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Letter Cite This: Org. Lett. 2019, 21, 310−314

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An Intramolecular Cycloaddition Approach to the Kauranoid Family of Diterpene Metabolites Brenda Callebaut,† Jan Hullaert,† Kristof Van Hecke,‡ and Johan M. Winne*,† †

Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, 9000 Gent, Belgium XStruct, Department of Chemistry, Ghent University, Krijgslaan 281 S3, 9000 Ghent, Belgium

‡

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S Supporting Information *

ABSTRACT: Synthetic studies toward the ent-kauranoid family of diterpene natural products are reported. An intramolecular (4 + 3) cycloaddition allows the direct elaboration of diverse natural product frameworks, encompassing a challenging bicyclo[3.2.1]octane core. The established routes comprise only a few synthetic operations (3−5 steps), transforming a range of simple starting materials into the tetracyclic scaffolds that are commonly found in many ent-kaurene metabolites.

O

natural product inspired synthesis, the kauranoid skeleton can also be identified as a highly privileged scaffold.5 To date, general and concise synthetic approaches to the intruiging 6:6:6:5 ring system encompassing the [3.2.1]bicyclic core are still rare.3,4 Snider’s racemic 18-step isosteviol synthesis stands out in this regard (Scheme 1a),6 which elaborates the ent-beyerane framework in just 12 steps via an impressive free radical polyene cyclization, completing isosteviol in 18 linear steps. The beyerane scaffold found in isosteviol shares its overall connectivity with the ent-kaurane core, but it is, in fact, a regioisomeric and stereoisomeric skeleton which can interconvert via a rearrangement to the more commonly found ent-kaurane skeleton (C-12 migrates between C-16 and C-13; see Figure 1 ). Baran more recently reported the shortest (racemic) synthesis of steviol,7 completing the kaurane core in just 12 steps as an “overbred” intermediate (Scheme 1b), with an additional C-12 to C-16 bond that is cleaved during the final stages of the synthesis. A similar strategy for the kaurane and beyerane frameworks was developed by Abad in 2006,8 first establishing a C-12 to C-16 reconnected core in just 9 steps, using an intramolecular cyclopropanation approach. In 1986, De Clercq reported the shortest racemic total synthesis of a gibberellin plant hormone,9 comprising 16 linear steps and taking only 8 steps to elaborate the 6:5:6:5 tetracyclic core via an intramolecular Diels−Alder reaction with a furan diene (Scheme 1d). Gibberellic acids are ent-kaurene metabolites that have undergone a C-8 migration from C-7 to C-6, with conservation of the challenging bicyclo[3.2.1]octane core (Figure 1). Very recently, Njardarson reported another concise racemic entry to

ne of the most diverse and, at the same time, structurally intriguing subfamily of plant diterpenes is formed by the ent-kauranes (Figure 1).1,2 The parent geranylgeranyl pyro-

Figure 1. Common tetracyclic scaffolds found in ent-kaurene metabolites and three representative natural products that have been classical targets for total synthesis.

phosphate diterpenoid is directly transformed to ent-kaurene via two cyclase enzymes, each catalyzing a bicyclization event, yielding a remarkable tetracyclic framework, which, in itself, is the direct precursor of a huge family of skeletally complex natural products, also including the well-known gibberellin plant hormones. The chemical biodiversity and complexity found in ent-kaurene metabolites actually approaches that found in steroids, since over a thousand kaurene metabolites are known, which continue to attract considerable interest from both a synthetic and a biological point of view.3,4 Drawing on the arguments of biology-oriented synthesis, or © 2018 American Chemical Society

Received: November 28, 2018 Published: December 20, 2018 310

DOI: 10.1021/acs.orglett.8b03810 Org. Lett. 2019, 21, 310−314

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Organic Letters Scheme 1. Concise Synthetic Approaches for Kauranoids

Scheme 2. Synthesis of Gibberellane Scaffolds 7a and 7b

the gibberellane core requiring only 9 steps,10 using an intramolecular Diels−Alder reaction to establish a [2.2.2]bicycle which can be rearranged to a [3.2.1]bicyclic system via a 1,2- (or 1,5-) carbon shift (Scheme 1d). We now report our own synthetic studies in this field, aiming at a direct elaboration of the [3.2.1]bicyclic system via an intramolecular (4 + 3) cycloaddition (Schemes 1e and 2).11 The results reported herein establish a very short and conceptually straightforward entry into kaurane-type scaffolds. We set out to synthesize kaurane-type scaffolds as part of a program to further establish the utility of furan-mediated allyl cation (4 + 3) cycloadditions (Scheme 1e), a remarkably efficient synthetic method for seven-membered ring systems that was first observed by Pattenden and Winne in 2009,12 and has since been developed by our group and others in recent years.13,14 The methodology has been used to elaborate a bicyclo[3.2.1]octane system in previous studies aimed at a gelsemine substructure by Zhang, Li, and co-workers,14 using an intermolecular approach, and also in an intramolecular version in a synthesis of the zizaene sesquiterpene scaffold by Laplace and Winne.15 These results raise expectations concerning the viability of such an approach for the important and ubiquitous kaurane-type scaffolds (cf.n Scheme 1e). Thus, we identified bromo-aldehyde 1 as a suitable starting material (Scheme 2), which can be obtained in a single step from the corresponding commercial bromonitrile.16 Addition of a lithiated furan moiety, followed by substitution of the unreacted primary bromide with the cyclopentadienyl anion would provide the intramolecular cycloaddition precursor 2 in a very small number of synthetic operations. In fact, best results were obtained using a one-pot procedure to perform the addition and substitution reactions on the bis-electrophile 1.

Not unexpectedly, treatment of 1 with lithiated 2-methyl furan, followed by workup, gave the cyclic ether 3 as the major reaction product. However, by making sure the nucleophilic oxyanion is captured in situ by trimethyl silyl chloride, and then adding an excess of cyclopentadienyl sodium, a very clean three-component assembly of the silyl ether 2 was obtained, without detectable formation of the tetrahydrofuran-type product 3. With precursor 2 in hand, our investigation next involved the generation of the furfuryl cation derived from 2 as a suitable dienophile for the pendant cyclopentadiene moiety (cf. Scheme 1e). Although the expected gibberellane-type cycloadduct 4 was formed under our three standard reaction conditions (see Table 1, entries 1−3),13a,15,17 it was invariably isolated together with a complex mixture of isomeric products which could be assigned the overall tetracylic structure 5. These isomers most likely result from the “incorrect” Cp Table 1. Intramolecular Annulation Studies of Silyl Ether 2

311

entry

reaction conditions (2 in CH2Cl2)

yield (%)

ratio 4:5

1 2 3 4

0.8 equiv FeCl3·6H2O, 0 °C, 0.75 h 2.0 equiv CF3CO2H, −10 °C, 1.5 h 0.2 equiv Ga(OTf)3, rt, 1.25 h cf. entry 3, performed on gram scale

16 23 50 98

1:3 4:5 1:1 1:1

DOI: 10.1021/acs.orglett.8b03810 Org. Lett. 2019, 21, 310−314

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Organic Letters

product-derived screening collections.19 Finally, the homologous bromo-aldehyde 11 gave access to the ring-expanded scaffold 15, again obtained as a single diastereomer. Having established the feasibility of an intramolecular (4 + 3) approach for gibberellane-type scaffolds, we next turned to an investigation of the “parent” kauranoid scaffolds with a sixmembered B-ring, with its steroid-like trans-fusion to a saturated A-ring (Figure 1). For this purpose, we identified bromoaldehyde 17 as a very interesting starting material (Scheme 3). This unsaturated aldehyde can be prepared in two

isomer wherein the furfuryl cation is attacked from a different Cp position, resulting in monocyclized products (see the Supporting Information). Using Wu’s conditions with gallium(III) triflate,18 best results were obtained on a small scale screening (Table 1, entry 3), and the observed product ratio indeed closely resembles that of the interconverting Cp positional diene isomers of the starting material. Upon scaleup to gram scale, without intermediate purification of the labile silyl ether 2, we were pleased to find that these conditions gave an almost quantitative conversion to 4 and 5 (Table 1, entry 4). A hydroboration of the alkene moieties allowed a straightforward separation of the monohydroxyl compounds 6a and 6b derived from 2, and the dihydroxyl compounds derived from 5. Starting from four grams of 1, more than one gram of 6a and 6b were isolated. Final Swern oxidation gave the separable regio-isomeric ketones 7a and 7b, both obtained in a synthetically useful overall yield from bromoaldehyde 1. Furthermore, these crystalline derivatives provided a conclusive structural and stereochemical assignment of the natural gibberellane/gibbane framework via single-crystal X-ray diffraction analysis. The relatively low yields for the key cycloaddition are counterbalanced by the small number of steps and rapid increase in molecular weight and complexity. Encouraged by the remarkable brevity and level of stereocontrol in the assembly of the tetracyclic core shared by gibberellane plant hormones (viz 1 → 4, 6, 7), we next explored the scope of this attractive sequence using a number of readily available bromo-aldehydes (Figure 2). The

Scheme 3. Synthesis of the Kauranoid Scaffolds 20 and 21

steps from the commercial bromoalkene 16 via a wellestablished regioselective and stereoselective allylic oxidation protocol.20 Before exploiting the double electrophilic nature of this intermediate in the one-pot bisfunctionalization protocol described above for bromoaldehyde 1, we envisaged the use of the electron-poor alkene as a good synthetic handle to install the trans-substituted six-membered A-ring found in kauranederived diterpenoids, via a straightforward Diels−Alder reaction. Using simple isoprene and a Lewis acid catalyst the resulting bromoaldehyde 18 was cleanly afforded as a single regio-isomer and stereoisomer, which was then subjected to the one-pot procedure to give the intramolecular cycloaddition precursor 19 in 66% yield. This intermediate was obtained as a mixture of inconsequential C-9 diastereomers, and its NMR analysis was further complicated by the presence of the expected positional diene isomers of the Cp moiety. Nevertheless, when silyl ether 19 was subjected to allyl cationgenerating conditions, only two reaction products were obtained, shown to be stereoisomers 20 and 21, both encompassing the expected kaurane-type scaffold. The major isomer 20 can be separated by flash chromatography and readily crystallized in pure form, allowing the unambiguous assignment of the relative stereochemistry, corresponding to that found in the beyerane-series of ent-kaurene metabolites. Intriguingly, the diastereoselectivity, with respect to the BCDring fusion, thus seems to be almost completely inverted, with respect to the A-ring aromatic scaffolds 4 and 12−15 (vide

Figure 2. Additional gibberellane-type scaffolds 12−15 (obtained in racemic form) from simple bromo-aldehyde starting materials 8−11, and a comparison to the structure found in natural gibberic acid.

“unbiased” substrate 4-bromopentaldehyde 8 gave the expected partial kauranoid scaffold 12 with the same level of overall efficiency and stereoselectivity. Similarly, the more substituted bromo-aldehydes 9 and 10 gave very similar results to those obtained with bromoaldehyde 1. The cycloadduct 14 was even obtained with good stereocontrol of the additionally introduced stereocenter, with the major relative stereochemistry corresponding to that found in the closely related naturally derived gibberic acid, which recently attracted significant interest as a scaffold to develop focused natural 312

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synthesis of precursor 23 from bromoaldehyde 18 via the onepot procedure was severely hampered by the lower reactivity of the lithiated sulfur heterocycle toward the aldehyde function, resulting in an unavoidable competition with the formation of cyclic ether 24, and necessitating an intermediate workup and purification. Nevertheless, sufficient amounts of the required cycloaddition precursor 23 could thus be prepared to allow a study of its intramolecular annulation. This proceeded in only modest yield, returning the expected beyerane scaffold 25 as the major reaction product. However, a range of several minor inseparable annulation products 26 were formed and coisolated, which were tentatively assigned a fused 6:6:5:5 ring system, based on the 1H NMR spectral similarity to known hydropentalene ring systems.22 These minor side products appear to correspond to the product of a competitive allyl cation (3 + 2) cycloaddition. Indeed, in previous studies on this heterocycle, we found that (3 + 2) cycloaddition pathways can also occur.13a,21 In summary, although the inherent diene isomerism of cyclopentadienyl units clearly limits the efficiency of our reported strategy, we have nevertheless achieved a remarkably short, and also scalable entry into the wide class of kaurane metabolite-type scaffolds. We have demonstrated six different sequences starting from different bromo-aldehydes with low but consistent overall yields, offering good to excellent stereocontrol, with regard to both of the naturally occurring beyerane and the kaurane/gibbane bicyclo[3.2.1]octane relative configurations. Although the use of this approach as a “late stage” transformation in a multistep synthesis of natural products may be limited, it should offer good opportunities for the rapid exploration of kauranoid chemical space via the generation of diversely substituted scaffolds derived from exceedingly simple building blocks in just a few synthetic operations. Work along these lines is currently underway and will be reported in due course.

supra). The minor diastereomer 21 could be tentatively assigned the natural kaurane relative stereochemistry, also found in norkauranoid 15, based on 2D NMR analysis performed on an enriched sample (see the Supporting Information). After exploring our three standard reaction conditions for the annulation of 19 and some optimization (cf. Table 1; see the Supporting Information), the best results were now obtained with trifluoroacetic acid (40% isolated yield), using prolonged reaction times at 0 °C. Interestingly, we were unable to observe monocyclized side products under any of these conditions, or even isolate any other side products corresponding to the incorrect Cp-regioisomer of 19. This may reflect the significant increase in distance between C-9 and C-15, which could favor intermolecular reactions over intramolecular ones in the case of the Cp-regio-isomeric furfuryl cation intermediates, ultimately resulting in an intractable mixture of oligomers as easily separated side products. The major isomer is readily separated by flash chromatography, typically providing 10%−20% isolated yield of the pure diastereomer 20 (5%−10% overall from 17). With the pure furanobeyerane 20 in hand, we also briefly explored the decoration and functionalization of this scaffold into more natural product-like motifs (Scheme 4). Simple Scheme 4. Additional Derivatization and Cycloaddition Experiments To Access Advanced Intermediates towards Kauranoid Natural Products

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03810. Experimental procedures; spectral and X-ray crystallography data (PDF) Accession Codes

CCDC 1861785−1861787 contain the supplementary crystallographic data for compounds 20, 7b and 7a. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_ request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

treatment with mCPBA gave a regioselective and stereoselective olefin epoxidation with competitive oxidative cleavage of the furan ring, releasing the core tetracyclic beyerane 22 as the major isolated reaction product. Finally, inspired by recent research results from our group involving allyl cation-type cycloadditions derived from dihydrodithiin-substituted alcohols,13a,21 we also briefly explored this heterocycle type. One advantage of this cycloaddition-mediating sulfur heterocycle is the fact that it can be removed via hydrodesulfurization, resulting in the product of a formal (4 + 3) cycloaddition of a naked allyl cation. The

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Johan M. Winne: 0000-0002-9015-4497 313

DOI: 10.1021/acs.orglett.8b03810 Org. Lett. 2019, 21, 310−314

Letter

Organic Letters Author Contributions

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The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Jan Goeman (Ghent University) for help with MS analyses, and Tim Courtin and Dieter Buyst of the NMR Expertise Centre (Ghent University) for help in NMR experiments. B.C. thanks FWO Vlaanderen for a scholarship. J.H. thanks IWT/VLAIO Hermes Fonds for a scholarship. K.V.H. thanks the Hercules Foundation (project AUGE/11/ 029 “3D-SPACE: 3D Structural Platform Aiming for Chemical Excellence”) and the Special Research Fund (BOF)−UGent (Project No. 01N03217) for funding. J.W. thanks the Special Research Fund (BOF)−UGent (Project No. STA043-17).

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DOI: 10.1021/acs.orglett.8b03810 Org. Lett. 2019, 21, 310−314