Synthesis of Bridged Diketopiperazines by Using the Persistent Radical Effect and a Formal Synthesis of Bicyclomycin

Article abstract of DOI:10.1002/anie.201504883

A conceptually new and unified approach to diverse bridged diketopiperazines (DKPs) with widely variable ring sizes was developed by taking advantage of the persistent radical effect. This method enables synthesis of the core structures of bridged DKP alk

Full text of DOI:10.1002/anie.201504883

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201504883
German Edition: DOI: 10.1002/ange.201504883
Radical Cyclization
Synthesis of Bridged Diketopiperazines by Using the Persistent Radical
Effect and a Formal Synthesis of Bicyclomycin
ˇ
Tynchtyk Amatov, Radek Pohl, Ivana Císarovµ, and Ullrich Jahn*
In memory of Ekkehard Winterfeldt
Abstract: A conceptually new and unified approach to diverse
bridged diketopiperazines (DKPs) with widely variable ring
sizes was developed by taking advantage of the persistent
radical effect. This method enables synthesis of the core
structures of bridged DKP alkaloids and was applied to
a formal synthesis of the antibiotic bicyclomycin.
N
atural products are a very important driving force and
a source of inspiration for organic chemistry and drug
discovery. Developed by evolutionary selection for optimal
interactions with biological targets, the majority of them bear
complex three-dimensional structures.[1] Bridged diketopiper-
azine (DKP) alkaloids such as 1–3, which contain a bicyclo-
[n.2.2]piperazinedione ring system (n ꢀ 2), constitute a grow-
ing class of peptide-derived secondary metabolites, and they
demonstrate natureꢀs chemical craftsmanship in generating
diverse and complex architectures (Figure 1A).[2]
Unnatural bioactive bridged DKPs have also been
discovered as important scaffolds. The highly selective
inhibition of a-glucosidase over b-glucosidase exhibited by
compounds 4 and 5 might be useful for the design of small-
molecule antidiabetic medications (Figure 1B).[3] Bridged
DKPs are also precursors for conformationally locked
bridged piperazines (6–7), another class of privileged struc-
tures, many of which have been reported to be strong ligands
for CNS receptors.[4]
Figure 1. Bioactive bridged DKPs and piperazines.
A number of approaches to the diazabicyclo[2.2.2]octane
system present in numerous prenylated indole alkaloids such
as stephacidin A (1) have been developed.[5,6] However,
approaches to bridged DKP systems with larger bridges,
and especially to heteroatom-bridged DKPs such as bicyclo-
mycin (2) and cottoquinazoline D (3), are very rare. They
capitalized on polar reactions like intramolecular alkylations
of DKP enolates that contain a pendant side chain bearing
a good leaving group[4a,7] or cyclization to N-acyliminium
Scheme 1. Known polar approaches to the bridged DKP core of 2 and
a new radical approach based on the persistent radical effect (PRE).
intermediates, which are limited to bicyclomycin-type com-
pounds (Scheme 1).[6j,8,9]
[*] T. Amatov, Dr. R. Pohl, Dr. U. Jahn
Institute of Organic Chemistry and Biochemistry
Academy of Sciences of the Czech Republic
Radical cyclizations using traditional methods have only
been reported in the context of total syntheses of alkaloids
containing the diazabicyclo[2.2.2]octane core by the Myers,[10]
Trost,[11] and Simpkins groups.[6c–e] An oxidative enolate
coupling was used by Baran and co-workers to achieve the
total synthesis of 1.[12]
ˇ
Flemingovo nµmestí 2, 16610 Prague (Czech Republic)
E-mail: jahn@uochb.cas.cz
ˇ
Dr. I. Císarovµ
Department of Inorganic Chemistry, Faculty of Science
Charles University in Prague
Radical approaches to alkaloids such as 2 and 3 and
unnatural bridged DKPs with longer bridges are absent in the
literature. This is not surprising, since the inherently short life
Hlavova 2030/8, 12843 Prague (Czech Republic)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504883.
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times of the generated radical species do not favor cyclization
to medium-sized bridged ring systems under conventional
conditions. Premature radical coupling reactions, radical
quenching by hydrogen atom abstraction from solvent
molecules or reaction mediators such as metal hydrides, and
intramolecular 1,n-H transfer processes often outcompete the
slow cyclization step.
afforded diazabicyclo[2.2.2]octan-3,6-diones 14a–e resulting
from 6-exo-trig cyclization in high yields (Table 1, entries 1–
5).[20] The diastereoselectivity was low with N-benzyl groups,
but was significantly improved when using the more bulky N-
benzhydryl group (entry 3). Substrates 13 f,g, which contain
We hypothesized that application of the persistent radical
effect (PRE) would be an attractive atom-economic solution
to these shortcomings.[13] This powerful principle governs the
selective cross-coupling of two different radical species that
are produced at equal rates, where one is transient and the
other persistent. Although the utility of the PRE was
recognized from the onset in polymer research, its application
in organic chemistry was neglected until Studerꢀs seminal
studies a decade ago.[14,15] The first application of the PRE as
a key step in total synthesis was only recently reported by
Theodorakis and co-workers, who used a 5-exo-trig cycliza-
tion toward fusarisetin A.[16]
Given the importance of bridged DKPs and the recent
growth of interest in three-dimensional heterocyclic architec-
tures in medicinal chemistry,[1,17] methods that allow rapid
access to diverse bridged DKP motives are highly desired.
Herein, we present a unified, practical, general, and concep-
tually new radical approach to diverse bridged DKPs. Central
is the facile and reversible thermal bond homolysis of hitherto
unknown alkoxyamines 8 to generate captodatively stabilized
transient DKP radicals 10 and the persistent radical TEMPO
(9; Scheme 1).[18] This degenerative process confers a suffi-
ciently long lifetime for radical 10 to undergo irreversible
endo or exo cyclizations to pendant alkene units depending on
the tether length and substitution pattern, thereby steering
the equilibrium to the bridged DKP products.
Table 1: Synthesis of diverse diazabicyclo[n.2.2]alkanediones 14a–i from
alkoxyamines 13a–i.[a]
Entry
13
14[b]
Yield [%][c] (d.r.)[d]
1
79 (1:1)[e]
2
3
4
88 (2:1)
97 (5.6:1)
97[f]
5
6
92[g]
To test these hypotheses, several alkoxyamines 13 were
synthesized through alkylation of DKPs 11 followed by
oxidative enolate oxyamination in good to high overall yields
(Scheme 2).[19] Products 13 were isolated as 1:1 to 1:10 cis/
trans diastereomeric mixtures or as single trans isomers (see
the Supporting Information for details).
96
7
89 (4.6:1)[h]
8
9
72[i]
Scheme 2. Synthesis of DKP alkoxyamines 13.
94 (3.3:1)
Alkoxyamines 13 are stable to chromatography and can
be stored at room temperature and in daylight for at least
a year when they are purified and properly dried. They are
often crystalline, which allows confirmation of their structures
by X-ray crystallography (Figure 2).
Heating solutions of alkoxyamines 13a–e, which bear
terminal 1,2-di- or trisubstituted olefinic acceptors, in
degassed tBuOH at 1308C in a sealed tube for 1.5–2 h
[a] General conditions: 0.02m 13 in tBuOH, 1308C, 1.5–2 h. [b] Only the
major diastereomer is shown. [c] Yield of isolated product. [d] Deter-
mined by 1H NMR analysis of the crude mixture. [e] Additionally, 10% of
the 7-endo-trig cyclization product was isolated (see the Supporting
information). [f] Overall ratio 3.4:2:2:1.[20] [g] The ratio at the exocyclic
stereocenter could not be determined.[20] [h] (1S,5S)/(1R,5R) (see
Supporting information for details). [i] At 1708C. Bn=benzyl.
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bear allyloxy and methallyloxy groups, performed well in
thermal radical 8-endo cyclizations to give the oxa-DKPs 16a
and 16b, the latter of which again has an exo methylene
group. Their aza analogues 16c and 16d, which resemble the
bridged core of cottoquinazoline D (3), were also very
efficiently prepared. The structure of the major diastereomer
of the carbamate-protected N-bridged DKP 16d was con-
firmed by X-ray crystallography. To our knowledge, syntheses
of such medium-sized bridged ring systems by using radical
cyclization approaches have so far not been reported.
Figure 2. X-ray structures of alkoxyamines trans-13a and 13d.
Other cyclization modes also worked well (Scheme 4).
Precursor 17, which bears a prenyloxy group, furnished the
oxadiazabicyclo[3.2.2]nonanedione 18 through an efficient
1,1-disubstituted alkene units, selectively provided the 7-endo
cyclization product 14 f or the a-glucosidase inhibitor 4
(entries 6,7). The radical cyclization can also be performed
asymmetrically by using the 1-phenylethyl auxiliary or the
enantiomerically pure substrate 13h (entries 7,8). Compound
13h, which has an indole substituent, also reacted exclusively
through 7-endo-trig cyclization to give diazabicyclo-
[3.2.2]nonane 14h (entry 8). However, an analogous substrate
with a simple phenyl ring did not cyclize. Replacement of the
allyl by a homoallyl unit in 13i surprisingly resulted in an
efficient and exclusive 8-endo-trig cyclization to provide the
four-carbon-atom-bridged DKP 14i in high yield with pro-
nounced diastereoselectivity (entry 9).
Cyclizations leading to primary and secondary radicals
predictably gave the oxygenated products 14a,d,e,i, whereas
those generating tertiary radicals furnished the bridged DKPs
4 and 14b,c,f,h, which bear alkene units because of TEMPOH
elimination. The configurations of the products 14 were
determined on the basis of ROESY spectra (see the
Supporting Information).
The ease of the 8-endo-trig cyclization[21] of 13i immedi-
ately called for the testing of heteroatom-bearing cyclization
substrates 15, which were easily accessible (Scheme 3, see the
Supporting Information). Alkoxyamines 15a and 15b, which
Scheme 4. Diverse cyclization modes with alkoxyamines 17, 19, and
21.
and clean 7-exo-trig cyclization. Substrate 19, which bears
a homoallyloxy group, underwent a 9-endo cyclization at
1508C to give DKP 20, which has a five-atom bridge, in
moderate yield.[22] Notably, the product did not contain the
TEMPO fragment, which is unusual, since secondary alkoxy-
amines usually do not undergo homolysis at this temperature.
Strong transannular strain in the 9-membered bridged system
might be the reason for the facile TEMPOH elimination in
this case. Alkoxyamine 21, which bears both allyl and prenyl
groups, was designed as a probe molecule to study the direct
competition between the 7-exo and 8-endo cyclization modes.
A 8.4:1 ratio of the 8-endo/7-exo cyclization products 23 and
22, based on the yield of isolated products (9:1 by crude NMR
measurement), speaks for the importance of strain in the
transition state, which is more pronounced for the 7-exo-trig
cyclization pathway.
For direct comparison, the 8-endo-trig cyclization of
unstable phenylselenide 24 was studied under conventional
tributyltin hydride mediated conditions (Scheme 5). The
desired cyclization product 25 was obtained in only 56%
Scheme 3. 8-endo-trig cyclizations to give heteroatom-bridged DKPs 16
and an X-ray structure of 16d.
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In conclusion, we have developed a conceptually new
approach to diverse bridged diketopiperazines by introducing
a novel class of amino acid derived alkoxyamines as radical
surrogates and taking advantage of an inherently atom-
economic cyclization that makes use of the PRE. This method
provides efficient and practical access to diverse medium-ring
bridged DKPs. Importantly, the reaction times are short
compared to previously reported simple cyclizations,[15] which
Scheme 5. Conventional 8-endo-trig cyclizations.
À
can be attributed to facile homolysis of the C O bond to give
captodatively stabilized DKP radicals. The excellent potential
of the methodology was demonstrated in a formal total
synthesis of the antibiotic bicyclomycin. Applications of this
methodology to total syntheses of diverse alkaloid classes are
ongoing.
yield under mix-and-heat conditions, together with 40% of
the premature radical reduction product 26. Slow addition of
Bu3SnH by syringe pump was necessary to increase the yield
of the desired cyclization product 25 to 81%. These results
clearly demonstrate the advantage of our method, which is
simple to perform, tin-free, and atom-economic, since it
retains the alkoxyamine functionality in the product.
Acknowledgements
Finally, the method was applied to the formal total
synthesis of the antibiotic bicyclomycin (2; Scheme 6). To
accomplish this, a precursor with a so far unused allene group
as the radical acceptor was designed. The required alkoxy-
amine 30 was obtained in three steps from known dichloro-
acetamide 27[7a] through oxygenative cyclization to give 28
under basic conditions, Crabbe homologation[23] to give 29,
and enolate oxygenation under internal quench conditions.[24]
The key radical cycloisomerization took place very efficiently
to provide the bridged DKP 31, which has an internal double
bond.[25] Reductive removal of the tetramethylpiperidinyl unit
with zinc in acetic acid afforded allylic alcohol 32. It is
important to mention that the sensitive hemiaminal function-
ality at the bridgehead position survived the acidic and
reductive conditions. A reductive transposition of the internal
double bond to the exo position under the conditions
developed by Movassaghi and Ahmad[26] furnished Williamsꢀ
central intermediate 34 in 6 steps and 38% overall yield.
Compound 34 was previously converted to bicyclomycin in
four steps by Williams and co-workers.[27]
Generous financial support by the Institute of Organic
Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic (RVO: 61388963), the COST action CM1201
“Biomimetic Radical Chemistry”, and the Gilead Sciences &
IOCB Research Center is gratefully acknowledged. I.C.
thanks the Ministry of Education, Youth and Sports of the
Czech Republic (MSM0021620857) for financial support.
Keywords: alkaloids · bicyclomycin · bridged diketopiperazines ·
cyclization · radicals
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12153–12157
Angew. Chem. 2015, 127, 12321–12325
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Received: May 29, 2015
Published online: August 25, 2015
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