An efficient synthesis strategy to the core structure of 6-5-6-5-6-membered epipolythiodiketopiperazines

Article abstract of DOI:10.1021/ol500990f

A concise route to the core structure 1 of 6-5-6-5-6-membered epipolythiodiketopiperazines is described. The strategy relies on construction of the pyrrolines by double nucleophilic opening of a bis(oxabicyclo[2.2.1] heptene) 2, obtained after bidirectional condensation of N,N′- diacetyldiketopiperazine (4) with aldehyde 3.

Full text of DOI:10.1021/ol500990f

Letter
pubs.acs.org/OrgLett
An Efficient Synthesis Strategy to the Core Structure of 6−5−6−5−6-
Membered Epipolythiodiketopiperazines
Hannes F. Zipfel and Erick M. Carreira*
Laboratorium fur Organische Chemie, Eidgenossische Technische Hochschule Zurich, CH-8093 Zurich, Switzerland
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̈
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̈
S
* Supporting Information
ABSTRACT: A concise route to the core structure 1 of 6−5−6−5−6-membered epipolythiodiketopiperazines is described. The
strategy relies on construction of the pyrrolines by double nucleophilic opening of a bis(oxabicyclo[2.2.1]heptene) 2, obtained
after bidirectional condensation of N,N′-diacetyldiketopiperazine (4) with aldehyde 3.
he 2,5-diketopiperazine structural motif is found in a wide
the embedded fused pyrrolidines. Herein, we document the
realization of such an approach which demonstrates an efficient
entry into the full core structure of 6-5-6-5-6-membered ETPs.
The modular approach of this strategy also enables access to
analogues of ETP natural products, which are of interest in the
context of SAR studies.6
Diketopiperazine 1 was chosen as a target compound on which
to examine the viability of the synthetic strategy, as it would
enable late-stage diversification into a wide series of ETP natural
and non-natural products (Scheme 2). In this approach, 1 was
1
Tvariety of natural products and therapeutic agents. Among
the myriad of natural products constructed around this core, the
6−5−6−5−6- and 7−5−6−5−7-membered epipolythiodiketo-
piperazines (ETPs) are particularly intriguing. Their structural
complexity along with their anticancer, antiviral, and antifungal
activity provide compelling reasons for considerable interest in
this class of natural products (Scheme 1).2,3
Scheme 1. Strategies towards 6−5−6−5−6-Membered
Epipolythiodiketopiperazines
Scheme 2. Retrosynthetic Strategy
envisioned to be accessible by Lewis acid-mediated nucleophilic
opening of the bis(oxabicyclo[2.2.1]heptene) 2 using methods
recently developed in our group.7,8 Cyclization precursor 2 was
disconnected to diketopiperazine 4 and α-oxygenated aldehyde
3.
Oxabicyclic α-oxygenated aldehydes such as 3 have not been
subjected to study; in fact, to the best of our knowledge, there is
only one reported synthesis of such a compound.9a Initial
thoughts on the preparation of endo-aldehyde 3 by Diels−Alder-
The published syntheses of members of this hexacyclic
subgroup are characterized by late-stage assembly of a central
diketopiperazine core.3 We became interested in examining an
alternative approach in which the unsubstituted diketopiperazine
9 serves as a preassembled linchpin. In such a strategy,
installation of the C3 and C6 substituents and subsequent
bidirectional ring-forming reactions would allow rapid access to
Received: April 4, 2014
© XXXX American Chemical Society
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Letter
cycloaddition of an α-oxygenated acrolein derivative were set
aside, because furan Diels−Alder reactions are generally known
to have varying degrees of exo-selectivity.10 In addition, the Lewis
acid catalyzed reaction of α-silyloxy acrolein derivatives with
furan furnishes (4 + 3)-, rather than (4 + 2)-cycloadducts.9b−e
We were intrigued by the findings of Corey and Loh who
prepared diol 14 starting from bromoacrolein 11 (Scheme 3).11
corresponding alcohol 13 could thus be obtained in 85% ee,
which was determined by conversion to its benzoate and analysis
by SFC on a chiral stationary phase. Recrystallization from
ether−pentane furnished material in 60% overall yield and
98% ee.
Treatment of 13 with K2CO3 in dioxane−H2O yielded diol 14.
Upon scale-up of the reported procedure, reaction time and yield
were found to be highly variable, presumably due to the biphasic
reaction mixture. It was found that addition of 2.0 mol % of
18‑crown-6 as a phase transfer catalyst allowed the reaction to
proceed reliably within 20 h and in 83% yield. Selective
protection of the tertiary alcohol was then achieved by formation
of the benzylidene acetal followed by one-pot reduction with
DIBAL-H to give alcohol 15. This route enabled the preparation
of more than 20 g of alcohol 15 in a single batch.
Scheme 3. Synthesis of Alcohol 15
All attempts to isolate sensitive aldehyde 3 failed under a
variety of oxidation conditions. Presumably, its instability arises
from its tendency to undergo a retro-Diels−Alder reaction.15 In
order to circumvent this issue, we trapped aldehyde 3 in situ and
at low temperature by condensation with diketopiperazine 4
(Scheme 5).16 Swern oxidation of alcohol 15 yielded aldehyde 3
Scheme 5. Synthesis of Cyclization Precursor 2
In their key step, the Diels−Alder cycloaddition reaction of
bromoacrolein 11 with furan, 10 mol % of oxazaborolidinone 16
were used to prepare α-bromoaldehyde 12. Inspired by this
direct approach, we decided to thoroughly examine the entire
reaction sequence in the context of scalability as well as the
transformation of diol 14 into aldehyde 3.
Catalyst precursor 18 was easily prepared in two steps from
known β-methyltyrosine ethyl ester 17 which can be prepared as
either enantiomer in four steps from indole (Scheme 4).12
Scheme 4. Synthesis of Catalyst 16
at −78 °C, which was directly subjected to condensation with
N,N′-diacetyldiketopiperazine (4) to give olefin 19 in 79% yield.
A second condensation with in situ prepared aldehyde 3 then
yielded the desired cyclization precursor 2 in 47% yield over two
steps. In the optimized procedure, the reaction sequence was
performed in a one-pot operation by Swern oxidation of 2.6
equiv of alcohol 15 followed by the addition of one equivalent of
diketopiperazine 4 to give bis(alkylidene)diketopiperazine 2 in
an improved 57% yield. Careful control of the reaction
temperature throughout the sequence was crucial in order to
obtain high yields without decomposition of the sensitive
aldehyde 3.15 Initial attempts with an SiMe2t-Bu protected
tertiary alcohol instead of a benzyl protecting group only gave a
monocondensed product, and when reaction times were
prolonged only decomposition was observed.
The next step in the desired reaction sequence was the double
intramolecular opening of the oxabicyclo[2.2.1]heptenes in 2
(Scheme 6). The transformation was found to proceed smoothly
under slightly modified conditions from those originally
reported, wherein triethyl amine was replaced with 2,6‑luti-
dine.7,8 The resulting silyl ether 20 was then directly deprotected
with K2CO3 in MeOH to give 1 in 77% yield over two steps. The
transformation proved to be robust and allowed the convenient
preparation of more than 5 g of 1 in a single batch. X-ray
crystallographic analysis unambiguously established the correct
assignment of the structure. With 1 in hand, the core structure of
6−5−6−5−6−membered ETPs was completed. Because ETP
Overall, it was possible to obtain more than 50 g of 18 in
>99.5% ee in one batch, in a process without chromatographic
purification throughout the entire sequence.13 The published
procedure for the formation of oxazaborolidinone catalyst 16
describes refluxing a mixture of acid 18 and n-BuB(OH)2 in
toluene−THF with azeotropic removal of water at 110 °C over
the course of 20 h. We decided to investigate a modification of
this procedure commencing with n-BuBCl2. In the event, the
reaction of 18 and 1.0 equiv of n-BuBCl2 in CH2Cl2 proceeded to
completion at ambient temperature within 1 h to give 16.14
Attention was then turned to the Diels−Alder reaction of
bromoacrolein 11 with furan (Scheme 3). We were pleased to
find that the reaction could be conducted with only 6.5 mol % of
16 to achieve full conversion to 12 as noted by thin layer
chromatography. Due to its tendency to undergo cycloreversion,
bromoaldehyde 12 was reduced immediately by adding the
reaction mixture to a solution of NaBH4 in THF−H2O. The
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Letter
Hydrogenation of 25 with concomitant acetonide cleavage led
to completion of the synthesis of polyol 26 as a highly
functionalized diketopiperazine.
Scheme 6. Double Nucleophilic Opening of 2
It is quite remarkable that the presence of an acid sensitive
acetonide is tolerated during the Me3SiOTf-mediated annulation
reaction, highlighting the practicality of the approach, even on
highly functionalized molecules.
In summary, we have achieved a concise synthesis of the core
structure of 6−5−6−5−6-membered ETPs in six steps from
bromoacrolein 11, allowing the synthesis of gram amounts of
diketopiperazine 1 and thus successfully demonstrating the new
synthetic strategy. Pentacycle 1 is a highly functionalized
intermediate that can serve as a platform for the synthesis of a
wide range of ETP natural products as well as synthetic
analogues.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for all
1
reactions and products, including H and 13C NMR spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
a
X-ray crystal structure was obtained for ent-1. See Supporting
Information for details.
AUTHOR INFORMATION
■
natural products (see Scheme 1) incorporate pyrrolidines, the
reduction of the pyrrolines was examined. Subjection of 1 to
hydrogenation with Pd/C allowed the reduction of the enamides
to furnish 21 in 43% yield over two steps as a single
diastereoisomer, as determined by 1H NMR spectroscopic
analysis.
Corresponding Author
*E-mail: carreira@org.chem.ethz.ch.
Notes
The authors declare no competing financial interest.
As a consequence of the interesting potential uses of ETPs in
pharmacology, we sought to demonstrate the approach to
implementation of the synthesis of structural analogues.2
Therefore, alcohol 15 was subjected to dihydroxylation followed
by protection to afford acetonide 22 (Scheme 7). Swern
ACKNOWLEDGMENTS
■
H.F.Z. thanks the Fonds der Chemischen Industrie for support
(Kek
́
ule-Stipendium). Dr. Michael Worle, Dr. Nils Trapp, and
̈
Michael Solar (Small Molecule Crystallography Center, ETH
Zurich) are gratefully acknowledged for X-ray crystallographic
analyses.
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Scheme 7. Application to the Synthesis of Analogue 26
REFERENCES
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C
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D
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