A Transannular Rearrangement Reaction of a Pyrroloindoline

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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

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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.

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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).

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

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 anticancer.3 Despite their extensive biological activities, unique chemical structure, and enormous potential to be developed as pharmaceuticals,4 few approaches to synthesize these structures have been reported to date. In 2005, the O̅ mura group accomplished the synthesis of the framework of oxaline and neoxaline for the first time.5a Following a similar methodology, O̅ mura 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 © XXXX American Chemical Society

Received: June 17, 2019

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DOI: 10.1021/acs.orglett.9b02084 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters 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· H2O) together with Hünig’s base (N,N-diisopropylethylamine) 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 diketopiperazine 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.

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 compound 26 was treated with tBuOK and O2 in THF at −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. Reaction of compound 26 with tBuOK 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 αB

DOI: 10.1021/acs.orglett.9b02084 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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 4bromobenzyl 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). 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 Cl3CCN/H2O219 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 confirmed by 1H 2D NMR (HMBC and HSQC).21

Scheme 8. Attempts To Prepare Crystals Suitable for X-ray Analysis

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 diketopiperazine-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

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.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 crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], 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 O̅ 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.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. C

DOI: 10.1021/acs.orglett.9b02084 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters ORCID

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Michael R. Gau: 0000-0002-4790-6980 Jeffrey D. Winkler: 0000-0001-8264-5491 Madeleine M. Joullié: 0000-0003-4907-3721 Notes

The authors declare no competing financial interest.

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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 highresolution mass spectra.

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