Oxidative radical cyclizations of diketopiperazines bearing an amidomalonate unit. Heterointermediate reaction sequences toward the asperparalines and stephacidins

Article abstract of DOI:10.1080/10715762.2016.1223295

A novel approach to the diazabicyclo[2.2.2]octane core of prenylated bridged diketopiperazine alkaloids is described by direct oxidative cyclizations of functionalized diketopiperazines mediated by ferrocenium hexafluorophosphate or the Mn(OAc)₃?2H₂O/Cu(OTf)₂ system. Divergent reaction pathways take place depending on the substitution pattern of the substrates and the oxidation conditions such as temperature or the presence or absence of persistent radical TEMPO. For ester-substituted diketopiperazines, the ester group exerts a significant influence on the reaction outcome and stereochemistry of the radical cyclizations.

Full text of DOI:10.1080/10715762.2016.1223295

Free Radical Research
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Oxidative radical cyclizations of diketopiperazines
bearing an amidomalonate unit.
Heterointermediate reaction sequences toward
the asperparalines and stephacidins
Tynchtyk Amatov, Martin Gebauer, Radek Pohl, Ivana Cisařová & Ullrich Jahn
To cite this article: Tynchtyk Amatov, Martin Gebauer, Radek Pohl, Ivana Cisařová & Ullrich
Jahn (2016): Oxidative radical cyclizations of diketopiperazines bearing an amidomalonate unit.
Heterointermediate reaction sequences toward the asperparalines and stephacidins, Free
Radical Research, DOI: 10.1080/10715762.2016.1223295
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Date: 14 November 2016, At: 07:32

FREE RADICAL RESEARCH, 2016
http://dx.doi.org/10.1080/10715762.2016.1223295
ORIGINAL ARTICLE
Oxidative radical cyclizations of diketopiperazines bearing an
amidomalonate unit. Heterointermediate reaction sequences toward the
asperparalines and stephacidins
a
a
a
b
a
Tynchtyk Amatov , Martin Gebauer , Radek Pohl , Ivana Cisa ꢀr ov ꢁa and Ullrich Jahn
a
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, Prague 6, Czech Republic;
Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030/8, Prague 2, Czech Republic
b
ABSTRACT
ARTICLE HISTORY
A novel approach to the diazabicyclo[2.2.2]octane core of prenylated bridged diketopiperazine
alkaloids is described by direct oxidative cyclizations of functionalized diketopiperazines mediated
by ferrocenium hexafluorophosphate or the Mn(OAc) ꢀ2H O/Cu(OTf) system. Divergent reaction
Received 7 July 2016
Revised 3 August 2016
Accepted 6 August 2016
3
2
2
pathways take place depending on the substitution pattern of the substrates and the oxidation
conditions such as temperature or the presence or absence of persistent radical TEMPO. For
ester-substituted diketopiperazines, the ester group exerts a significant influence on the reaction
outcome and stereochemistry of the radical cyclizations.
KEYWORDS
Alkaloids; diketopiperazines;
radical cyclizations; single
electron transfer; oxidation
Introduction
independently by Williams [8], Liebscher [9], and more
recently by Scheerer [10–13] and others [14,15].
Alkaloids containing the central diazabicyclo[2.2.2]oc-
tane core structure constitute an ever expanding family
of secondary metabolites with wide structural diversity.
To date, nearly 70 secondary metabolites containing
this central core structure have been isolated from vari-
ous species of fungi, which is a testament to nature’s
ability to create diverse structures using a limited num-
ber of building blocks such as proline, tryptophan, and
dimethylallyl pyrophosphate (DMAPP) [1]. The members
of this superfamily of alkaloids include subfamilies like
the brevianamides I, asperparalines II, paraherquamides
III, having an attached five-membered ring, or the ste-
phacidins IV, malbrancheamides V, or the recently iso-
lated taichunamides VI [2] with an attached six-
membered ring to the common diazabicyclo[2.2.2]oc-
tane core (Figure 1).
Because of their fascinating structures and intriguing
biosynthesis, as well as promising biological properties,
they enjoyed significant attention from the scientific
community [3–6]. A provocative biosynthetic hypothesis
involving an oxidative hetero-Diels–Alder cycloaddition,
that generates the central diazabicyclo[2.2.2]octane
core, was proposed by Porter and Sammes [7]. Based on
that, biomimetic synthetic strategies were pursued
More commonly, approaches employing various
reactive intermediates en route to the central core were
reported (Scheme 1) [3–6]. The majority of them
focused on reactive a-carbonyl intermediates, but all
proceeded only via a single type of reactive species, i.e.
via cations or radicals or anions. For example, S 2’ cycli-
N
zations of diketopiperazine (DKP) enolates were used by
Williams’ group in their approaches to both breviana-
mide B (I) [16,17] and stephacidin A (IV) [18–22],
whereas Sarpong et al. used an intramolecular enolate
amidation [23]. Myers’ [24] and Trost’s [25,26] groups
used radical cyclizations to construct the diazabicy-
clo[2.2.2]octane skeleton, whereas Simpkins’ group
developed both cationic [27–29] and radical [30,31] cyc-
lization cascades to malbrancheamide B (V) and stepha-
cidin A (IV), respectively. Baran and coworkers applied
in contrast an intramolecular oxidative coupling of dien-
olates in their approach to IV [32–34].
Our laboratory has a long-standing interest in devel-
oping reaction sequences that proceed via multiple
intermediate types of different oxidation state in a sin-
gle pot, by switching between them with the help of
single electron transfer (SET) oxidation [35–46]. Such
CONTACT Ullrich Jahn
, 16610 Prague 6, Czech Republic
Supplemental data for this article can be accessed here.
jahn@uochb.cas.cz
Jahn Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti
2
ß 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial NoDerivatives License (http://creativecommons.org/Licenses/by-
nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed,
or built upon in any way.

2
T. AMATOV ET AL.
Figure 1. Representative alkaloids containing the diazabicyclo[2.2.2]octane ring system.
Scheme 1. Approaches to bridged prenylated DKP alkaloids employing reactive a-carbonyl intermediates.
redox switching of intermediates allows the design of
novel heterointermediate reaction sequences and con-
stitutes an unconventional version of the umpolung
principle. We hypothesized that this strategy may be
applied as an approach to bridged DKP alkaloids
containing the central diazabicyclo[2.2.2]octane core
(Scheme 2).
The projected sequence includes deprotonation of
DKPs A followed by SET oxidation of the resulting eno-
lates B to DKP radicals C, which are expected to

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3
Scheme 2. Design principle of a heterointermediate tandem approach toward bridged diketopiperazine alkaloids.
Scheme 3. Synthesis of proline building blocks 3 and 5.
undergo a 6-exo-trig radical cyclization to form the cen-
tral diazabicyclo[2.2.2]octane core. The bicyclic tertiary
radical D would subsequently be prone to another SET
oxidation furnishing tertiary carbocation E, being sub-
ject to coupling with a built-in nucleophile thus termi-
nating the reaction sequence to give advanced
intermediates, such as F en route to alkaloids such as II,
IV, or V. Such sequences can indeed be regarded as
umpolung because a reactivity switch is enabled purely
as a result of the redox (polarity) change. For example,
the enolate B is not reactive toward the pendent unacti-
vated alkene side-chain, but gains reactivity on oxida-
tion to radical C. Likewise, the bicyclic nucleophilic
radical D will display poor reactivity to built-in nucleo-
philes, but further oxidation to tertiary carbocation E
enables polar termination. Herein we report initial
studies implementing this strategy en route to asper-
paralines II or stephacidins IV using DKPs A.
Results and discussion
Known prenylated and allylated proline derivatives 2
and 4 were prepared by reported methods [32–34]. A
racemic approach was initially pursued because of its
convenience in model studies and methodology devel-
opment. Methyl N-Boc-prolinate was deprotonated by
LiHMDS and the resulting enolate was subject to alkyl-
ation by prenyl or allyl bromide, respectively, in good
yields (Scheme 3). Because the acidic cleavage of the
Boc group in 2 led to the free pyrrolidine with unsatis-
factory purity (not shown), 2 was saponified to

4
T. AMATOV ET AL.
Scheme 4. Peptide coupling of tryptophan derivatives 6 and 7 with prolinates 3 and 5.
Scheme 5. DKPs 12 by silica gel-promoted cyclization and Boc protection.
carboxylic acid 3. Acidic deprotection of 4 gave an easy
to handle salt 5 as a colorless solid.
mixture at this temperature (Scheme 6). Upon work-up
and chromatographic purification of the reaction mix-
ture, dimer 15 was isolated as the only product in 22%
yield as a single diastereomer of unassigned configur-
ation along with 50% recovered starting material. No
trace of cyclized 14 was detected. This result proved
that SET oxidation of the corresponding enolate worked
as also indicated by the full consumption of 13, but
showed that the radical cyclization must have a too
high barrier to compete with dimerization to 15 and
probably hydrogen abstraction from tetrahydrofuran
(THF) leading to recovery of 12a.
Prenylated and allylated prolines 3 and 5 were ini-
tially coupled with tryptophans 6 and 7 (Scheme 4).
Guanidinium/uronium [47] peptide coupling reagents
such as HATU (8a) and HBTU (8b) furnished the desired
dipeptides 9 and 10 in high yields. Although the reac-
tions using 8a were significantly faster than with 8b,
the cheaper reagent 8b was generally preferred.
Attempts with carbodiimide coupling reagents were in
contrast unsuccessful.
Dipeptides 9 and 10 were subjected to a high yield-
ing thermal cyclization mediated by silica gel giving
indole-substituted diketopiperazines 11a and 11b, simi-
larly to the previously reported method for simpler
diketopiperazines (Scheme 5) [48]. Both DKPs 11 were
obtained as 1:1 mixtures of cis- and trans-isomers, which
can be separated for characterization purposes.
Reasoning that the planned SET-induced cyclization
sequence would be facilitated by protection of the
nitrogen atoms by acceptor groups, DKPs 11 provided
Based on this result, DKP 12b with the allyl side
chain was similarly deprotonated and the reaction mix-
ture was warmed to room temperature before 13 was
added to enable the subsequent oxidative cyclization.
Unexpectedly, product 16 being isomeric to the starting
material was isolated in 86% yield (Scheme 7). The
assignment of the pyrrolidine-2,4-dione skeleton is
1
13
based on its H, C, and 2D NMR spectra and the rela-
tive configuration on NOE experiments. Thus, after
deprotonation of 12b to enolate 17 a Chan-type
rearrangement took place on warming, which resulted
in contraction of the DKP ring via aziridine-type inter-
mediate 18, even before 13 was added. Repeating this
1
2a and 12b in good yields by exhaustive Boc
protection.
With an efficient, reproducible, and practical synthe-
sis of DKPs 12 developed, the original SET-induced cyc-
lization was investigated. DKP 12a was deprotonated
ꢁ
reaction at –30 C also resulted in Chan rearrangement
ꢁ
with LiHMDS at –78 C and the SET oxidant ferrocenium
with 52% yield. A literature search revealed that this
type of ring contraction is typical for Boc-protected
hexafluorophosphate 13 was added to the reaction

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5
Scheme 6. SET oxidation/dimerization of DKP 12a.
Scheme 7. Chan-rearrangement of DKP 12b.
DKPs upon deprotonation at higher temperatures
To achieve this, building blocks 3 and 5 were con-
verted by standard coupling mediated by HBTU (8b) to
proline-glycine dipeptides 19 and 21, which were sub-
jected to silica gel-mediated cyclizations as described
before and subsequent N-alkylation providing the corre-
sponding DKPs (Scheme 8). Their deprotonation, fol-
[
49–51], because the electron withdrawing carbamate
protecting group renders the amide carbonyl group
electrophilic enough toward intramolecular attack of
the enolate.
These results indicated that DKPs with electron-
accepting protecting groups at the nitrogen atom are
not suitable for oxidative SET-induced radical cycliza-
tions because of competing rearrangements at higher
temperatures, which are necessary to trigger the cycli-
zations. Therefore, the attention turned to DKPs bearing
additional acceptor substituents at the carbon atom at
the radical site and innocent protecting groups at
nitrogen.
lowed by alkoxycarbonylation with Boc O or methyl
2
chloroformate, gave model DKPs 20 and 22 with an
amidomalonate unit and prenyl or allyl groups, respect-
ively. The alkoxycarbonylation to 20 was carried out
with two equivalents of LiHMDS, leading to the enolate
of 20, whose protonation occurred selectively from the
face opposite to the prenyl group, giving exclusively
cis-20, which was confirmed by observation of a weak

6
T. AMATOV ET AL.
Scheme 8. Synthesis of DKPs 20 and 22, containing the amidomalonate unit.
Scheme 9. Oxidative cyclization attempts with 20.
NOE contact between the t-butyl and prenyl methylene
groups. DKP ester 22 was in contrast isolated as a single
diastereomer, when the stoichiometry was carefully
controlled at a substrate: base 1:1.1 ratio, but presum-
ably as the trans-isomer, because the alkoxycarbonyla-
tion is assumed to proceed trans to the allyl group.
With DKPs 20 and 22 in hand their oxidative cycliza-
and d/l-dimers 23 in excellent yield in a 1:1 ratio
(Scheme 9). This result pointed to the efficiency of the
SET oxidation, however, the following 6-exo-trig radical
ꢁ
cyclization seems to be slow even at 0 C, since no
products having the bridged DKP core were detected.
However, carrying out the SET oxidation of the enolate
at ambient temperature led to a complex mixture, in
which the desired product 24 was detected in small
amounts.
tions were studied under a variety of conditions. When
ꢁ
2
0 was deprotonated with LiHMDS at –78 C and
ꢁ
warmed to 0 C, the resulting enolate was indeed sta-
ble. Its SET oxidation using 13 at 0 C for 1 h gave meso-
When the enolate of 20 was oxidized in the presence
of one equivalent of persistent radical TEMPO 25
ꢁ

FREE RADICAL RESEARCH
7
Figure 2. X-ray crystallography of dimer d/l-23. The thermal ellipsoids are displayed at 30% probability level.
Scheme 10. Oxidative cyclization of 22 in the presence of TEMPO.
followed by addition of 13 in small portions under simi-
units are oriented almost perpendicular to each other
with the larger prenyl and tert-butyl ester units in cis-
orientation to each other.
ꢁ
lar conditions and the temperature was raised from 0 C
to room temperature after oxidation, a single tricyclic
product 26a was isolated, which contained the alkoxy-
amine unit (Scheme 9). The configuration at the newly
generated stereocenter was assigned based on a NOE
contact between the N-Me group and the C–H group of
the bridge. Thus, the cyclization proceeded stereoselec-
tively to give the required syn-configuration for the
application of the methodology toward asperparalines
II or stephacidins IV (cf. Figure 1). The reaction pro-
ceeded surprisingly cleanly compared to the room tem-
perature oxidation in the absence of 25. In contrast,
when 25 was added as a homogenized mixture with 13
in small portions, the cyclization was less clean. The low
yield of the cyclization product 26a can be attributed to
its instability, since tertiary alkoxyamines tend to easily
DKP ester 22, bearing an allyl group, also underwent
the oxidative radical cyclization/oxygenation sequence
using 13 and TEMPO 25 (Scheme 10). In this case bicyc-
lic product 26b was formed in a significantly higher
54% yield as a 4:1 mixture of inseparable diastereomers.
The configuration of the major diastereomer was the
same as in 26a based on the same NOE contact.
Similarly as above, no coupling with the initial radical
was observed.
The clean and facile formation of bridged products
26a,b can be rationalized by two mechanisms that do
not exclude each other (Scheme 11). Common is the
deprotonation to enolate 28. After SET oxidation to rad-
ical 29, a direct cyclization may proceed and termin-
ation by coupling of tricyclic radical 30 with persistent
TEMPO (25) gives products 26a,b. Alternatively, the
rather clean formation of bridged DKPs 26 may be con-
trolled by the persistent radical effect [52–55]. The fact
that products 27, which would form by direct coupling
of radicals 29 with TEMPO, could not be isolated, points
to their facile reversible homolysis even at ambient
ꢁ
eliminate TEMPOH. Indeed, upon storage at –20 C over
a period of a year a significant elimination of TEMPOH
was observed. Interestingly alkoxyamine 27, the cou-
pling product of the initial uncyclized amidomalonate
radical with 25, was not observed.
The structure of d/l-23 was unambiguously con-
firmed by X-ray crystallography (Figure 2). The two DKP

8
T. AMATOV ET AL.
Scheme 11. Mechanism of formation of tricyclic products 26.
Scheme 12. Mn(OAc) ꢀ2H O/Cu(OTf) -mediated oxidative double cyclization of DKPs 20 and 32.
3
2
2
temperature to regenerate persistent 25 and transient
DKP radicals 29. This degenerate process confers life
time to transient 29 by inhibiting its dimerization to 23
hexafluorophosphate (13) are Mn(OAc) ꢀ2H O/Cu(II)-
3
2
promoted inner-sphere cyclizations of b-dicarbonyl
compounds [56–60], in which Cu(II) serves for efficient
termination of the sequences. Oxidative radical cycliza-
tions or additions of a-amidomalonates to alkenes, are-
(
cf. Scheme 9) and thus steers the reaction toward cyc-
lization to tricyclic radicals 30, which irreversibly couple
with 25 to give the bridged core structures 26a,b [48].
Interestingly, the cyclization of the DKP tert-butyl ester
gives a lower yield, but exclusive diastereoselectivity,
whereas the cyclization of the methyl ester occurs in
better yield, but lower diastereoselectivity, which paral-
lels the results obtained below.
nes, and alkynes with Mn(OAc) /Cu(II) reagent systems
3
are precedented from Citterio’s [61], Miller’s [62,63], and
Burton’s [64,65] groups. However, they have so far not
been applied in the synthesis of bridged heterocyclic
systems. Refluxing 20 with two equivalents of
Mn(OAc) ꢀ2H O and one equivalent of Cu(OTf) , condi-
3
2
2
An alternative to outer-sphere electron transfer-
mediated radical cyclizations triggered by ferrocenium
tions reported by Burton in the synthesis of fused lac-
tone-pyrrolidinones [64], gave the double cyclization

FREE RADICAL RESEARCH
9
Scheme 13. Mechanistic rationale of Mn(III)/Cu(II)-mediated radical cyclizations.
product 24 as a single diastereomer, but in a low 20%
yield, along with unexpected trioxopiperazine 31
alkyl group. Favorable cleavage of the tert-butyl group
is the exclusive pathway starting from DKP 20, affording
lactone 24 via path c. The methyl group in the oxycar-
benium ion resulting from DKP 32 is much less reactive
via pathway c and thus stabilization of 38 via elimin-
ation according to path d and hydrolysis via path e
become competitive leading to a mixture of 24, 33,
and 34.
(
Scheme 12), when untreated old Mn(OAc) ꢀ2H O was
3
2
used. When Mn(OAc) ꢀ2H O was washed with glacial
acetic acid and dried prior to use, the yield of double
cyclization product 24 increased to 45%. However, the
decarboxylative oxidation product 31 was also obtained
3
2
in
a
pronounced 42% yield. Methyl ester 32,
synthesized in analogy to 22, furnished under the man-
ganese-mediated oxidative cyclization conditions an
inseparable mixture of bridged alkene 33 as the major
component, and tertiary alcohol 34 as well as tricyclic
product 24 as the minor constituents. The much lower
diastereoselectivity complicated the analysis of the
compound mixture further. However, trioxopiperazine
The selective stabilization of the tert-butyloxy carbe-
nium ion to lactone 24 comes, however, with a price,
since apparently hydrolysis of DKP tert-butyl ester 20
competes under the acidic reaction conditions. The
resulting DKP carboxylic acid is in equilibrium with its
manganese(III) salt 39, which is subjected to oxidative
Anderson–Kochi decarboxylation to DKP radical 40 [66],
which undergoes further oxidation leading ultimately to
oxo-DKP 31. This path is not available to the more acid-
stable DKP methyl ester 32. Attempted oxidation of the
corresponding DKP lacking the ester group failed to
give oxo-DKP 31, thus excluding sequential acid-medi-
ated dealkoxycarbonylation and subsequent oxidation
to radical 40 as a viable pathway.
31 was not formed.
The results can be rationalized by first assuming oxi-
dative generation of radicals 35 from DKPs 20 or 32
probably via a fleeting manganese(III) enolate (Scheme
1
3, not shown). DKP radicals 35 may cyclize according
to path a in a facile 6-exo trig cyclization leading to ter-
tiary cyclized radicals 36. These electron-rich radical
species will be subjected to single electron oxidation by
The tert-butyl ester unit in DKP radical 35 also steers
the diastereoselectivity of the radical cyclization to rad-
ical 36 much better than the corresponding methyl
ester group. This result is in accordance with observa-
tions from Simpkins’ group, who also noticed an
the Cu(OTf) co-oxidant. The resulting carbocation 37
2
will couple to the bridgehead ester unit leading to
tetracyclic oxycarbenium ion 38. The fate of this react-
ive intermediate is strongly dependent on the ester

1
0
T. AMATOV ET AL.
increase of the diastereoselectivity in such cyclizations
upon increasing the bulkiness of the substituents at the
a-position of DKPs [67].
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In conclusion, single and double oxidative cyclizations
to rapidly construct the central diazabicyclo[2.2.2]oc-
tane core of the asperparalines II or stephacidins IV
were developed. Both, the ferrocenium ion-mediated
and the Mn(OAc) /Cu(OTf) -mediated methodology
711–740.
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bicyclo[2.2.2]diazaoctane ring system common to the
paraherquamides, stephacidins and related prenylated
indole alkaloids. Chem Soc Rev 2009;38:3160–3174.
3
2
may lead to key building blocks. While the ferrocenium
ion-mediated reactions provide compounds with an
alkoxyamine unit, which may be further transformed,
the access to lactone 24 as a single diastereomer from
tert-butyl ester 20 by the Mn(OAc) /Cu(OTf) -mediated
5.
Williams RM. Natural products synthesis: enabling tools
to penetrate nature's secrets of biogenesis and biome-
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6. Nising CF. Recent synthetic approaches towards the
antiproliferative natural products avrainvillamide and
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cyclizations validates the feasibility of the original pro-
posal. The major lesson learned is that the nature of the
substituents at the later bridgehead position, and here
especially the ester unit is determining the outcome
and the diastereoselectivity of the reactions signifi-
cantly. Future studies can be on this basis directed to
finding optimal solutions to improve the double cycliza-
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During revision of this manuscript an article describing
the total synthesis of the notoamides F, I, R and sclero-
tiamide using an intramolecular aza-Prins reaction to
construct the diazabicyclo[2.2.2]octane core was pub-
lished: Zhang B, Zheng W, Wang X, Sun D, Li C.
Total Synthesis of Notoamides F, I, and R and
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(þ)-malbrancheamide B.
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10.1002/anie.201604754.
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Intermolecular Diels–Alder cycloaddition for the con-
struction of bicyclo[2.2.2]diazaoctane structures: formal
synthesis of brevianamide B and premalbrancheamide.
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Disclosure statement
The authors do not declare financial interest.
1
1
4. Qin WF, Xiao T, Zhang D, Deng LF, Wang Y, Qin Y.
Total synthesis of (–)-depyranoversicolamide B. Chem
Commun 2015;51:16143–16146.
5. Cabanillas A, Davies CD, Male L, Simpkins NS. Highly
enantioselective access to diketopiperazines via cin-
chona alkaloid catalyzed Michael additions. Chem Sci
Funding
Generous financial support by the Institute of Organic
Chemistry and Biochemistry, Czech Academy of Sciences
[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
2
015;6:1350–1354.
6. Williams RM, Glinka T, Kwast E. Facial selectivity of the
intramolecular S 2' cyclization: stereocontrolled total
synthesis of brevianamide B. Am Chem Soc
988;110:5927–5929.
1
N
[MSM0021620857] for financial support.
J
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17. Williams RM, Glinka T, Kwast E, Coffman H, Stille JK.
Asymmetric, stereocontrolled total synthesis of
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