A Unified Strategy to 6-5-6-5-6-Membered Epipolythiodiketopiperazines: Studies towards the Total Synthesis of Scabrosin Diacetate and Haematocin

Article abstract of DOI:10.1002/chem.201500918

The family of epipolythiodiketopiperazine (ETP) natural products consists of over 200 members possessing a wide diversity of structures and biological activity. Recently, the subgroup of 6-5-6-5-6-membered ETPs has gained substantial attention, which has

Full text of DOI:10.1002/chem.201500918

DOI: 10.1002/chem.201500918
Full Paper
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A Unified Strategy to 6–5–6–5–6-Membered
Epipolythiodiketopiperazines: Studies towards the Total Synthesis
of Scabrosin Diacetate and Haematocin
Hannes F. Zipfel and Erick M. Carreira*[a]
Abstract: The family of epipolythiodiketopiperazine (ETP)
natural products consists of over 200 members possessing
a wide diversity of structures and biological activity. Recently,
the subgroup of 6–5–6–5–6-membered ETPs has gained sub-
stantial attention, which has resulted in several total synthe-
ses. Despite all the efforts that have been invested into ac-
cessing these complex structures, no synthesis of scabrosin
diacetate (1a) and its related esters has been reported.
Herein, our attempts towards scabrosin diacetate (1a) and
haematocin (3) starting from diketopiperazine 12a as a late-
stage intermediate are presented. Diketopiperazine 12a can
be conveniently accessed in multigram quantities from alde-
hyde 18 and diketopiperazine 21 and was envisioned to
serve as a general platform for the synthesis of 6–5–6–5–6-
membered ETPs.
Introduction
The 2,5-diketopiperazine (2,5-DKP) scaffold is a privi-
leged structural motif found in numerous natural
products and therapeutic agents.[1] Epipolythiodiketo-
piperazines (ETPs) are 2,5-DKPs sulfenylated at the 3-
and 6-position (for selected examples, see Figure 1).
In the wake of the broad range of interesting biologi-
cal activities, ranging from anticancer and antiviral to
antifungal,[2] several syntheses of members from this
class of natural products have been reported since
the first isolation of an ETP, gliotoxin (4), in 1936.[2d,3]
The scabrosin esters (1a,b) were isolated in 1978
from the lichen Xanthoparmelia scabrosa by Elix and
Jones, but their original structural assignment (2) was
incorrect.[5] Twenty years later, Andersen reported the
isolation of ambewelamides A (1c) and B (1d) from
lichen of the Usnea species.[6] After this discovery, in
Figure 1. Selected ETPs.
1999, new efforts by Elix et al. resulted in structural
revision of the scabrosin esters based on multidimen-
sional NMR spectroscopic techniques and single-crystal X-ray
diffraction. These studies led to the conclusion that the ambe-
welamides (1c,d) and scabrosin esters (1a,b) are the same mo-
lecular entity.[7]
Catalytic generation of reactive oxygen species by redox cy-
cling, and mixed disulfide formation by thiol-disulfide ex-
change with cysteine residues of vital proteins.[2,4,8] Despite
their intriguing structural features and potent cytotoxicity, only
one synthetic study on the scabrosin esters has been reported
to date.[9]
The scabrosin esters display potent anticancer activity down
to the low nanomolar range.[6–8] Their high biological activity is
thought to be mediated mostly by two distinct mechanisms:
Biosynthetically, the ETPs are derived from aromatic amino
acids by oxidative dearomatization. The scabrosin esters (1)
have been proposed to arise from phenylalanine anhydride ep-
oxidation to give 8, followed by SN2’ epoxide opening
(Scheme 1). Further epoxidation, esterification, and sulfenyla-
tion is then thought to take place.[6] In contrast to this hypoth-
esis, recent insight into the biosynthesis of the related ETP ara-
notin showed that sulfur introduction takes place prior to the
[a] H. F. Zipfel, Prof. Dr. E. M. Carreira
Laboratorium für Organische Chemie
Eidgençssische Technische Hochschule Zürich
Vladimir-Prelog-Weg 3, 8093 Zürich (Switzerland)
E-mail: erickm.carreira@org.chem.ethz.ch
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500918.
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the condensation of 21 with (electron-poor) aromatic
aldehydes has been known since 1939, it was not
until 2000 that Loughlin reported its double conden-
sation with aliphatic aldehydes.[16b–e] Following this
strategy, we prepared alcohol 22 (Scheme 3). Howev-
er, oxidation to the corresponding aldehyde 18
under numerous conditions such as DMP,[17] PCC,[18]
PhI(OAc)2/TEMPO,[19] and Swern oxidation[20] failed.
After careful investigation, we found that the corre-
sponding aldehyde was unstable at ambient temper-
ature. Consequently, trapping of the transient alde-
hyde was attempted in situ at low temperature with
diketopiperazine 21 and base. In an initial attempt,
the use of NEt3 or tBuOK did not allow for any isola-
tion of the desired product 11. In the end, DBU was
Scheme 1. Proposed biosynthesis and our biomimetic approach to the scabrosin esters
(1).
initial arene epoxidation step.[10] This pathway may also be
possible for the scabrosin esters.
found to mediate both the Swern oxidation of 22 and the con-
densation of the transient aldehyde 18 with diketopiperazine
In addition to our efforts in using oxabicyclo[2.2.1]heptenes
as valuable intermediates in organic synthesis,[11,12a] we recently
reported a novel strategy to rapidly assemble functionalized 6–
5–6-fused and 6–5–6–5–6-fused diketopiperazines.[12b] Herein
we present our efforts towards synthesizing scabrosin diace-
tate (1a) and haematocin (3). The strategy relies on the previ-
ously established opening of the oxabicyclo[2.2.1]heptenes in
diketopiperazine 11. This reaction resembles the proposed bio-
synthetic pathway to the scabrosin esters in that the oxabicy-
clo[2.2.1]heptenes in intermediate 11 serve as surrogates for
the epoxybenzene moieties of diketopiperazine 8. The strategy
is different from previous approaches to construct 6–5–6–5–6-
fused ETP natural products,[3b–e] in that a two-directional ap-
proach is followed:[13] The core structure 9 is constructed first
and is then functionalized on both symmetry equivalent sides
of the molecule.
Results and Discussion
In a first generation synthetic approach we aimed at convert-
ing a-aminolactone 13 into the dimeric symmetrical diketopi-
perazine H4-11 (Scheme 2). Conditions known to be effective in
the formation of diketopiperazines were unsuccessful.[14] More-
over, the tendency of lactone 13 to cyclize rapidly after hydrol-
ysis or alcoholysis precluded the use of standard peptide cou-
pling techniques to access diketopiperazine H4-11. As an alter-
native, we envisioned using double alkylation of the bis(enola-
te)synthon 15 with electrophile 14.
Scheme 2. Retrosynthetic strategy towards key intermediate (H4)-12.
The use of epoxide 16 and bromide 17 as electrophilic com-
ponents was first investigated in the alkylation reaction with
Schçllkopf-type dihydropyrazine 19, N,N’-dibenzyl-diketopiper-
azine 20, and N,N’-diacetyldiketopiperazine 21 in the presence
or absence of Lewis acids.[15] Neither of the attempts showed
any trace of alkylated product H4-11. This might be due to the
high steric hindrance of alkylating agents 16 and 17, and as
a result, a more reactive electrophile was investigated.
Scheme 3. Synthesis of diketopiperazine 11:[12b] a) (COCl)2 (1.5 equiv), DMSO
(2.0 equiv), CH2Cl2, À788C; then 22 (1.0 equiv), 30 min; then 21 (0.38 equiv),
DBU (15 equiv), À78 to 08C, 2 d, 57% (based on 21); b) 2,6-lutidine
(8.0 equiv), TMSOTf (6.0 equiv), CH2Cl2, 0 to 238C, 16 h; then K2CO3
(8.0 equiv), MeOH/THF (4:1), 238C, 30 min, 77% (2 steps). DBU=1,8-diazabi-
cyclo[5.4.0]undec-7-ene; TMS=trimethyl-silyl; Tf=trifluoromethanesulfonyl.
We were intrigued by the findings of Loughlin et al. who re-
ported the potassium tert-butoxide mediated condensation of
N,N’-diacetyldiketopiperazine 21 with aliphatic aldehydes to
yield bis(alkylidene)diketopiperazine fragments.[16a] Although
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21. Hence, bis(alkylidene)diketopiperazine 11 could
be obtained in 57% yield and >20:1 diastereoselec-
tivity with respect to olefin geometrical isomers. The
transformation is believed to be initiated by addition
of the enolate of 21 to aldehyde 18 to give alkoxide
23. Acetyl migration furnishes 24 and elimination
completes the condensation process to give 11.
TMSOTf-mediated ring opening followed by in situ
silyl deprotection completed the synthesis of inter-
mediate 12a.
With the completed pentacyclic core 12a in hand,
the route to scabrosin diacetate (1a) called for
double epoxidation of the allylic alcohols. Subjection
of diketopiperazine 12a to [VO(acac)2]/tBuOOH lead
to complete decomposition of the starting material
and trace amounts of fully aromatized diketopipera-
zine 29 were identified in the mixture of products
(Scheme 4). Decomposition was also observed under
conditions of the Sharpless and Jacobsen epoxida-
tions as well as with peracids such as mCPBA or
AcOOH. Under buffered conditions (mCPBA/NaHCO3
or F3CCO3H/Na2HPO4) and neutral conditions (DMDO,
TFDO), competing oxidation of the dihydropyrrole
precluded the isolation of desired epoxide 25.
We believe that trace amounts of (Lewis)acid cata-
lyze the elimination of benzyl alcohol from 26 to give
protonated pyrrole 27. Proton loss followed by elimi-
nation then gives the fully aromatized diketopipera-
zine 29. In order to support this hypothesis, we treat-
ed pentacyclic intermediate 12a with 10 mol% of
MsOH in CH2Cl2 and indeed obtained the highly in-
soluble elimination product 29 in 94% yield.
Scheme 4. Attempted synthesis of bis(epoxide) 25: a) MsOH (10 mol%), CH2Cl2, 238C,
1 h, 94%; b) mCPBA (1.5 equiv), CH2Cl2, 238C, 16 h, 93%; c) COCl)2 (1.5 equiv), DMSO
(2.0 equiv), CH2Cl2, À788C; then 30 (1.0 equiv), 45 min; then 21 (0.4 equiv), DBU
(15 equiv), À78 to 238C, 16 h, 81% (based on 21); DMDO=dimethyldioxirane, Ms=me-
thanesulfonyl; mCPBA=3-chloroperoxybenzoic acid; DMSO=dimethylsulfoxide;
DBU=1,8-diaza-bicyclo[5.4.0]undec-7-ene.
Focus was therefore set onto introducing the epoxides at an
earlier stage of the synthesis: It was not possible to epoxidize
the bis(oxabicyclo[2.2.1]heptene) 11 to furnish heptacycle 31
directly (Scheme 4, bottom). The reason for this may be the
acid sensitivity of the alkylidenediketopiperazine, as was the
case for diketopiperazine 12a. Fortunately, it was feasible to
access the desired epoxide 31 in two steps by epoxidation of
alcohol 22 and subsequent subjection of alcohol 30 to the pre-
viously developed oxidation/condensation sequence with N,N’-
diacetyldiketopiperazine (21).
All attempts to employ the bis(epoxide) 31 in further trans-
formations to give the fully assembled 6–5–6–5–6-core of dike-
topiperazine 25 failed. Although competing epoxide opening
was anticipated under the ring-opening conditions, we found
that epoxide 31 did not undergo any reaction at all. Upon
heating of the reaction mixture, slow decomposition was ob-
served.
We subsequently examined a sequence involving allylic oxi-
dation and nucleophilic epoxidation of 12a (Scheme 5). Be-
cause of its acid sensitivity, we investigated the use of neutral
MnO2 for its oxidation to bis(enone) 32. The use of activated
MnO2 and short exposure to the oxidant were essential to
obtain good yields. Enone 32 was rather unstable and, there-
fore, used directly after its preparation in the following epoxi-
dation step. Initial attempts to epoxidize enone 32 under
Scheme 5. Attempted synthesis of bis(epoxide) 35: a) MnO2 (35 equiv),
238C, 30 min, 84%; b) tBuOOH (10 euqiv.), DBU (2.0 equiv), CH2Cl2, À508C,
90 min, 86%; c) H2, (1 bar) Pd/C (2.5 equiv), AcOEt, 238C, 30 min, 64%;
Ms=methanesulfonyl; Tf=trifluoromethanesulfonyl; DTBP=2,6-di-tert-bu-
tylpyridine; DIAD=diisopropyl azodicarboxylate; Burgess’ reagent=1-me-
thoxy-N-triethylammoniosulfonyl-methanimidate; Martin’s sulfurane=
bis[a,a-bis(trifluoromethyl)benzenemethanolato]diphenylsulfur; TFAA=tri-
fluoroacetic anhydride; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
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Weitz–Scheffer conditions (H2O2/NaOH)[21] or Meth–Cohnm
conditions (tBuOOH/nBuLi and Ph3COOH/KHMDS)[22] failed pos-
sibly because of the sensitivity of both 32 and 33 to base. An
organocatalytic approach reported by List et al.,[23] which was
anticipated to be less basic, did not give any of the desired
product. Eventually, treatment of enone 32 at À508C with
tBuOOH/DBU[24] and quenching of the mixture with acetic acid
at low temperature allowed the isolation of bis(epoxide) 33 in
86% yield. Single-crystal X-ray crystallographic analysis unam-
biguously confirmed the assignment of the structure.[25]
Subsequent hydrogenation of the double bonds with con-
comitant removal of the benzyl ethers to give diol 34 proved
to be troublesome. With catalytic amounts of hydrogenation
[28]
catalysts, such as Pd/C, Pd(OH)2/C,[26] Pd-black,[27] or Rh/Al2O3
in various solvents (AcOEt, MeOH, THF and AcOH) it was im-
possible to drive the reaction to full conversion—even under
increased pressure of hydrogen (up to 10 bar).[29] Transfer hy-
drogenation with different hydrogen sources, such as HCOO-
NH4,[30a] iPrOH,[30b] or 1,4-cyclohexadiene[30c] also failed to give
more than trace amounts of the desired product 34. In the
end, the use of 2.5 equivalents of Pd/C allowed for the selec-
tive conversion of benzyl ether 33 to bis(hydroxyketone) 34 in
64% yield.
Scheme 6. Synthesis of diol 38 and attempted elimination to diene 39:
a) LiHB(sBu)3 (4.0 equiv), THF, À788C, 10 min, 80%; b) BzCl (10 equiv), NEt3
(10 equiv), DMAP (10 equiv), CH2Cl2, 0 to 238C, 4 h, 98%; c) H2 (1 bar), Pd/C
(2.5 equiv), AcOEt, 238C, 2 h, 68%; Bz=benzoyl; DMAP=4-(dimethylamino)-
pyridine.
With key intermediate 34 in hand, elimination of
the tertiary alcohol was investigated. Dehydrations of
similar systems have previously been reported with
Al2O3/MgSO4 or Tf2O/DIPEA/DMAP.[31] With b-hydroxy-
ketone 34, however, these conditions as well as nu-
merous other elimination protocols investigated
mostly led to complete decomposition. Only in a few
cases, aromatization of the A-ring was observed by
Scheme 7. Retrosynthetic strategy towards haematocin (3).
analysis of the NMR spectra of the unpurified reac-
tion mixtures. This observation suggested that 33
was highly prone to further elimination. To avoid this
problem, an alternative strategy was attempted. Ketone reduc-
tion and protection of the resulting diol 36 gave benzoate 37
(Scheme 6). Then, debenzylation and hydrogenation of the
double bonds yielded diol 38. Yet again, under a variety of
conditions, elimination of the tertiary alcohols to give diene 39
was unsuccessful. This was observed independently of the
elimination mode (attempted syn- or anti-elimination and E1-
or E2-elimination conditions respectively). We reasoned that
ring strain in the A-rings of heptacycle 39 renders elimination
difficult.
yield. Single-crystal X-ray analysis unambiguously confirmed
the relative configuration of the product.[35] TBS-protection and
hydrogenation with excess Pd/C proceeded uneventfully to
yield bis(b-hydroxyketone) 43. In contrast to the unsuccessful
elimination of the tertiary alcohols in diol 34 (Scheme 5), the
dehydration of diol 43 proceeded smoothly at 08C and in
15 min with Martin’s sulfurane to give bis(enone) 40. The same
conditions only led to decomposed starting material in the
case of bis(epoxyketone) 34. This suggests the strained epox-
ides as the main reason for the failed dehydration.
After having developed a fast and scalable synthesis of ad-
vanced intermediate enone 32, we planned to use a similar
synthetic strategy to access the haematocin (3) core
(Scheme 7). Key intermediate 41 was first thought to be acces-
After the preparation of enone 40, we attempted to convert
it into bis(diene) 50 by means of deprotonation and trapping
of the kinetic enolate with Comins’ reagent[36a] or
(RO)2P(O)Cl[36b,c] followed by reductive defunctionalization. Sev-
eral bases such as LDA, LiHMDS, NaHMDS, and KHMDS with
and without solvent additives, such as HMPA or DMPU, were
examined, but none of the conditions successfully gave 45. In-
spired by the work of Corey, we tried to convert diketone 40
into silylenol ether 45c as a precursor for the corresponding
bis(vinyl triflate) 45a.[37] Utilizing Corey’s[38] internal quench
procedure (TBSCl and LDA) for silyl enol ether formation failed
to give any 45c. Treatment of 40 with TBSOTf and NEt3 yielded
exclusively the isomeric bis(enol ether) 44, which suggests that
[32a]
sible by reduction of bis(epoxyketone) 33, but neither SmI2
[32b,c]
nor (PhSe)2/NaBH4
gave diol 41 (Scheme 8). In the former
case, SmI2 also led to partial reduction of the enamides and
gave a complex mixture of products.[33] In the latter case we
observed no reaction. We believe that steric hindrance renders
nucleophilic attack highly disfavored.
Bis(enone) 32 could be subjected to a sequence consisting
of Cu-catalyzed 1,4-borylation[34] and an oxidation of the inter-
mediate boronate with neutral H2O2 to give diol 41 in 61%
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Scheme 9. Attempted synthesis of tetraene 50: a) NaBH4 (5.0 equiv),
CeCl3·7H2O (6.0 equiv), MeOH, À78 to 08C, 85%; b) (CF3CO)2O (5.0 equiv),
NEt3 (10 equiv), CH2Cl2, 238C, 30 min; then [Pd(PPh3)4] (30 mol%), NEt3
(10 equiv), THF, 608C, 2 h, 43% (2 steps); c) 4-nitrobenzoic acid (6.0 equiv),
PPh3 (8.0 equiv), DIAD (6.0 equiv), CH2Cl2, 0 to 238C, 15 min, 56%; d) LiOH
(4.0 equiv), THF/MeOH (5:1), 238C, 10 min, 40%; DIAD=diisopropyl azodicar-
boxylate.
Scheme 8. Synthesis of diketone 40 and attempted conversion into tetraene
50: a) B2pin2 (2.5 equiv), MeOH (4.0 equiv), CuCl (20 mol%), (S)-BINAP
(20 mol%), tBuONa (20 mol%), THF, 1 h; then 30% H2O2 (20 equiv), THF, 3 h,
61%; b) TBSOTf (4.0 equiv), 2,6-lutidine (6.0 equiv), CH2Cl2, 0 to 238C, 1 h,
62%; c) H2 (1 bar), Pd/C (2.0 equiv), AcOEt, 238C, 1 h, 67%; d) Martin’s sulfu-
rane (2.2 equiv), CH2Cl2, À78 to 08C, 15 min, 74%; LDA=lithium diisopropyl-
amide; HMDS=bis(trimethylsilyl)amide; Tf=trifluoromethane-sulfonyl;
B2pin2 =bis(pinacolato)diboron; BINAP=2,2’-bis(diphenylphosphino)-1,1’-bi-
naphthyl, Martin’s sulfurane=bis[a,a-bis(trifluoromethyl)benzenemethanola-
to]diphenylsulfur.
The key bidirectional opening of bis(oxabicyclo[2.2.1]heptane)
11 enabled the rapid construction of the bis(tetrahydroindole)
core 12a and simultaneously installed the functional groups
necessary for further elaboration. Although it was not possible
to transform the late-stage intermediate 12a into either scab-
rosin diacetate (1a) or haematocin (3), it was possible to
access a wide diversity of functionalized 6–5–6–5–6-membered
diketopiperazines. These results should encourage the future
use of this strategy to access highly functionalized diketopiper-
azines for SAR studies or natural products synthesis.
deprotonation at the g-position is favored under these condi-
tions.
Additionally, we have reported the first detailed study to-
wards scabrosin diacete (1a), an ETP natural product that has
not been synthesized previously despite considerable efforts
towards the total syntheses of other family members. The re-
sults presented herein provide insight that should be helpful
in devising synthetic strategies.
Inspired by Nicolaou’s synthesis of haematocin (3),[3e] we ex-
plored accessing diene 50 by Luche-reduction of the bis(e-
none) 40 followed by palladium-catalyzed elimination of the
corresponding bis(trifluoroacetate) (Scheme 9). Accordingly, re-
duction of enone 40 gave diol 46 in 85% yield; however, tri-
fluoroacetylation followed by treatment with [Pd(PPh3)4] and
NEt3 exclusively produced tetraene 47 instead of 50. Moreover,
direct elimination of the hydroxyl groups of 46 with Burgess’
reagent also resulted in formation of 47.
Acknowledgements
We are grateful to Dr. M. D. Wçrle, Dr. N. Trapp and M. Solar
for X-ray crystallographic analysis of compounds 33 and 41,
and to Dr. M.-O. Ebert, R. Arnold, R. Frankenstein and P. Zum-
brunnen for NMR spectroscopic measurements. H.F.Z. grateful-
ly acknowledges the Fonds der Chemischen Industrie for sup-
port (KØkule-Stipendium).
The same results were obtained when the configuration at
C6 and C6’ was inverted by use of Mitsunobu reaction to give
48: If nitrobenzoate 48 was subjected to NEt3/[Pd(PPh3)4] or if
alcohol 49 was treated with Burgess’ reagent we could only
obtain small amounts of tetraene 47 instead of 50. These ob-
servations suggest that formation of the desired cyclohexa-1,3-
diene motif of pentacycle 50 is kinetically unfavored.
Keywords: amides
·
epipolythiodiketopiperazines
·
epoxidation · haematocin · scabrosin diacetate
Conclusion
[1] A. D. Borthwick, Chem. Rev. 2012, 112, 3641–3716.
[2] a) P. Waring, R. D. Eichner, A. Müllbacher, Med. Res. Rev. 1988, 8, 499–
524; b) P. Waring, J. Beaver, Gen. Pharmacol. 1996, 27, 1311–1316;
c) D. M. Gardiner, P. Waring, B. J. Howlett, Microbiology 2005, 151, 1021–
In summary, we have devised a concise and scalable route to
the core structure of 6–5–6–5–6-fused ETP natural products.
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1032; d) T. R. Welch, R. M. Williams, Nat. Prod. Rep. 2014, 31, 1376–
1404.
[16] First report of a double condensation of aliphatic aldehydes with N,N’-
diacetyldiketopiperazine (21): a) W. A. Loughlin, R. L. Marshall, A. Car-
reiro, K. E. Elson, Bioorg. Med. Chem. Lett. 2000, 10, 91–94; representa-
tive examples of condensations of 21 with aromatic aldehydes: b) A. R.
Katritzky, W.-Q. Fan, M. Szajda, Q.-L. Li, K. C. Caster, J. Heterocycl. Chem.
1988, 25, 591–597; c) L. X. Wang, Y. Z. Shi, M. H. Xu, H. W. Hu, Org. Prep.
Proced. Int. 1996, 28, 226–230; d) M. L. Bolognesi, H. N. A. Tran, M. Sta-
[3] Review: a) E. Iwasa, Y. Hamashima, M. Sodeoka, Isr. J. Chem. 2011, 51,
420–433; selected syntheses of 6–5–6–5–6-membered epipolythiodi-
ketopiperazines: b) K. C. Nicolaou, S. Totokotsopoulos, D. Gigu›re, Y.-P.
Sun, D. Sarlah, J. Am. Chem. Soc. 2011, 133, 8150–8153; c) J. A. Codelli,
A. L. A. Puchlopek, S. E. Reisman, J. Am. Chem. Soc. 2012, 134, 1930–
1933; d) H. Fujiwara, T. Kurogi, S. Okaya, K. Okano, H. Tokuyama, Angew.
Chem. Int. Ed. 2012, 51, 13062–13065; Angew. Chem. 2012, 124, 13239–
13242; e) K. C. Nicolaou, M. Lu, S. Totokotsopoulos, P. Heretsch, D. Gi-
gu›re, Y.-P. Sun, D. Sarlah, T. H. Nguyen, I. C. Wolf, D. F. Smee, C. W. Day,
S. Bopp, E. A. Winzeler, J. Am. Chem. Soc. 2012, 134, 17320–17332.
[4] a) R. Munday, Chem.-Biol. Interact. 1982, 41, 361–374; b) R. Munday, J.
Appl. Toxicol. 1987, 7, 17–22; c) C. L. L. Chai, G. A. Heath, P. B. Huleatt,
G. A. O’Shea, J. Chem. Soc. Perkin Trans. 2 1999, 389–391; d) C. L. L.
Chai, P. Waring, Redox Rep. 2000, 5, 257–264; e) A. M. Hurne, C. L. L.
Chai, P. Waring, J. Biol. Chem. 2000, 275, 25202–25206; f) P. H. Bernardo,
C. L. L. Chai, G. J. Deeble, X.-M. Liu, P. Waring, Bioorg. Med. Chem. Lett.
2001, 11, 483–485; g) P. H. Bernardo, N. Brasch, C. L. L. Chai, P. Waring,
J. Biol. Chem. 2003, 278, 46549–46555.
ˇ
derini, A. Monaco, A. López-Cobenas, S. Bongarzone, X. BiarnØs, P.
López-Alvarado, N. Cabezas, M. Caramelli, P. Carloni, J. C. MenØndez, G.
Legname, ChemMedChem 2010, 5, 1324–1334.
[17] a) B. D. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156; b) B. D.
Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277–7278.
[18] E. J. Corey, G. Schmidt, Tetrahedron Lett. 1979, 20, 399–402.
[19] A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli, J. Org.
Chem. 1997, 62, 6974–6977.
[20] K. Omura, D. Swern, Tetrahedron 1978, 34, 1651–1660.
[21] E. Weitz, A. Scheffer, Chem. Ber. 1921, 54, 2327–2344.
[22] a) C. Clark, P. Hermans, O. Meth-Cohn, C. Moore, H. C. Taljaard, G. van
Vuuren, J. Chem. Soc. Chem. Commun. 1986, 1378–1380; b) O. Meth-
Cohn, C. Moore, H. C. Taljaard, J. Chem. Soc. Perkin Trans. 1 1988, 2663–
2674; c) P. L. Bailey, W. Clegg, R. F. W. Jackson, O. Meth-Cohn, J. Chem.
Soc. Perkin Trans. 1 1993, 343–350; for an example of the use of
Ph3COOK in the Meth—Cohn epoxidation: d) C. Li, R. P. Johnson, J. A.
Porco, Jr., J. Am. Chem. Soc. 2003, 125, 5095–5106.
[5] W. R. Begg, J. A. Elix, A. J. Jones, Tetrahedron Lett. 1978, 19, 1047–1050.
[6] D. E. Williams, K. Bombuwala, E. Lobkovsky, E. D. de Silva, V. Karunar-
atne, T. M. Allen, J. Clardy, R. J. Andersen, Tetrahedron Lett. 1998, 39,
9579–9582.
[7] M. A. Ernst-Russell, C. L. L. Chai, A. M. Hurne, P. Waring, D. C. R. Hockless,
J. A. Elix, Aust. J. Chem. 1999, 52, 279–283.
[23] X. Wang, C. M. Reisinger, B. List, J. Am. Chem. Soc. 2008, 130, 6070–
6071.
[8] C. L. L. Chai, J. A. Elix, P. B. Huleatt, P. Waring, Bioorg. Med. Chem. 2004,
12, 5991–5995.
[9] M. D. Middleton, B. P. Peppers, S. T. Diver, Tetrahedron 2006, 62, 10528–
10540.
[10] C.-J. Guo, H.-H. Yeh, Y.-M. Chiang, J. F. Sanchez, S.-L. Chang, K. S. Bruno,
C. C. C. Wang, J. Am. Chem. Soc. 2013, 135, 7205–7213.
[24] V. K. Yadav, K. K. Kapoor, Tetrahedron 1995, 51, 8573–8584.
[25] CCDC-1045963 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_re-
quest/cif.
[26] W. M. Pearlman, Tetrahedron Lett. 1967, 8, 1663–1664.
[27] For an example of the use of Pd-black in the hydrogenolysis of
a benzyl ether, see: A. J. Pallenberg, Tetrahedron Lett. 1992, 33, 7693–
7696.
[28] For an example of the use of Rh/Al2O3 in the hydrogenolysis of
a benzyl ether, see: Y. Oikawa, T. Tanaka, O. Yonemitsu, Tetrahedron Lett.
1986, 27, 3647–3650.
[29] S. Hawker, M. A. Bhatti, K. G. Griffin, Chim. Oggi 1992, 10, 49.
[30] a) T. Bieg, W. Szeja, Synthesis 1985, 76–77; b) M. Del Carmen Cruzado,
M. Martín-Lomas, Tetrahedron Lett. 1986, 27, 2497–2500; c) A. M. Felix,
E. P. Heimer, T. J. Lambros, C. Tzougraki, J. Meienhofer, J. Org. Chem.
1978, 43, 4194–4196.
[31] a) D. Menberu, K. D. Onan, P. W. Le Quesne, J. Org. Chem. 1992, 57,
2100–2104; b) M. T. Barros, C. D. Maycock, M. R. Ventura, Tetrahedron
1999, 55, 3233–3244.
[32] a) G. A. Molander, G. Hahn, J. Org. Chem. 1986, 51, 2596–2599; b) M.
Miyashita, T. Suzuki, A. Yoshikoshi, Tetrahedron Lett. 1987, 28, 4293–
4296; c) M. Miyashita, T. Suzuki, M. Hoshino, A. Yoshikoshi, Tetrahedron
1997, 53, 12469–12486.
[33] The reduction of alkylidenediketopiperazines with SmI2 has been re-
ported previously: S. G. Davies, H. Rodríguez-Solla, J. A. Tamayo, A. R.
Cowley, C. Concellón, A. C. Garner, A. L. Parkes, A. D. Smith, Org. Biomol.
Chem. 2005, 3, 1435–1447.
[34] X. Feng, J. Yun, Chem. Commun. 2009, 6577–6579.
[35] CCDC-1045964 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.
[11] Review: a) C. S. Schindler, E. M. Carreira, Chem. Soc. Rev. 2009, 38, 3222–
3241; b) C. S. Schindler, C. R. J. Stephenson, E. M. Carreira, Angew. Chem.
Int. Ed. 2008, 47, 8852–8855; Angew. Chem. 2008, 120, 8984–8987; c) S.
Diethelm, C. S. Schindler, E. M. Carreira, Org. Lett. 2010, 12, 3950–3953;
d) C. S. Schindler, L. Bertschi, E. M. Carreira, Angew. Chem. Int. Ed. 2010,
49, 9229–9232; Angew. Chem. 2010, 122, 9415–9418; e) S. Diethelm,
C. S. Schindler, E. M. Carreira, Chem. Eur. J. 2014, 20, 6071–6080.
[12] a) C. S. Schindler, S. Diethelm, E. M. Carreira, Angew. Chem. Int. Ed. 2009,
48, 6296–6299; Angew. Chem. 2009, 121, 6414–6417; b) H. F. Zipfel,
E. M. Carreira, Org. Lett. 2014, 16, 2854–2857.
[13] For an overview over two-directional syntheses of natural products,
see: a) C. S. Poss, S. L. Schreiber, Acc. Chem. Res. 1994, 27, 9–17; b) S. R.
Magnuson, Tetrahedron 1995, 51, 2167–2213; c) M. Vrettou, A. A. Gray,
A. R. E. Brewer, A. G. M. Barrett, Tetrahedron 2007, 63, 1487–1536.
[14] a) H. T. Openshaw, N. Whittaker, J. Chem. Soc. C 1969, 89–91; b) K.-W.
Yang, J. G. Cannon, J. G. Rose, Tetrahedron Lett. 1970, 11, 1791–1794;
c) B. Singh, Tetrahedron Lett. 1971, 12, 321–322; d) H. Yazawa, K.
Tanaka, K. Kariyone, Tetrahedron Lett. 1974, 15, 3995–3996; e) A. Basha,
M. Lipton, S. M. Weinreb, Tetrahedron Lett. 1977, 18, 4171–4174; f) W.
ˇ
Liu, D. D. Xu, O. Repic, T. J. Blacklock, Tetrahedron Lett. 2001, 42, 2439–
2441; g) C. Han, J. P. Lee, E. Lobkovsky, J. A. Porco, Jr., J. Am. Chem. Soc.
2005, 127, 10039–10044; h) T. Ohshima, Y. Hayashi, K. Agura, Y. Fujii, A.
Yoshiyama, K. Mashima, Chem. Commun. 2012, 48, 5434–5436; i) H.
Morimoto, R. Fujiwara, Y. Shimizu, K. Morisaki, T. Ohshima, Org. Lett.
2014, 16, 2018–2021.
[15] Alkylation of Schçllkopf-type dihydropyrazines with epoxides: a) K.
Hammer, C. Rømming, K. Undheim, Tetrahedron 1998, 54, 10837–
10850; b) K. Hammer, K. Undheim, Tetrahedron: Asymmetry 1998, 9,
2359–2368; c) M. Andrei, K. Undheim, Tetrahedron: Asymmetry 2004,
15, 53–63; d) M. Andrei, J. Efskind, T. Viljugrein, C. Rømming, K. Un-
dheim, Tetrahedron: Asymmetry 2004, 15, 1301–1313; e) E. P. Jones, P.
Jones, A. J. P. White, A. G. M. Barrett, Beilstein J. Org. Chem. 2011, 7,
1570–1576; alkylations of N-protected 2,5-diketopiperazines with epox-
ides: f) R. M. Williams, J.-S. Dung, J. Josey, R. W. Armstrong, H. Meyers, J.
Am. Chem. Soc. 1983, 105, 3214–3220; g) R. M. Williams, L. K. Maruya-
ma, J. Org. Chem. 1987, 52, 4044–4047; alkylation of Schçllkopf-type di-
hydropyrazines: h) U. Schçllkopf, U. Groth, C. Deng, Angew. Chem. Int.
Ed. Engl. 1981, 20, 798–799; Angew. Chem. 1981, 93, 793–795.
[36] a) D. L. Comins, A. Dehghani, Tetrahedron Lett. 1992, 33, 6299–6302;
b) T. Hayashi, T. Fujiwa, Y. Okamoto, Y. Katsuro, M. Kumada, Synthesis
1981, 1001–1003; c) K. C. Nicolaou, R. Yu, L. Shi, Q. Cai, M. Lu, P.
Heretsch, Org. Lett. 2013, 15, 1994–1997.
[37] Y. Mi, J. V. Schreiber, E. J. Corey, J. Am. Chem. Soc. 2002, 124, 11290–
11291.
[38] E. J. Corey, A. W. Gross, Tetrahedron Lett. 1984, 25, 495–498.
Received: March 7, 2015
Published online on July 14, 2015
Chem. Eur. J. 2015, 21, 12475 – 12480
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