a] and Christoph Müller*[a]
Dedicated to Prof. Heinz Faulstich for more than fifty years of amanitin research
Abstract: Alpha-Amanitin and related amatoxins are studied for
more than 6 decades mostly by isolation from death cap
mushrooms. The total synthesis however remained challenging
due to unique structural features such as posttranslational
modified isoleucine (dihydroxyisoleucine) and a tryptathion bridge
dividing the macrocycle into two rings. Alpha-amanitin is a potent
inhibitor of RNA polymerase II. Interrupting basic transcription
processes of eukaryotes leads to apoptosis of the cell. This
unique mechanism makes the toxin an ideal payload for antibody
drug conjugates (ADC). Only microgram quantities of toxins,
when delivered selectively to tumor sites by conjugating to
antibodies are sufficient to eliminate malignant tumor cells of
almost every origin. By solving the stereoselective access to
dihydroxyisoleucine, a photochemical synthesis of the tryptathion
precursor, solid phase peptide synthesis and macrolactamization
we obtained a scalable synthetic route towards synthetic α-
amanitin. This makes α-amanitin and derivatives now accessible
for the development of new ADCs.
interactions [4]. The inhibition constant Ki in HeLa cells was found
to be 3x10-9 [5]. The interaction is mainly based on strong
hydrogen bonds and hydrophobic interactions shown for
mammalian derived Pol II with a 3000 times higher binding than
to yeast Pol II [6]. Inhibition of RNA Pol II leads finally to apoptosis
of the cell. In contrast to other cytotoxins α-amanitin
advantageously kills both, rapidly growing and quiescent cells.
This has been demonstrated in xenograft tumor models at sub-
[7]
lethal doses or in an antibody drug conjugate (ADC) targeted
therapy of pancreatic cancer xenografts [8]
.
The promising, new approach towards tumor therapy
increases the demand for α-amanitin to enable further studies.
Since fermentation yields are low [9] and the bioprocess is not yet
fully understood [10], α-amanitin gets more and more into the focus
of synthetic organic chemists [2]
.
Despite of the high toxicity in humans (LD50 = 50-100 µg/kg),
α-amanitin 1 remained a target structure throughout decades
(scheme 1) [1, 2]. Recently, this compound raised a lot of interest
as a potential anti-tumor agent. The toxin was first isolated as the
major product of Amanita phalloides and characterized in 1978 in
its beta-form 2 by crystallisation in combination with 1H-NMR-
studies [1, 3]
.
Scheme 2. Retrosynthetic Analysis.
Retrosynthetic analysis (scheme 2) and synthetic strategy
considerations are mostly affected by the long history of α-
amanitin chemistry [1]. Retro-macrolactamisation to 3 and most
strikingly, the retro-Savige-Fontana cyclisation [11], resulted in
linear octapeptide 4 as a synthetic precursor. Synthesis of the
octapeptide was pre-defined by the synthetic route and protection
group strategy of 4,5-dihydroxyisoleucine (DHIL) 5. This
pretended a C-terminal coupling to immobilized hydroxy-L-
proline 7 at the beginning of the SPPS as previously described in
the phalloidin synthesis [12]. The remaining five amino acids were
assembled by the more favourable Fmoc strategy plus 3a,6-
dihydroxy-hexahydro-pyrrolo[2,3-b]indole-2-carboxylic acid (Hpi)
6 finally. Key building blocks are DHIL 5 and Hpi 6 therefore.
Scheme 1. Alpha-- and beta-Amanitin.
Co-crystallisation with yeast derived RNA polymerase II
(Pol II) revealed strong inhibitor properties through multiple
[a]
Dr. C. Lutz, Dr. W. Simon, Dr. S. Werner-Simon, Professor Dr. A.
Pahl, Dr. C. Müller
Heidelberg Pharma Research GmbH, 68529 Ladenburg
Department of Chemistry
E-mail: Christoph.Mueller@hdpharma.com
DHIL
5 carries three adjacent stereocenters to be assembled
in the right configuration. A first racemic synthesis goes back to
1957 [13]. A major hurdle of the DHIL synthesis is the possible
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201914935
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COMMUNICATION
spontaneous lactonization at any stage, making the right choice
of protecting groups crucial.
Olefin homologation under standard conditions by Swern
oxidation and Wittig reaction to 12, was followed by AD-mix beta
dihydroxylation with a preference (70:30) for the desired isomer
13. Isomers were easily separated by chromatographic resolution.
After acetylation 14, the phenyl fluorenyl group was deprotected
under acidic conditions to 15 prior benzyl group removal by
hydrogenation to yield amino acid 16. A twostep procedure
became necessary due to removal of the phenyl fluorenyl
protecting group from the product. Lactonization was not
observed throughout the synthesis.
Newer approaches e.g. applied the Mannich reaction [14, 15, 16]
,
Claisen rearrangement [2b, 17] or
a
Brown crotylation in
combination with the Strecker amino acid synthesis [2b]. The
common diol motif was mostly introduced by well known
dihydroxylation procedures [18]. These DHIL approaches resulted
in the synthesis of α-amanitin and γ-amanitin so far [2a, 2b]
.
Besides the DHIL synthesis, the tryptathione bridge dissecting
the macrocycle into two rings is quite challenging. Introduction of
a pre-build tryptathion starting from L-Trp and L-Cys is possible,
but quite tedious. Synthesis needs sulfenyl chloride or iodine pre-
[22]
activated Cysteine-dimer reacting with Tryptophan
. An
orthogonal protection group strategy becomes then necessary to
build up the framework.
Closing the ring after assembling 8 amino acids is more
straightforward. Besides exotic mercury [23] and successful iodine
[24]
cyclisation
in the synthesis of phalloidin structures, amatoxin
synthesis is strongly related to a reaction first described by Savige
and Fontana [25] and applied by Zanotti [26]. Key intermediate is the
oxidized form of L-Tryptophan derivative Hpi, that reacts under
acidic conditions prompt and neatly with nucleophiles such as
sulfur from L-cysteine to form the right-hand ring of α-amanitin.
[27],[28]
Hpi is accessible by peracid or DMDO oxidation
and was
applied in the first total synthesis of α-amanitin by Perrin et al [2b]
.
Unfortunately, these methods use hazardous oxidizers and
therefore are difficult to use on a larger scale.
A further access has been shown by photooxygenation of L-
tryptophan with oxygen [29]. A very mild access with high
functional group tolerance.
O
O
OH
HO
OH
Boc
Scheme 3. Dihydroxyisoleucine (DHIL) Synthesis. Conditions: a) PhCHO,
NaBH(OAc)3, THF, 0°C; b) PhFlBr, Pb(NO3)2, H3CCN, RT, 57%, 2 steps; c)
LiHMDS, MeI, THF, -30°C; d) LiAlH4, THF, 0°C to RT, 60% 2 steps; e) (COCl)2,
DMSO, -80°C, then Et3N; f) Ph3PCH3+Br-, NaH, DMSO, RT, 83%, 2 steps; g)
AD-mix beta H2O/tBuOH, 35°C, chrom. Purification, 68% major isomer,
96.8%ee; h) Ac2O, Et3N, CH2Cl2, 82.5%; i) F3CCO2H in CH2Cl2, 86%; j) H2/Pd/C,
1N HCl in EtOH, 92.8% (Abbr.: PhFlBr; Phenylfluorenylbromid)
a, b
O
N
NHBoc
O
N
O
H
N
O
H
17
18
Scheme 4. 6-Acetoxy 3a-hydroxy pyrrolo indene (Hpi) Synthesis. a) hν/sens/O2;
b) Me2S, 69%
We choose to start with 4-methyl aspartate ester as building
block, readily available from commercial source. Full protection
was accomplished by tert-butyl esterification at C-1 under
standard conditions 8[19] (scheme 3), reductive amination with
Thus, we were able to oxidize 6-acetoxy-N-Boc-L-tryptophan
(17) directly to a mixture of cis-/trans- 6-acetoxy-N-Boc-hydroxy-
pyrroloindene (18, scheme 4). The cis-/trans- mixture can be
used without any implication of the stereochemical outcome of the
benzaldehyde and phenyl fluorenyl protection of the amine 9 [20]
.
Regio- and stereoselective methylation with LHMDS/MeI at C-3
gave in a 5:1 selectivity the desired isomer 10 while the
combination of KHMDS/MeI favors the opposite due to chelate
formation of the intermediate potassium salt as described
elsewhere [21]. This worked out for tert-butyl esters as well,
facilitating regioselective reduction of the methyl ester with LiAlH4
to alcohol 11 in the following step.
The low alkylation selectivity was ruled out by LiAlH4 reduction
to alcohol 11 (Scheme 4). While the undesired diastereomer leads
to a facile lactonization product, the desired isomer halts at the
alcohol stage 11 and can be separated easily in high
diastereomeric purity.
cyclisation/tryptathion formation [30]
.
However, 6-hydroxy-L-
tryptophan is of limited commercial availability which makes
alternative routes attractive (scheme 5).
Thus, easily accessible 6-benzyloxy indene-3-carbaldehyd (19)
was protected with Cbz and reacted with a Horner-Wadsworth-
Emmons reagent to yield olefin 20 with an E/Z ratio of 98:2. After
enantioselective hydrogenation tryptophan derivative 21 was
obtained in 95.6 %ee [31]. After hydrogenative deprotection to 22
and acetylation of the 6’-HO-position, precursor 17 was obtained.
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10.1002/anie.201914935
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COMMUNICATION
O
H2N
O
N
H
HN
O
PS
O
O
O
O
O
S
a- e
N
H
O
O
O
OH
H
N
OAll
N
O
O
O
NH
N
H
Fmoc
O
N
N
H
O
O
23
O
24
O
OH
O
O
O
O
O
H
N
O
HN
N
O
H
O
HN
O
f
25
S
N
N
O
HO
O
H
N
H
O
NH
O
O
N
H
O
O
h, g
g
Scheme 5. 6-Hydroxytryptophan Synthesis. Conditions: a) CbzCl, Et3N, DMAP,
RT, 76%; b). Boc-2-Phosphonoglycine benzyl dimethyl ester, DBU, 73%; c)
[Rh((R,R)-DiPAMP)COD]BF4; H2 d) Pd/C, H2; e) Ac2O,1N NaOH, 68%, 2 steps
HO
RO
RO
HO
HN
O
O
S
H
N
H
O
N
O
N
H
HN
N
O
O
H
O
O
HN
HN
O
Having the key building blocks in hand, SPPS (scheme 6)
was straightforward. FmocHypOAll was immobilized on THP resin
23 (1.0 mmol/g) [22]. After allyl deprotection of the resin, DHIL was
coupled C-terminal by PyBOP/DIEA activation under microwave
conditions [50W, 10 min] and N2 bubbling. After Fmoc
deprotection with piperidene, the following amino acids, Fmoc-
Asp(OAll)OH, FmocCys(Trt)OH, FmocGlyOH, FmocIleOH,
FmocGlyOH were coupled iteratively, followed by 6’-Acetoxy-N-
Boc-Hpi 18 as final building block. The octapeptide is cleaved off
the resin with TFA for 15 minutes, washed into a reaction flask
and stirred until complete cyclisation of the first ring (Savige-
Fontana reaction, 30 minutes) to yield intermediate 24. The
bicycle 25 is formed by macrocyclization with DPPA/DIEA under
dilute condition. The acetyl and allyl protection groups were
cleaved off at once with ammonia in methanol to yield 26. In case
of β-amanitin, the allyl ester is selectively removed with
Pd(PPh3)4/HCO2H/TEA to 27, followed by deprotection of the
three acetyl groups with ammonia to obtain 28. Intermediates
were purified by preparative HPLC (some purification steps can
be omitted or substituted by precipitation due to low side product
formation). Final sulfoxidation was performed with mCPBA
yielding the desired R-1 or R-2 over the S-diastereomer in a ratio
of 2:1[2b]. Both isomers can be easily separated by preparative
RP-HPLC. The obtained α- and β-amanitin 1, 2 show identical
NMR and CD spectra compared to their natural counterparts (see
supplementary material).
In conclusion, we presented a facile route to natural α-and β-
amanitin (1 and 2). Key building blocks, such as DHIL 16 and Hpi
22 are readily available starting form natural building blocks. The
two additional stereocenters of DHIL 16 are accessible by
selective alkylation and oxidation procedures on a multi-gram
scale. Assembling of the octapeptide precursor was performed by
microwave assisted coupling but can be easily scaled up to
traditional shake flask methodology. The final steps (Savige-
Fontana cyclisation, macrolactamisation and acetyl deprotection)
ran smoothly without significant formation of side products.
Selectivity of the sulfoxidation needs further improvement,
however, recycling of the undesired S-sulfoxide is possible by
reduction to 30 and 32 [32]. Today, the process is already up-
scaled and able to deliver Amatoxin derivatives on a multi gram
scale in GMP quality.
S
N
O
N
N
RO
HO
N
H
HO
O
HO
O
H
H
N
H
N
NH
NH
N
H
O
O
N
H
O
O
O
O
NH2
OH
26
27, R=Ac
28, R=H
i
HO
HO
HO
HO
O
O
H
N
H
N
O
O
HN
N
H
HN
N
H
O
O
O
O
HN
HN
-
-
O
O
S+
S+
N
O
O
N
HO
N
H
HO
O
O
N
H
HO
HO
H
N
H
N
NH
NH
N
H
O
O
O
N
H
O
O
O
NH2
1, alpha-Amanitin
OH
2, beta-Amanitin
Scheme 6. α- and β-Amanitin Synthesis. Conditions: a) Pd(PPh3)4, DMBA,
DCM, RT, o/n; b). 16, PyBOP, iPr2NEt, HOBt, DCM/DMF 1:1, Microwave; c)
20% Piperidine, NMP, Microwave; d) steps b, c iteratively repeated with
FmocAsp(OAll)OH, FmocCys(Trt)OH, FmocGlyOH, FmocIleOH, FmocGlyOH,
22; e) TFA neat, 30 minutes, 47%; f) DPPA, iPr2NEt, dilution, 48%; g) 7N NH3
in MeOH, (30, 73%; 31, 57%); h) Pd(PPh3)4, HCO2H/TEA, RT, 30 min, 67%; i)
mCPBA (1, 54%; 2, 47%)
This can be seen as a cornerstone for the commercial use of
amatoxin based antibody drug conjugates (ADCs), so called
antibody targeted amatoxin conjugates (ATACs). After
attachment of stable or cleavable linkers at different functional
groups of α-amanitin, toxin-linker derivatives are conjugated to
antibodies [33] or small molecular targeting formats. ATACs show
very promising results as highly potent and selective anti tumor
agents [8]
.
Experimental Section
Detailed methodology is provided in the supporting information with
accompanying spectra and other key data reports.
Keywords: α-Amanitin • β-Amanitin • amino acid • peptides •
SAvige-Fontana reaction • solid phase synthesis • total synthesis
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10.1002/anie.201914935
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COMMUNICATION
A scalable route to α- and β-Amanitin:
The bicyclic octapeptide is build up by
solid phase assembling of a linear
octamer followed by two consecutive
cyclisation steps in solution. The key
non-proteinogenic amino acids, 6-
hydroxy tryptophan and (3R, 4R)-
dihydroxyisoleucine are accessible via
multi step synthesis on a multi-gram
scale. Accessibility of Amatoxins is a
cornerstone for the commercial
development of new payload linkers for
antibody drug conjugates.
Christian Lutz, Werner Simon, Susanne
Werner-Simon, Andreas Pahl and
Christoph Müller*
Page No. – Page No.
α- and β-Amanitin Total Synthesis
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