Stereocontrolled and versatile total synthesis of bispyrrolidinoindoline diketopiperazine alkaloids: structural revision of the fungal isolate (+)-Asperdimin

Article abstract of DOI:10.1002/chem.200901056

Homo- and heterodimeric bispyrrolidinoindoline diketopiperazine alkaloids have been synthesized following a concise, versatile, and stereoselective route. Highlights of the sequence are a diastereoselective construction of the C3a-bromo-hexahydropyrrolo[2

Full text of DOI:10.1002/chem.200901056

DOI: 10.1002/chem.200901056
Stereocontrolled and Versatile Total Synthesis of Bispyrrolidinoindoline
Diketopiperazine Alkaloids: Structural Revision of the Fungal Isolate
(+)-Asperdimin
Carlos Pꢀrez-Balado, Paula Rodrꢁguez-GraÇa, and ꢂngel R. de Lera*[a]
Abstract: Homo- and heterodimeric
bispyrrolidinoindoline diketopiperazine
alkaloids have been synthesized follow-
ing a concise, versatile, and stereoselec-
tive route. Highlights of the sequence
are a diastereoselective construction of
kaloids, respectively. Stereochemical di-
versity is achieved through the choice
of the appropriate amino acids com-
bined with the base-induced epimeriza-
tion of the C2-acyl-hexahydropyrrolo-
WIN 64821 1, (+)-WIN 64745 2 and
(+)-asperdimin 6 as well as analogues
(5, 22, 32, 44) with different relative
and absolute configuration have been
efficiently synthesized. The flexibility
of this synthetic methodology has fa-
cilitated the structural revision of the
natural product (+)-asperdimin, whose
structure has been corrected to diaste-
reomer 6.
AHCTUNGTRENN[GUN 2,3-b]indole at C2. According to this
strategy, the natural products (+)-
the C3a-bromo-hexahydropyrrolo
b]indole nucleus, its Co -induced C3a
C3a’ dimerization, and the twofold or
G
I
Keywords: alkaloids · asperdimin ·
bispyrrolidinoindolines · dimeriza-
tion · heterodimers
sequential
amide-bond
formation
before cyclization to the diketopipera-
zine of the homo- or heterodimeric al-
Introduction
WIN 64821 (1) and (+)-WIN 64745 (2) were isolated from
Aspergillus sp. and identified as substance P antagonists for
the human neurokinin-1 and the cholecystokinin B recep-
tors.[2] (À)-Ditryptophenaline 4 was extracted from several
strains of Aspergillus flavus, and although structurally relat-
ed to (+)-WIN 64821 (1), it shows only moderate activity in
the same assays.[3] (+)-Verticillin A 3 was obtained from
Verticillium sp. and exhibits antimicrobial activity against
Gram positive bacteria and potent antitumor activity in
HeLa cell lines.[4] Verticillins belong to the epidithiodiketo-
piperazines group, with potent biological activities attributed
to the redox properties of the disulfide bridge.[5] The hetero-
dimeric analogue 5, which we propose to call (+)-asperdi-
min, was isolated from extracts of Aspergillus niger in 2004
and shows antiviral activity against certain viruses (flavivi-
ruses and picornaviruses). The nucleotide segment or inter-
nal ribosomal entry site (IRES) that guides the host-depen-
dent viral polyprotein synthesis is inhibited by (+)-asperdi-
min.[6]
Bispyrrolidinoindoline diketopiperazine alkaloids are
a
family of dimeric natural products that consist of two subu-
nits of a hexahydropyrrolo[2,3-b]indole fused to a diketopi-
AHCTUNGTRENNUNG
perazine ring.[1] Both subunits are connected to each other
through the C3 and C3’ atoms, forming a characteristic ar-
rangement of two contiguous quaternary stereogenic centers
with the same configuration. These compounds are of fungal
origin and show a considerable structural diversification that
is effected by the fungiꢀs biosynthetic machinery through
permutations on the amino acids that condense with trypto-
phan, modifications at the amide nitrogen, disulfide bridge
construction, and hydroxylations. Some representative mem-
bers of this family of alkaloids are depicted in Scheme 1.
Apart from their striking architecture, which has attracted
the attention of several synthetic groups, these compounds
exhibit a variety of interesting biological activities. (+)-
An early total synthesis, based on a biomimetic oxidative
dimerization step (3% yield), confirmed the absolute config-
uration of (À)-ditryptophenaline 4 in 1981 and completed
the structure that was previously established by X-ray crys-
tallography.[3b] A more efficient and elegant approach to
(À)-4, and the first synthesis of the homodimeric (À)-
WIN 64821 (ent-1), was reported by Overman and Paone in
[a] Dr. C. Pꢁrez-Balado, P. Rodrꢂguez-GraÇa, Prof. Dr. ꢃ. R. de Lera
Departamento de Quꢂmica Orgꢄnica
Facultade de Quꢂmica, Universidade de Vigo
As Lagoas/Marcosende, 36310 Vigo (Spain)
E-mail: qolera@uvigo.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901056.
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FULL PAPER
Scheme 2. Synthetic plan (please note the different numbering of the bis-
pyrrolidinoindolines). Boc=tert-butyl carbamate, Cbz=N-carbobenzyl-
A
carbamate,
HATU=O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetra-
AHCTUNGTRENNUNG
step. Ring-closure by condensation between the methyl
esters and the pending amino groups of 8, after N-carboben-
zyloxy carbamate (Cbz) deprotection, would afford 7. Tetra-
peptide 8 could be obtained by coupling tetra-amine 9 with
the appropriate amino acids, which are available as l- or d-
enantiomers, which allows direct control of the configura-
tion at C15/C15’. Dimeric hexahydropyrroloindole 9 could
be accessed by dimerization of the functionalized
Scheme 1. Bispyrrolidinoindoline diketopiperazine alkaloids.
2001.[7] At the beginning of 2008, the total synthesis of natu-
ral (+)-WIN 64821 (1) and (À)-4 was disclosed by Movassa-
ghi and co-workers by using a CoI-mediated dimerization of
C3a-bromocyclotryptophans as the key step.[8] More recent-
ly, we have reported the first total synthesis of heterodimer-
ic (+)-WIN 64745 (2) and an alternative preparation of (+)-
WIN 64821 (1).[9]
The structures depicted in Scheme 1 illustrate the un-
matched power of nature to achieve structural diversity by
altering the stereogenicity of the quaternary carbons, the
substituents at C15/C15’ and the configuration of the diketo-
piperazine stereocenters. For example, the reported[6] struc-
ture of (+)-5 and (À)-ditryptophenaline 4 have the same
configuration of the hexahydropyrroloindole junction but
the opposite one at the diketopiperazine stereocenters. The
same relationship is found between (+)-WIN 64821 (1) and
(+)-verticillin A (3). On the contrary, (+)-WIN 64821 (1)
and (À)-ditryptophenaline (4) differ in the relative configu-
ration at the hexahydropyrroloindole ring fusion, whereas
(À)-WIN 64821 (ent-1) and diketopiperazine (+)-5 feature
the same configuration in every stereogenic center with the
exception of C11/C11’.
hexahydropyrroloACTHNUTRGNEUNG[2,3-b]indole 10 mediated by transient rad-
ical species generated at the C3a position. Radical species
are usually rather insensitive to steric hindrance owing to
weak solvation interactions and resulting in ideal candidates
À
for the C C bond formation between two tertiary centers.
The preparation of the hexahydropyrrolo
A
would instead be based on a diastereoselective cyclization of
the tryptophan derivative 11 in the presence of a suitable
electrophile. We present herein a concise and flexible strat-
egy that has led to the total synthesis of the natural products
(+)-WIN 64821 (1), (+)-WIN 64745 (2) and (+)-asperdimin
as well as several synthetic analogues. In the course of this
endeavor we found some discrepancies between the spectro-
scopic data of the synthetic sample and those reported[6] for
natural (+)-5. Careful examination of the available data led
us to propose structure (+)-6 for the natural product, which
was confirmed by the efficient synthesis of that diastereoiso-
mer.
Taking into account this diversity in terms of stereochem-
istry and amino acid content, we began a program directed
towards the development of a flexible and versatile strategy
for the synthesis of these alkaloids. As illustrated in
Scheme 2, we envisioned a late-stage construction of the di-
ketopiperazine rings subsequent to the key dimerization
Results and Discussion
First-generation synthesis of bispyrrolidinoindoline diketopi-
perazines: As the dimerization reaction was the key step of
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ꢃ. R. de Lera et al.
the planned synthetic route, we directed our initial efforts to
exploring the feasibility of the desired C3-C3’ bond forma-
tion by using free-radical species generated from appropri-
ate precursors. Based on the precedent observations of Dan-
ishefsky and co-workers, who detected dimerization prod-
ucts during the radical prenylation of a C3a-phenylselenyl
hexahydropyrroloindole,[10] we started our studies with sele-
nides 14a and 14b (Scheme 3). These were readily prepared
Scheme 4. By-products of the photochemical dimerization.
and occasionally alcohol 18 (Scheme 4), which is presumably
formed by reaction with residual oxygen that is present in
the reaction media. We were unable to identify any other
by-products, with the exception of phenyl tributylstannyl sel-
enide. Given that PhSeS-nBu3 was isolated in high yields
(ꢀ90%) and the starting material was completely con-
sumed, we reasoned that the initial steps of the reaction in-
À
volving the homolytic cleavage of the Sn Sn bond and the
radical abstraction of the phenylselenyl substituent were not
responsible for the low yields, but rather a degradation of
either the benzylic radical intermediate 15 or the final prod-
uct under the reaction conditions. Unfortunately, milder
photochemical activation protocols utilizing lamps of lower
potency (200 W and 150 W) in combination with sensitizers
returned only starting material.[13] Despite the lack of spec-
troscopic evidence, we felt confident to propose 16 as the
Scheme 3. Photochemical dimerization mediated by tin. PSP=N-phenyl-
selenophthalimide, PPTS=pyridinium p-toluenesulfonate
structure of the dimeric hexahydropyrroloACTHNURTGNEU[GN 2,3-b]indole
products as the photochemical dimerization by collapse of
the radical species 15 was expected to preserve the cis-con-
figured ring junction of the 5,5-ring system and the C2/C2’
configuration.
in good yields by treating the d-tryptophan derivatives 13a
and 13b with N-phenylselenophthalimide (N-PSP) and pyri-
dinium p-toluenesulfonate (PPTS) in dichloromethane. As
previously reported, selenocyclisation of 13a and 13b af-
forded the exo diastereoisomer as the major compound.[10]
Traditionally the exo and endo stereochemical notation for
Although yields were not satisfactory in this step, we
judged that the available amounts of the key dimer 16b
were sufficient to establish a proof of principle of the syn-
thetic strategy and we next focused on the construction of
the diketopiperazine rings. Thus, bishexahydropyrroloindole
16b was fully deprotected to tetraamine 19 in 84% yield
(Scheme 5), first by treatment of 16b with iodotrimethylsi-
lane (TMSI) in acetonitrile at 08C to remove the tert-butyl
carbamate (BOC) groups, and then by hydrogenolysis of the
Cbz groups mediated by Pd/C in methanol. The condensa-
tion between the pyrrolidine amino groups of 19 and 2
equivalents of N-Cbz-d-serine 20 was assayed with O-(7-aza-
benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluo-
relative configuration of hexahydropyrroloACHTNUTRGNEUNG[2,3-b]indoles de-
scribes the outside or inside arrangement, respectively, of
the acyl group at the C2 position relative to the cavity de-
fined by the ring fusion.[11] This remarkable diastereose-
lectivy has been studied by our group by using density func-
tional theory (DFT) calculations, which indicate that a possi-
ble mechanism of reaction involves the formation of diaste-
reomeric C2-phenylselenyl indoline-azetidine spiranes as in-
termediates that undergo a concerted rearrangement to give
the C3a-functionalized hexahydropyrrolo
[2,3-b]indoles. A
ACHTUNGTRENrNUGN ophosphate (HATU) as the coupling agent in the presence
slightly lower transition-state energy in the generation of
the corresponding spirane favors the exo product forma-
tion.[12]
of Et3N and dimethylformamide (DMF) as the solvent.[14]
After some experimentation, we obtained the expected tet-
rapeptide 21 (70% yield), which could not be characterized
owing to severe NMR spectroscopic line broadening even at
elevated temperatures, with rotameric effects arising from
the carbamate N-protecting groups and the peptide bonds.
Finally, N-Cbz deprotection by hydrogenolysis catalyzed by
Pd/C in MeOH provided the corresponding primary amino
groups, which underwent condensation with the pending
methyl esters in the same reaction flask to give the dimeric
diketopiperazine 22 in 91% yield. The successful prepara-
tion of 22 showed the viability of our synthetic plan, which
led to the synthesis of the bispyrrolidinoindoline diketopi-
With the selenides in hand, we tried the crucial homodi-
merization in the presence of hexaalkyldistannanes and pho-
tochemical initiation. The expected bispyrrolidinoindoline
16b was obtained in 30% yield (22% yield for 16a) under
the best determined conditions (450 W medium-pressure Hg
lamp, 50 mol% nBu6Sn2, 0.3m in toluene, sealed tube). At-
tempts to improve these yields by using a wide range of re-
action conditions proved unfruitful. Besides the desired
dimer, in all cases, we observed the formation of reduction
product 17 (ꢀ30% yield under the optimized conditions)
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Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids
FULL PAPER
remarkably upfield signal at a
chemical shift of 3.1 ppm,
whereas the exo isomer shows a
more-common resonance at ap-
proximately 3.7 ppm. As ob-
served for the selenocyclization,
the exo product 23 was largely
the major one, in a 96/4 ratio.
Upon treating bromide 23
bearing two tert-butyl carba-
mate groups with [CoCl-
AHCTUNGTRENNUNG
(PPh3)3][17] in acetone at 258C
(Scheme 7) according to Mo-
vassaghiꢀs conditions,[15] bispyr-
rolidinoindoline 16a was ob-
tained in 54% yield along with
Scheme 5. Construction of the diketopiperazine rings.
perazine in only six steps from the initial tryptophan deriva-
tive.
Second-generation synthesis: Although this work was ongo-
ing, Movassaghi and Schmidt reported an elegant and highly
concise synthesis of the calycanthaceous alkaloids (À)-caly-
canthine, (+)-chimonanthine, and (+)-folicanthine utilizing
the CoI-mediated dimerization of a C3a-bromo-hexahydro-
pyrroloindole as the key step.[15] Analogous dimerizations of
alkyl halides induced by CoI have been also reported by
Baldwin, Yamada and co-workers.[16] Given the good yields
of such dimerizations, we decided to undertake a straightfor-
ward synthesis of C3a-bromo-hexahydropyrroloACTHNUTRGENUG[N 2,3-b]in-
doles, which would be used as substrates in the dimerization
mediated by CoI as an alternative strategy to the low-yield-
ing photochemical dimerization of the seleno derivatives 14.
Guided by our computational studies on selenocyclization,
we assayed the bromocyclization of tryptophan derivatives
with N-bromo succinimide (NBS) under the same conditions
(1 equiv of PPTS, dichloromethane, 258C). According to the
DFT calculations, the mechanistic path computed for the ac-
tivation with the electrophilic bromine closely resembles the
pathway with selenium, which appears to be a good indica-
tion in favor of the feasibility of the reaction.[12] We were
pleased to confirm that the expected C3a-bromo-
Scheme 7. Preparation of the dimeric hexahydropyrroloindole core.
the reduction product 17a (15% yield, Scheme 4). Although
the mechanistic details for the CoI-induced dimerization
remain still unclear, the isolation of 17a as a by-product,
similar to the tin-induced photochemical dimerization, sup-
ports the hypothesis of a radical-mediated process.[15]
Movassaghiꢀs account also proved that the CoI dimeriza-
tion takes place with full retention of configuration as the
structure of the synthetic (+)-chimonantine prepared by
using the CoI-promoted dimerization was confirmed unam-
biguously by single-crystal X-ray analysis.[15] Encouraged by
these results, we directed our efforts towards the total syn-
thesis of (+)-WIN 64821 (1). For this purpose, we first ad-
dressed the stereochemistry of the fused diketopiperazine
rings, given the fact that the configuration at C2/C2’ in
dimer 16a was opposite to that of the one required for the
targeted natural product 1. To set the right configuration at
C2/C2’, we took full advantage of the thermodynamic pref-
hexahydropyrroloACHTUNGTRENNUNG[2,3-b]indole was obtained in good yields
and excellent diastereoselectivities (Scheme 6). The exo/
1
endo ratio was readily established by H NMR spectroscopy
(when possible) owing to the characteristic methyl ester res-
onance of both diastereoisomers. The endo isomer shows a
erence of exo-2-acyl hexahydropyrroloACTHNUTRGNEUNG[2,3-b]indoles to place
the acyl group at the endo position under basic equilibrating
conditions.[11] This striking bias for the endo isomer, which
has been attributed to torsional interactions around the
bicyclo
bility to our methodology. Thus, treatment of the exo dimer
[3.3.0]octane nucleus,[18] provided a significant flexi-
ACHTUNGTRENNUNG
Scheme 6. Bromocyclization of 13 to pyrrolidinoindoline. NBS=N-
bromo succinimide.
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ꢃ. R. de Lera et al.
16a with 4 equivalents of lithium bis(trimethylsilyl)amide
(LiHMDS) at À158C in THF, followed by quenching of the
corresponding lithium enolates with MeOH at À788C, af-
forded the diastereomeric endo dimer 25 in almost quantita-
tive yield (Scheme 7). The use of just 2 or 3 equivalents of
base led to incomplete conversions. Subsequent cleavage of
the four N-BOC groups (93% yield) was performed with
TMSI in acetonitrile at 08C.[19]
The two-fold coupling of 26 with N-Cbz-l-phenylalanine
27[20] was successfully carried out in the presence of HATU
and Et3N in DMF to give the tetrapeptide 28. This was puri-
fied but not characterized owing to the typical NMR spec-
troscopic line broadening showed by this type of peptides.
However, the ensuing hydrogenolysis of the N-Cbz protect-
ing groups catalyzed by Pd/C in MeOH provided the di-
stereochemistry of the diketopiperazine ring). Heating at
reflux in acetonitrile, even with microwave irradiation, did
not take the reaction to completion. Basic conditions
(Et2NH in MeOH, 258C) led to the degradation of the start-
ing material. Finally, the ring closure was efficiently effected
by heating neat 29 for 15 min at 1808C to afford the target
compound 1 in 95% yield. The spectroscopic data and the
specific rotation ([a]D20 +2278 (c 0.15, MeOH); lit.: [a]D
+2008 (c 0.15, MeOH) of the synthetic (+)-WIN 64821 (1)
were in agreement with those published for the natural pro-
duct.[2a] Additionally, the C15/C15’-epimeric-WIN 64821 32
was readily synthesized from the tetraamine 26 and d-phe-
nylalanine. Alternatively, in this case, we used the commer-
cially available N-Fmoc-d-phenylalanine 30 (Fmoc=9-fluo-
renylmethyl carbamate) to check the scope of the HATU-
promoted peptide coupling. The replacement of the N-Cbz
protecting group by a more hindered Fmoc group did not
have a deleterious effect on the coupling. Subsequent Fmoc-
deprotection under basic conditions (Et2NH in MeOH at
258C) directly afforded the diketopiperazine 32 (73% yield
over the two steps, Scheme 8).
ACHTUNGTRENNUNGamine 29 (81% yield over the two steps), which was isolated
and characterized (Scheme 8). In contrast to the spontane-
Shortly after our synthesis of (+)-WIN 64821 had been
completed, Movassaghi et al. published an elegant first total
synthesis of the same alkaloid and (À)-ditryptophenaline 4
utilizing a late-stage dimerization promoted by [CoCl-
AHCTUNGTRENNUNG
(PPh3)3].[8] Despite the similarities, our approach offered
still some advantages, like the flexible construction of dike-
topiperazines 22, 1 and 32 from the common precursor 16
with an excellent stereochemical control. Furthermore, we
found that the early dimerization strategy could be success-
fully used in the synthesis of heterodimeric diketopiperazine
alkaloids such as (+)-WIN 64745 (2).
In the course of our investigations on the total synthesis
of 1, we observed that the best yields for the twofold cou-
pling between tetraamine 26 and N-Cbz-l-phenylalanine 27
required the use of 2.5-3 equivalents of 27; with just 2 equiv-
alents, the yields were lower and products with a single dike-
topiperazine ring were observed by mass spectrometry
(ESI+). We reasoned that the formation of the two peptide
bonds was not equally favorable and a sequential introduc-
tion of two different amino acids could be feasible. When 26
was treated with 1 equivalent of N-Cbz-l-leucine 33,[21]
1
equivalent of HATU, and 2 equivalents of Et3N in DMF at
258C, a mixture of the mono- and biscoupled products,
easily monitored by TLC, was obtained. With the aim of at-
taining greater selectivity, the coupling was assayed at lower
temperatures. We were pleased to observe the selective for-
mation of the monocoupled product at À158C. This out-
come might be caused by conformational changes induced
by the first peptide-bond formation that makes the second
condensation slower. To avoid unnecessary purification
steps, peptide 34 was not isolated, but treated instead with
1.2 equivalents of N-Cbz-l-phenylalanine 27 in the presence
of 1.2 equivalents of HATU and 2.4 equivalents of Et3N in
the same reaction flask to produce the heterodimeric tetra-
peptide 35 (Scheme 9). When the hydrogenolysis of 35 was
performed in a 9:1 MeOH/H2O mixture, the expected dia-
Scheme 8. Total synthesis of (+)-WIN 64821 (1) and C15/C15’-epi-
WIN 64821 (32). a) 27, HATU, Et3N, DMF, 258C. b) H2, Pd/C, MeOH,
258C, 81% (2 steps). c) 1808C, 15 min, 95%. d) 30, HATU, Et3N, DMF,
258C, e) Et2NH, MeOH, 258C, 73% (2 steps). Fmoc=9-fluorenylmethyl
carbamate, LiHMDS=lithium bis(trimethylsilyl)amide.
ous ring closure of deprotected 21 (Scheme 5), the amida-
tion reaction between the amino and the methyl ester
groups of 29 to form the diketopiperazines turned out to be
surprisingly more difficult (apparently owing to the different
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Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids
FULL PAPER
neat diamine at 1808C for
15 min (92% yield, Scheme 10).
Much to our surprise, compari-
son of the 1H and 13C NMR
spectra of 5 with the NMR
spectroscopic data reported[6]
showed that synthetic 5 was
similar, but not identical to the
natural product (see the Sup-
porting Information). More-
over, the specific rotation of
synthetic 5 ([a]2D3 À2908 (c=
0.004 in MeOH)) was far differ-
ent and of opposite sign to the
one reported for the natural al-
kaloid ([a]D +1328 (c=0.004 in
MeOH)). These discrepancies
between synthetic 5 and the
Scheme 9. Total synthesis of (+)-WIN 64745 (2).
mine 36 was obtained in a 74%
combined yield. The total syn-
thesis of (+)-WIN 64745 (2)
was completed upon heating
the neat diamine 36 at 1808C
for 15 min (95% yield). The ac-
complishment of the first total
synthesis of 2 was confirmed by
comparison with the spectro-
scopic data and the specific ro-
tation ([a]2D7 +3018 (c=0.012 in
MeOH); lit.: [a]D +2808 (c=
0.012 in MeOH)) reported for
an authentic sample of (+)-
WIN 64745.[2a]
Synthesis and structural revi-
sion of (+)-asperdimin: Given
Scheme 10. Synthesis of the proposed structure for (+)-asperdimin (5).
that the configuration of the
hexahydropyrrolo[2,3-b]indole
ACHTUNGTRENNUNG
ring fusion is conserved along
the dimerization process and that this can be traced back to
the configuration of the tryptophan derivative used in the
bromocyclization step, an additional benefit of this approach
is the easy entry into the two enantiomeric series of homo-
bispyrrolidinoindolines. The same sequence of reactions
starting from l-tryptophan readily provided the enantiomer-
ic tetraamine ent-26 in four steps. With the intermediate ent-
26 in hand, we addressed the total synthesis of the most
recent addition to this family of fungal alkaloids, the struc-
ture of which was reported as 5.[6] Thus, tetraamine ent-26
was sequentially coupled to the requisite amino acids N-
Cbz-d-leucine 37 (1 equiv, À158C) and N-Cbz-d-valine 38[22]
(1.2 equiv, 258C) in the presence of HATU and Et3N to give
the tetrapeptide 39. Subsequent cleavage of the N-Cbz
groups by Pd/C-catalyzed hydrogenolysis afforded the di-
natural compound prompted us to consider alternative
structures. Examination of the specific optical rotation data
of this family of dimeric alkaloids shows that the [a]D sign is
highly consistent with the configuration of the hexahydro-
pyrroloindole junction at C2/2’ and C3/3’. A positive [a]D
would indicate that the natural asperdimin has the same
configuration (R,R,R,R) at C2/2’ and C3/3’ than WIN 64821
1 and WIN 64745 2, but opposite to the series of ditrypto-
phenaline 4 and ent-1. The configuration at C15/15’ was
originally established by acidic hydrolysis of a sample of
(+)-asperdimin and comparison of the resulting amino acids
with valine and leucine standards following Marfeyꢀs
method.[23] According to this procedure, the natural product
contains d-valine and d-leucine at the diketopiperazine
rings.
A
We reasoned then that the C11/11’ configuration was the
key of the stereochemical puzzle, and decided to prepare
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ꢃ. R. de Lera et al.
figuration at C11/11’ was readi-
ly prepared in two steps from
the
tetraamine
endo
26
(Scheme 7). In an analogous
manner, 26 was coupled to N-
Fmoc-d-leucine 41 and N-
Fmoc-d-valine 42 before Fmoc-
deprotection and cyclization to
6. The spectroscopic data and
specific rotation ([a]2D0 +1468
(c=0.004 in MeOH); lit.:[6][a]D
+1328 (c=0.004 in MeOH) of
the synthetic sample more
closely matched those reported
for the natural product.[25] Al-
though the trans arrangement
of the diketopiperazine sub-
stituents had not been observed
previously in this type of
dimers, it is not uncommon
Scheme 11. Synthesis of the diastereoisomer 44.
within the cyclotryptACTHUNTGRENNGaU mine and
cyclotryptophan family of natu-
ral products:[1] asperazine[26] (46) and pestalazines[27] (47, 48)
(Scheme 13) exhibit this arrangement as well as the same
diastereomer 44 (Scheme 11) taking into account that the
substituents on the diketopiperazine rings are cis in all
known members of this family (ditryptophenaline 4,
WIN 64821 1). exo-Tetraamine 19 (Scheme 5) was sequen-
tially treated with N-Fmoc-d-leucine 41[24] and N-Fmoc-d-
valine 42 in the presence of HATU as a coupling agent and
Et3N in DMF to afford the tetrapeptide 43. Subsequent
Fmoc-deprotection by using Et2NH in MeOH was accompa-
nied by concomitant ring closure to produce the diketopi-
perazine 44 in 67% yield over the two steps. To our disap-
pointment, 44 did not match the natural product either, as
1
confirmed by examination of the H and 13C NMR spectra
(see the Supporting Information).
Scheme 13. Non-C3–C3’ connected cyclotryptamine–cyclotryptophan al-
kaloids.
At this point, we considered the reverse configuration at
the C11/11’ stereocenters. Given the versatility of our meth-
odology, diastereomer 6 (Scheme 12) with the opposite con-
configuration at the hexahydro-
pyrroloindole
junction
as
WIN 64821, verticillin A, and
asperdimin. To the best of our
knowledge (À)-ditryptophena-
line 4 remains the only member
of this dimeric alkaloid class
with the opposite configuration
(S,S,S,S) at the ring-fusion ste-
reocenters, an intriguing biosyn-
thetic signature for the produc-
ing species.
Conclusions
In summary, a versatile, concise,
and stereoselective approach to
Scheme 12. Total synthesis of (+)-asperdimin (6).
9934
www.chemeurj.org
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9928 – 9937

Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids
FULL PAPER
40 mL). The combined organic layers were washed with brine (2ꢆ
20 mL), dried over Na2SO4, and the solvents were removed under re-
duced pressure. The residue was purified by flash chromatography on
silica gel (70:30 hexane/EtOAc) to afford 155 mg (54% yield) of the title
compound as a white foam. [a]2D7 +1268 (c=0.19 in CHCl3). 1H NMR
(400 MHz, [D6]DMSO, 808C): d=7.4 (d, J=7.9 Hz, 2H, H7/H7’), 7.16 (t,
J=7.5 Hz, 2H, H6/H6’), 7.15 (d, J=7.6 Hz, 2H, H4/H4’), 6.91 (td, J=7.5,
0.9 Hz, 2H, H5/H5’), 6.08 (s, 2H, H8a/H8a’), 3.70 (dd, J=9.4, 7.0 Hz,
2H, H2/H2’), 3.67 (s, 6H, 2x CO2CH3), 2.65 (dd, J=12.6, 7.0 Hz, 2H,
H3A/H3A’), 2.24 (dd, J=12.6, 9.4 Hz, 2H, H3B/H3B’), 1.56 (s, 18H, 2x
CO2tBu), 1.32 ppm (br, 18H, 2xCO2tBu); 13C NMR (100 MHz,
[D6]DMSO, 808C): d=171.4 (s, 2xCO2CH3), 151.3 (s, 2xOCON), 150.5 (s,
2xOCON), 141.2 (s, C7a/C7a’), 130.3 (s, C3b/C3b’), 128.7 (d, C6/C6’),
123.5 (d, C4/C4’), 122.2 (d, C5/C5’), 115.9 (d, C7/C7’), 80.8 (s, 2xC-
homodimeric (C2 symmetry) and heterodimeric (C1 symme-
try) bispyrrolidinoindoline diketopiperazine alkaloids has
been demonstrated by using the highly diastereoselective
synthesis of
a C3a-bromo-hexahydropyrroloACHTUNTGRENUNG[2,3-b]indole
core and the subsequent CoI-induced dimerization to con-
À
struct the C3 C3’ central bond as key steps. Exerting con-
trol on peptide-bond construction before diketopiperazine
ring formation extends the method to the synthesis of the
C1-nonsymmetrical alkaloids by stepwise addition of the dif-
ferent amino acids that decorate the diketopiperazine fused
to the hexahydropyrrolo
epimerization of the exo- to the endo-C2-acyl-
hexahydropyrrolo[2,3-b]indole further expands the stereo-
ACHTUNGTRENN[UNG 2,3-b]indole core. The base-induced
ACHUNTGRENUN(G CH3)3), 80.0 (s, 2xCACHTUTGNERN(NUGN CH3)3), 78.6 (d, C8a/C8a’), 58.1 (s, C3a/C3a’), 57.7
(d, C2/C2’), 51.4 (q, 2x OCH3), 34.5 (t, C3/C3’), 27.4 (q, 2x CACHTUNGTRENNUNG(CH3)3),
ACHTUNGTRENNUNG
À
À
chemical diversification of the approach to the synthesis of
the C11/C11’ epimers. The natural products (+)-WIN 64821
1, (+)-WIN 64745 2, and (+)-asperdimin 6 and several ana-
logues have been synthesized in a highly efficient manner
according to this flexible strategy, which has additionally fa-
cilitated the structural revision of (+)-asperdimin. This revi-
sion reinforces the vital role that total synthesis continues to
play in determining the actual structures of natural prod-
ucts.[28]
27.3 ppm (q, 2x C
N
(2S,2’S,3aR,3a’R,8aS,8a’S)-2,3,2’,3’-Tetrahydro-[3a,3a’]biACTHUNTGRENNUG[pyrroloACHTUNGTRENNUNG[2,3-
b]indolyl]-1,2,8,1’,2’,8’-hexacarboxylic Acid 1,8,1’,8’-tetra-tert-butyl ester
2,2’-dimethyl ester (25): Lithium bis(trimethylsilyl)amide (1.0m in THF,
1.36 mL, 1.36 mmol, 4 equiv) was added dropwise to a stirred solution of
the dimer 16a (284 mg, 0.34 mmol) in THF at À158C. The mixture was
further stirred for 20 min, then cooled to À788C. MeOH (1.5 mL) was
added dropwise and the resulting solution was allowed to warm to room
temperature. A saturated NH4Cl aqueous solution (10 mL) was added
and the layers were separated. The aqueous layer was extracted with
AcOEt (2ꢆ10 mL) and the combined organic layers were washed with
brine (20 mL), dried over Na2SO4, and the solvents were removed under
reduced pressure. The residue was purified by flash chromatography on
silica gel (70:30 hexane/EtOAc) to afford 282 mg (99% yield) of the title
compound as a white foam. [a]2D4 +1058 (c=0.20 in CHCl3). 1H NMR
(400 MHz, CDCl3): d=7.4–7.2 (br, 2H, ArH), 7.07 (t, J=7.7 Hz, 2H,
ArH), 6.91 (d, J=7.4 Hz, 2H, ArH), 6.77 (t, J=7.4 Hz, 2H, ArH), 6.33
(s, 2H, H8a/H8a’), 4.49 (br s, 2H, H2/H2’), 3.02 (s, 6H, 2x CO2CH3), 2.50
(br s, 4H, H3A/H3B/H3A’/H3B’), 1.58 (s, 18H, 2x CO2tBu), 1.5–1.3 ppm
(br, 18H, 2x CO2tBu); 13C NMR (100 MHz, CDCl3): d=171.3 (s,
2xCO2CH3), 152.2 (s, 4xOCON), 143.5 (s, 2x), 130.4 (s, 2x), 129.6 (d, 2x),
Experimental Section
For full experimental details on the synthesis of 1, 2, 5, 22, 32, and 44,
the spectroscopic characterization of all compounds described in the text,
and copies of 1H and 13C NMR spectra, see the Supporting Information.
(2R,3aS,8aS)-3a-Bromo-2,3,3a,8a-tetrahydro-pyrroloACTHNUGRTENUNG[2,3-b]indole-1,2,8-
tricarboxylic acid 1,8-di-tert-butyl ester 2-methyl ester (23a): N-bromo-
succinimide (0.70 g, 3.90 mmol, 1 equiv) and pyridinium p-toluenesulfo-
nate (0.98 g, 3.90 mmol, 1 equiv) was added to a solution of the d-trypto-
phan derivative 12a (1.63 g, 3.90 mmol) in CH2Cl2 (33 mL) under argon.
The resulting yellow solution was stirred at 258C for 5 h. The mixture
was treated with a 10% NaHCO3 aqueous solution (20 mL) and a 10%
Na2S2O4 aqueous solution (20 mL). The organic layer was dried over
Na2SO4 and the solvents were removed under reduced pressure. The resi-
due was purified by flash chromatography (70:30 hexane/EtOAc) to
125.3 (d, 2x), 122.6 (d), 117.7 (d, 2x), 82.0 (s, 4xC
C8a’), 77.4 (d, C2/C2’), 59.1 (s, C3a/C3a’), 52.0 (q, 2x OCH3), 35.6 (t, C3/
C3’), 28.6 ppm (q, 4x C(CH3)3); IR (NaCl): n=2978 (m, C-H), 2932 (w,
ACHTUGNTRENUN(NG CH3)3), 79.2 (d, C8a/
C-H), 1759 (w, CO), 1713 (s, CO), 1481 (m), 1392 (m), 1367 (m), 1158
(s), 1016 (m), 857 (m), 752 cmÀ1 (s); MS (ESI+): m/z (%): 857 ([M+Na]+
, 70), 835 ([M+1]+, 100), 779 (12), 679 (17); HRMS (ESI+): m/z: calcd
for C44H59N4O12, 835.4124; found, 835.4109.
afford 1.648 g (85% yield) of the title compound as a white foam. [a]D27
+
1518 (c=0.39 in CHCl3). 1H NMR (400 MHz, CDCl3): d=7.7–7.3 (br,
1H, ArH), 7.3–7.2 (m, 2H, ArH), 7.04 (t, J=7.4 Hz, 1H, ArH), 6.32 (s,
1H, H8a), 3.81 (dd, J=10.2, 6.3 Hz, 1H, H2), 3.66 (s, 3H, CO2CH3), 3.13
(dd, J=12.6, 6.3 Hz, 1H, H3A), 2.74 (dd, J=12.6, 10.2 Hz, 1H, H3B),
1.55 (s, 9H, CO2tBu), 1.4–1.2 ppm (br, 9H, CO2tBu); 13C NMR
(100 MHz, CDCl3): d=171.7 (s, CO2CH3), 152.3 (s, 2xOCON), 141.7 (s),
133.0 (s), 130.8 (d), 124.6 (d), 123.4 (d), 118.8 (d), 84.0 (d, C8a), 82.4 (s,
(2S,2’S,3aR,3a’R,8aS,8a’S)-2,3,8,8a,2’,3’,8’,8a’-Octahydro-1H,1’H-
[3a,3a’]biACHTNUGTRENNUG[pyrroloACHTUNTGREN[NGUN 2,3-b]indolyl]-2,2’-dicarboxylic acid dimethyl ester
(26): Iodotrimethylsilane (77 mL, 0.54 mmol, 5.0 equiv) was added drop-
wise to a solution of the protected dimer 25 (90 mg, 0.11 mmol) in aceto-
nitrile (2.5 mL) at 08C. The resulting yellow solution was stirred at 08C
for 30 min. Polymer-bound benzyldiisopropylamine (50–90 mesh; Al-
drich, 210 mg) and then wet MeOH (3 mL) were added. The cooling
bath was removed and the suspension was stirred for 15 min. The resin
was filtered and washed with acetonitrile (10 mL) and MeOH (10 mL),
the solvents of the collected filtrate were removed under reduced pres-
sure and the residue was purified by flash chromatography on silica gel
(90:9.5:0.5 CH2Cl2/MeOH/Et3N) to afford 44 mg (93% yield) of the title
compound as a white solid. m.p. (CH2Cl2): 130–1338C. [a]2D0 +1398 (c=
0.16 in MeOH). 1H NMR (400 MHz, CD3OD): d=7.22 (d, J=7.3 Hz,
2H, H4/H4’), 7.06 (t, J=7.4 Hz, 2H, H6/H6’), 6.73 (t, J=7.3 Hz, 2H, H5/
H5’), 6.61 (d, J=7.4 Hz, 2H, H7/H7’), 4.78 (s, 2H, H8a/H8a’), 3.88 (dd,
J=6.0, 3.9 Hz, 2H, H2/H2’), 3.27 (s, 6H, 2x CO2CH3), 3.13 (dd, J=13.0,
6.0 Hz, 2H, H3A/H3A’), 2.56 ppm (d, J=13.0 Hz, 2H, H3B/H3B’);
13C NMR (100 MHz, CD3OD): d=175.3 (s, CO2CH3), 152.3 (s, C7a/C7a’),
130.8 (s, C3b/C3b’), 130.5 (d, C6/C6’), 127.3 (d, C4/C4’), 119.9 (d, C5/
C5’), 111.7 (d, C7/C7’), 82.1 (d, C8a/C8a’), 63.4 (s, C3a/C3a’), 61.0 (d, C2/
C2’), 52.9 (q, 2x OCH3), 39.3 ppm (t, C3/C3’); IR (NaCl): n=3383 (m,
CACHTUNGTRENNUNG(CH3)3), 81.6 (s, CACHTUNGTRENNUNG(CH3)3, 59.9 (s, C3a), 59.6 (d, C2), 52.5 (q, OCH3),
42.2 (t, C3), 28.2 (q, 3x, CACHTUNRTGENNU(G CH3)3), 28.1 ppm (q, CCAHTUNTGERN(NUGN CH3)3); IR (NaCl): n=
À
À
2978 (w, C H), 2932 (w, C H), 1752 (m, CO), 1715 (s, CO), 1604 (w),
1477 (m), 1330 (s), 1254 (m), 1153 (s), 848 (m), 749 cmÀ1 (s); MS (ESI+):
m/z (%): 521 ([M+Na]+ [81Br], 100), 519 ([M+Na]+ [79Br], 71), 387
(10), 385 (10), 339 (9), 283 (5); HRMS (ESI+): m/z: calcd for
C22H2981BrN2NaO6, 521.1080 and C22H2979BrN2NaO6, 519.1101; found,
521.1084 and 519.1102.
(2R,2’R,3aR,3a’R,8aS,8a’S)-2,3,2’,3’-Tetrahydro-[3a,3a’]biACTHUNTGRENNUG[pyrroloACHTUNTGREN[NUGN 2,3-
b]indolyl]-1,2,8,1’,2’,8’-hexacarboxylic acid 1,8,1’,8’-tetra-tert-butyl ester
2,2’-dimethyl ester (16a): Freshly prepared tris(triphenylphosphine)co-
ACHTUNGTRENNUNGbalt(I) chloride (791 mg, 0.90 mmol, 3 equiv) was added to a previously
degassed (N2 bubbling, 10 min) solution of bromide 23a (345 mg,
0.69 mmol) in freshly distilled acetone (6 mL) at 258C. The resulting blue
suspension was stirred for 20 min under an argon atmosphere. The mix-
ture was diluted with H2O (75 mL) and extracted with EtOAc (3ꢆ
Chem. Eur. J. 2009, 15, 9928 – 9937
ꢅ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9935

ꢃ. R. de Lera et al.
À
À
À
À
N H), 3280 (m, N H), 2979 (m, C H), 2947 (m, C H), 1731 (s, CO),
1604 (s), 1482 (s), 1468 (s), 1320 (m), 1240 (s), 1100 (m), 912 (m),
751 cmÀ1 (s); MS (ESI+): m/z (%): 457 ([M+Na]+, 6), 435 ([M+1]+,
100); HRMS (ESI+): m/z: calcd for C24H27N4O4, 435.2026; found,
435.2025.
Barrow, J. E. Brownell, A. Hong, A. M. Gillum, P. R. Houck, J.
AHCTUNGTRENNUNG ntibiot. 1994, 47, 391–398; e) C. J. Barrow, L. L. Musza, R.
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[4] a) H. Minato, M. Matsumoto, T. Katayama, J. Chem. Soc. Perkin
Trans. 1 1973, 1819–1825; b) H. Minato, M. Matsumoto, T. Kataya-
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[5] D. M. Gardiner, P. Waring, B. J. Howlett, Microbiology 2005, 151,
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[6] S. P. Ovenden, G. Sberna, R. M. Tait, H. G. Wildman, R. Patel, B.
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2093–2095.
[7] a) L. E. Overman, D. V. Paone, J. Am. Chem. Soc. 2001, 123, 9465–
9567. For structurally related alkaloids, see: b) L. E. Overman, D. V.
Paone, B. A. Stearns, J. Am. Chem. Soc. 1999, 121, 7702–7703;
c) L. E. Overman, J. F. Larrow, B. A. Stearns, J. M. Vance, Angew.
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[8] a) M. Movassaghi, M. A. Schmidt, J. A. Ashenhurst, Angew. Chem.
2008, 120, 1507–1509; Angew. Chem. Int. Ed. 2008, 47, 1485–1487;
b) (+)-11,11’-Dideoxyverticillin A has recently yielded to synthesis
by the same group using a short sequence which includes a radical-
based oxidation at the carbonyl Ca positions followed by trapping
of the acyliminium intermediates with trithiocarbonate, release of
the thiols and oxidation to give the epidithiodiketopiperazine rings,
see: J. Kim, J. A. Ashenhurst, M. Movassaghi, Science 2009, 324,
238–241.
(+)-Asperdimin (6): HATU (47 mg, 0.12 mmol) and Et3N (35 mL,
0.25 mmol, 2.0 equiv) were added to a solution of the tetraamine 26
(54 mg, 0.12 mmol) and N-Fmoc-d-leucine 41 (43 mg, 0.12 mmol) in
DMF (1.6 mL) and cooled to À158C. The reaction mixture was stirred at
À158C for 5 h, then allowed to reach 08C, and N-Fmoc-d-valine 42
(51 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol), and Et3N (43 mL,
0.31 mmol, 2.6 equiv) were added. The cooling bath was removed and
the mixture was further stirred for 14 h at 258C. The reaction was
quenched by the addition of H2O (10 mL) and extracted with EtOAc (3ꢆ
20 mL). The combined organic layers were washed with H2O (25 mL),
dried over Na2SO4 and the solvents were removed under reduced pres-
sure. The residue was purified by flash chromatography on silica gel
(95:5 CH2Cl2/MeOH) to give the coupled tetrapeptide, which was used
directly in the next step. Diethylamine (400 mL) was added to a solution
of the tetrapeptide 45 (120 mg) in MeOH (6 mL) and the mixture was
stirred for 6 h at 258C. The solvents were removed under reduced pres-
sure and the residue was purified by flash chromatography on silica gel
(95:5 CH2Cl2/MeOH) to afford 44 mg (64% combined yield over the two
steps) of the title compound as a white solid. m. p. (MeOH): 165–1698C.
[a]2D0 +1468 (c=0.004 in MeOH). 1H NMR (400 MHz, CD3OD): d=7.45
(dd, J=7.6, 2.5 Hz, 2H, H5/H5’), 7.2–7.1 (m, 2H, H7/H7’), 6.8–6.7 (m,
2H, H6/H6’), 6.66 (dd, J=7.9, 1.5 Hz, 2H, H8/H8’), 5.12 (s, 1H, H2),
5.02 (s, 1H, H2’), 4.26 (dd, J=8.9, 8.8 Hz, 1H, H11’), 4.24 (dd, J=8.9,
8.8 Hz, 1H, H11), 3.75 (dd, J=9.7, 5.1 Hz, 1H, H15’), 3.53 (d, J=5.6 Hz,
1H, H15), 3.28 (dd, J=14.0, 9.0 Hz, 1H, H12’), 3.3–3.2 (m, 2H, H12/
H12’), 2.75 (dd, 2H, J=14.2, 8.5 Hz, 1H, H12’), 2.59 (dd, J=14.1, 9.3 Hz,
1H, H12), 2.1–2.0 (m, 1H, H17), 1.7–1.6 (m, 1H, H18’), 1.5–1.4 (m, 1H,
H17’), 1.4–1.3 (m, 1H, H17’), 0.90 (d, J=7.2 Hz, 3H, H18), 0.88 (d, J=
6.7 Hz, 6H, H19’/H20’), 0.77 ppm (d, J=7.2 Hz, 3H, H18); 13C NMR
(100 MHz, CD3OD): d=171.4 (s, C13), 171.2 (s, C13’), 170.9 (s, C16’),
170.0 (s, C16), 150.5 (s, C9/C9’), 131.8 (s, C4), 131.7 (s, C4’), 130.7 (d, C7),
130.6 (d, C7’), 126.0 (d, C5), 125.9 (d, C5’), 120.4 (d, C6/C6’), 110.9 (d,
C8), 110.8 (d, C8’), 81.7 (d, C2’), 81.3 (d, C2), 64.4 (d, C15), 61.7 (s, C3/
C3’), 57.7 (d, C11), 57.5 (d, C11’), 57.2 (d, C15’), 42.5 (t, C17’), 38.8 (t,
C12), 37.9 (t, C12’), 34.0 (d, C17), 25.6 (d, C18’), 23.5 (q, C19’), 22.0 (q,
[9] C. Pꢁrez-Balado, A. R. de Lera, Org. Lett. 2008, 10, 3701–3704.
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2415–2417; b) S. V. Ley, E. Cleator, P. R. Hewitt, Org. Biomol.
Chem. 2003, 1, 3492–3494.
À
C20’), 19.6 (q, C19), 18.5 ppm (q, C18); IR (NaCl): n=3271 (br, w, N
À
À
À
H), 2958 (w, C H), 2928 (w, C H), 2871 (w, C H), 1667 (s, CO), 1606
(w), 1467 (m), 1430 (s), 1314 (m), 1255 (m), 1000 (m), 743 (m) cmÀ1; MS
(ESI+): m/z (%): 605 ([M+Na]+, 33), 583 ([M+H]+, 100); HRMS (ESI+
): m/z: calcd for C33H39N6O4, 583.3027; found, 583.3023.
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Acknowledgements
The authors are grateful to the European Union (EPITRON) and the
MEC-Spain (SAF2007–63880-FEDER) for financial support.
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9936
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Chem. Eur. J. 2009, 15, 9928 – 9937

Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids
FULL PAPER
[25] Unfortunately, we have been unable to obtain a sample or copies of
the spectra of the genuine natural product from the Meurer-Grimes
laboratory to compare the chromatographic and spectroscopic prop-
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Received: April 21, 2009
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Published online: August 13, 2009
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9937