A Transannular Rearrangement Reaction of a Pyrroloindoline Diketopiperazine

Article abstract of DOI:10.1021/acs.orglett.9b02084

Oxaline, glandicoline, and meleagrin contain a unique triazaspirocyclic structure. Attracted by their biological activities, we attempted a novel strategy, mimicking a proposed biosynthetic pathway for glandicoline B in Penicillium chrysogenum and Penicil

Full text of DOI:10.1021/acs.orglett.9b02084

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Transannular Rearrangement Reaction of a Pyrroloindoline
Diketopiperazine
́
Qiao Yan, Patrick J. Carroll, Michael R. Gau, Jeffrey D. Winkler,* and Madeleine M. Joullie*
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: Oxaline, glandicoline, and meleagrin contain a unique triazaspirocyclic structure. Attracted by their biological
activities, we attempted a novel strategy, mimicking a proposed biosynthetic pathway for glandicoline B in Penicillium
chrysogenum and Penicillium oxalicum and using a transannular rearrangement to the desired triazaspirocycle 15.
he triazaspirocycle moiety possesses a unique framework,
namely three nitrogen atoms attached to one carbon.
This rigid chemical scaffold exists in a number of biologically
active natural products (Figure 1) that exhibit different
synthesize these products through mimicking the biosynthetic
route, via a nitrone-promoted transannular rearrangement.
The biosynthesis of triazaspirocycles has been a subject of
investigation for several decades.1b,3a,b,6a,g,7 In 1983, Steyn and
Vieggar proposed the biosynthetic pathway shown in Scheme
1.6a Introduction of the hydroxyl group at the α-position of the
diketopiperazine led to the formation of a hemiaminal 6, which
on opening to a nine-membered ring 7 and reclosure afforded
glandicoline A (9).
T
Scheme 1. Proposed Biosynthetic Pathway for Glandicoline
A
Figure 1. Triazaspirocyclic natural products: neoxaline, oxaline,
glandicoline B, and meleagrin A.
activities: antibacterial,1 antifungal,1a antifouling,2 and anti-
cancer.3 Despite their extensive biological activities, unique
chemical structure, and enormous potential to be developed as
pharmaceuticals,4 few approaches to synthesize these struc-
̅
tures have been reported to date. In 2005, the Omura group
accomplished the synthesis of the framework of oxaline and
neoxaline for the first time.5a Following a similar methodology,
̅
Omura and Sunazuka et al. published the first total synthesis of
neoxaline in 2013.5b Later, the total syntheses of oxaline and
meleagrin A were published by the same groups,5c but their
attempts to obtain glandicoline B were unsuccessful.5c Many of
the naturally derived triazaspirocyclic compounds have been
shown to originate from the biosynthetic transformation of
roquefortine C.6 This pathway provided the inspiration to
Received: June 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02084
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A key revision to the initial biosynthetic pathway involves
the generation of a nitrone intermediate and the absence of
9.6g The updated proposed pathway for the biosynthesis of
glandicoline B (3) is shown in Scheme 2.6g The generation of a
nitrone intermediate (11) and introduction of a hydroxyl
group at the α-position of the diketopiperazine (12) precede
the transannular rearrangement that leads to the core structure
of 3.
Scheme 4. Formation of the Diketopiperazine and an
Attempt at α-Hydroxylation
Scheme 2. Proposed Biosynthetic Pathway for Glandicoline
B in Penicillium chrysogenum (RoqM and RoqO) and
Penicillium oxalicum (OxaD and OxaH)6g
Cleavage of the allyl group with tetrakis-
(triphenylphosphine)palladium and 1,3-dimethyl barbituric
acid afforded compound 23 (88%).
To effect the α-hydroxylation of the diketopiperazine in
compounds 22 and 23, we considered radical hydroxylation
using permanganate-based oxidants such as n-Bu4NMnO4 and
bis(pyridine) silver(I) permanganate (Py2AgMnO4), which
have been employed for related transformations by Movassaghi
and co-workers.12 Unfortunately, only oxidation of the allyl
group was observed (24, 39%).
To develop a synthetic strategy for the preparation of the
core structure of these natural products, we designed a model
substrate, illustrated in Scheme 3, in which the reverse prenyl
group and the imidazole side chains were simplified to methyl
groups.
Scheme 3. Model Structure Designed To Form the
Triazaspiro Moiety
Scheme 5. Introduction of a Potential OH on the α-Position
of Diketopiperazine
The first step in the construction of the model system
involved the attachment of the diketopiperazine ring to
pyrroloindoline 16 that has been described by Reisman and
co-workers.8,9 Using a catalytic amount of potassium
carbonate, the benzyl ester was transesterified to methyl ester
17 (Scheme 4) that was then hydrolyzed by lithium hydroxide
monohydrate in 1.5 h to afford acid 18 in a quantitative yield.8c
Carboxylic acid 18 and compound 19 were treated with
hexafluorophosphate azabenzotriazole tetramethyl uronium
(HATU) and 1-hydroxybenzotriazole monohydrate (HOBt·
These challenges were overcome using the protecting group
strategy13,14 outlined in Scheme 5. Compound 23 underwent
acetylation with acetic anhydride and pyridine to afford 25 in
88% yield. Treatment of compound 25 with di-tert-butyl
dicarbonate in the presence of DMAP and Et3N gave 26
(95%), a protected substrate for the key α-hydroxylation
reaction. However, reaction with Py2AgMnO4 did not afford
the desired hydroxylated product.12 Fortunately, when
H2O) together with Hunig’s base (N,N-diisopropylethyl-
̈
amine) to afford coupled product 20 in 85% yield.10 After
hydrolysis of the ester and removal of the TFA group with
lithium hydroxide monohydrate, compound 20 was converted
quantitatively to compound 21, the substrate for diketopiper-
azine ring formation. However, none of the desired product
was formed under basic conditions (DMAP, NH3·MeOH,
Et3N, etc.).11 Fortunately, we found that heating 21 under
neutral reaction conditions afforded compound 22 (92%) in
16 h.
compound 26 was treated with BuOK and O2 in THF at
t
−60 °C,15 the desired α-hydroperoxide 27 (69%), resulting
from reaction of the derived enolate with oxygen from the
convex β-face, was obtained as a crystalline solid and its
structure secured by single-crystal X-ray analysis.
t
Reaction of compound 26 with BuOK and oxygen at −60
°C until all starting material was consumed, followed by
treatment with triethyl phosphite to reduce the intermediate
hydroperoxide,15b led to the formation of the desired α-
B
DOI: 10.1021/acs.orglett.9b02084
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the basis of a related transformation by Ghorai et al.,22
we attempted to transform 14 directly to 15. Treatment of
nitrone 14 with LiClO4 and TBABF4 gave transannular
rearrangement product 15 (81%) as an amorphous powder.23
We next examined the reactions of 14, 15, 32, and 33 with
4-bromobenzoyl chloride in an effort to obtain crystals suitable
for X-ray crystallographic analysis. However, each of these
reactions led to the formation of amorphous products; except
for the isolation of compounds 34 and 35, all of the other
reactions afforded amorphous powder and failed to produce
single crystals. The reactions of compounds 32 and 33 with 4-
bromobenzyl chloride gave a mixture of three products
(Scheme 8), including an amorphous white powder (32%)
and inseparable crystalline compounds 34 and 35 in 58% yield
in a 3/1 ratio.
Scheme 6. Successful Installation of the Hydroxyl Group
and Removal of the Protecting Groups
hydroxylation product 28 (78%) in a one-pot reaction
(Scheme 6).
Scheme 8. Attempts To Prepare Crystals Suitable for X-ray
Analysis
Cleavage of the Boc protecting group with TFA provided 29
(78%) that was further deprotected to 30 (83%). Interestingly,
on standing at 0 °C, 29 underwent slow conversion to
dehydration product 31. The structure of compound 31 was
established by single-crystal X-ray analysis. This product may
be formed through a hydrogen shift.16
Initial attempts to oxidize the indoline in 30 to form the
corresponding nitrone-Na2WO4/H2O2,5b,c,17 m-CPBA,18 and
19
Cl3CCN/H2O2 all failed. However, the difficulties were
overcome as shown in Scheme 7. Compound 30 was oxidized
using MeReO3 as the catalyst, H2O2·urea as the oxidant, and
pyrazine carboxylic acid as the stabilizer20 to afford a
chromatographically separable mixture of products 32 (19%),
14 (26%), and 15 (20%), the structures of which were
21
1
confirmed by H 2D NMR (HMBC and HSQC).
The transannular nitrone rearrangement described herein
provides a novel approach to the synthesis of the core of 3 and
that of more complex natural products. This is the first use of
the MeReO3/H2O2·urea oxidation reaction in a diketopiper-
azine-containing pyrroloindoline. Further studies are now
underway in our laboratories, and our results will be reported
in due course.
Scheme 7. Completion of the Proposed Transannular
Rearrangement Reaction
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02084.
Experimental procedures, spectroscopic and analytical
data, copies of the NMR spectra of new compounds, and
X-ray plots and data for compounds 23, 24, 27, 31, and
34/35 (PDF)
Accession Codes
CCDC 1919011−1919015 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Upon standing of 32 in CDCl3, we observed the slow
conversion of 32 to 33 in quantitative yield in 16 h. On the
basis of the work of O
̅
mura and Sunazuka et al.,5c 32 and 33
could be reoxidized using PbO2 and AcOH to afford nitrone
14 (52%), which underwent the transannular rearrangement
reaction upon being exposed to a base (i.e., DMAP, Et3N, or
proton sponge) to give 15. However, these basic conditions
could not make substrate 14 be absolutely assumed.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mjoullie@sas.upenn.edu.
*E-mail: winkler@sas.upenn.edu.
C
DOI: 10.1021/acs.orglett.9b02084
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(5) (a) Sunazuka, T.; Shirahata, T.; Tsuchiya, S.; Hirose, T.; Mori,
R.; Harigaya, Y.; Kuwajima, I.; Omura, S. A Concise Stereoselective
̅
Route to the Indoline Spiroaminal Framework of Neoxaline and
Michael R. Gau: 0000-0002-4790-6980
Jeffrey D. Winkler: 0000-0001-8264-5491
Madeleine M. Joullie: 0000-0003-4907-3721
Oxaline. Org. Lett. 2005, 7, 941−943. (b) Ideguchi, T.; Yamada, T.;
̅
Shirahata, T.; Hirose, T.; Sugawara, A.; Kobayashi, Y.; Omura, S.;
́
Sunazuka, T. Asymmetric Total Synthesis of Neoxaline. J. Am. Chem.
Soc. 2013, 135, 12568−12571. (c) Yamada, T.; Ideguchi-Matsushita,
T.; Hirose, T.; Shirahata, T.; Hokari, R.; Ishiyama, A.; Iwatsuki, M.;
Notes
The authors declare no competing financial interest.
̅
Sugawara, A.; Kobayashi, Y.; Otoguro, K.; Omura, S.; Sunazuka, T.
Asymmetric Total Synthesis of Indole Alkaloids Containing an
Indoline Spiroaminal Framework. Chem. - Eur. J. 2015, 21, 11855−
11864.
ACKNOWLEDGMENTS
■
The authors thank the University of Pennsylvania for financial
support. The authors also thank Dr. Jun Gu and Lingchao Zhu
for NMR assistance and Dr. Charles W. Ross, III, for high-
resolution mass spectra.
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