Catalytic approaches to assemble cyclobutane motifs in natural product synthesis

Meng Wang and Ping Lu *
Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Lu, Shanghai 200433, P. R. China. E-mail:

Received 31st July 2017 , Accepted 27th September 2017

First published on 28th September 2017

Cyclobutanes, as the second most strained monocyclic all-carbon rings, are found in many complex natural products. Although recent methodological developments in the formation of cyclobutanes have been reviewed, few have focused on the topic of total synthesis of cylcobutane-containing natural products. Here we summarize recent advances in natural product synthesis, featuring late-stage functionalization of four-membered rings and novel strategies for the stereocontrolled assembly of cyclobutanes or cyclobutenes.

image file: c7qo00668c-p1.tif

Meng Wang

Meng Wang was born in Yantai, Shandong province. She received her B.S. degree in pharmacy from the East China University of Science and Technology in June 2017. In September, she joined Prof. Lu's group at Fudan University to pursue her Ph.D. degree. Her research interests focus on transition-metal catalysis and total synthesis of natural products.

image file: c7qo00668c-p2.tif

Ping Lu

Ping Lu obtained his B.S. degree from the University of Science and Technology of China in 2004. He then moved to the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and received his Ph.D. degree under the supervision of Prof. Shengming Ma in 2009. He conducted his postdoctoral research with Prof. Thorsten Bach (Technischen Universität München) and Prof. Armen Zakarian (University of California, Santa Barbara). In 2016, he started his independent academic career at the Department of Chemistry, Fudan University. Research in the Lu group combines the areas of natural product chemistry, complex molecule synthesis and methodology development.


Cyclobutanes, as important structural elements, are present in many natural products and bioactive molecules.1 Due to the highly-strained ring system, stereocontrolled synthesis of the cyclobutane ring, especially in an enantiopure form, remains a challenging and intriguing topic in the organic community.2 The structural novelty and potential biological activity of cyclobutane-containing natural products have attracted wide interest from synthetic chemists.

Methodological advances in catalysis have provided powerful synthetic arsenals in chemical bond formation or breaking processes, and new perspectives, benefiting from the methodological development, have flourished in total synthesis. For example, transition-metal catalyzed C–H functionalization has enabled chemists to achieve unprecedented routes to forge core structural skeletons in a highly efficient way.3

In this Highlight, we will focus on recent advances in the total synthesis of selected cyclobutane-containing natural products in recent years (2011–2017), as depicted in Fig. 1, which employ catalytic approaches to forge or functionalize all carbon four-membered rings as key steps. It will be split into two parts, one of which is dedicated to new functionalization methods of cyclobutanes or cyclobutenes which were prepared from [2 + 2]-cycloaddition. In the second part we will discuss some novel approaches, other than cycloadditions, to assemble enantiomerically enriched cyclobutane or cyclobutene motifs. Our goal was to provide a perspective view of the topic and some omissions are unavoidable for a number of reasons including space limitations.

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Fig. 1 Selected cyclobutane-containing natural products.

Catalytic functionalization of cyclobutane or cyclobutene

In this section, cyclobutane or cyclobutene motifs were synthesized from traditional [2 + 2]-cycloadditions in most cases. Starting from these four-membered ring substrates, novel functionalization strategies were employed to access the requisite core skeletons in natural product synthesis.

Piperarborenine B (1), isolated from the stem of Piper arborescens, has exhibited significant cytotoxicity against P-388, HT-29 and A549 cancer cell lines in vitro.4 Piperarborenine B has four substituents (one on each of the four carbons) on the cyclobutane ring, with two aryl groups on the opposite sides. It has a cistranscis relative configuration, presumably originating from the head-to-tail dimerization of the parent monomeric olefins. To overcome the limitations of regio- and stereocontrol in the dimerization of the two olefins, Baran and co-workers applied a guided sequential C–H arylation strategy onto the cyclobutane ring to install the two requisite aryl groups in the total synthesis of piperarborenine B (Scheme 1).5 The synthesis commenced with an efficient assembly of a cyclobutane ring from the commercially available starting material methyl coumalate (8). An irradiated electrocyclization of 8,6 followed by a hydrogenation reduction and coupling with 2-aminothioanisole (9),7 afforded the 1,3-cis cyclobutane 10 in 61% overall yield (on a gram scale). Under optimized conditions, the directed C–H arylation of 10 with 3,4,5-trimethoxyiodobenzene (11) provided the cis-arylation product 12 in 52% yield on a gram scale. It is noteworthy that the addition of HIFP (1,1,1,3,3,3-hexafluoro-2-propanol) and pivalic acid was proven to be crucial in terms of the isolated yield of the product and reducing the over-arylation byproduct. Epimerization of 12 with LiOt-Bu set the stage for the second arylation. The second cis-arylation with 3,4-dimethoxyiodobenzene (13) gave the product 14 in 46% yield using t-BuOH as a solvent instead of HPIF. A further three-step transformation smoothly resulted in piperarborenine B (1) on a 100 mg scale. This synthesis showcased the power of palladium catalyzed C–H functionalization on a cyclobutane ring for the first time.8 Since then, this strategy has been further employed in the synthesis of related cyclobutane-containing natural products (vide infra).

image file: c7qo00668c-s1.tif
Scheme 1 Selected key steps in the total synthesis of piperarborenine B (1) in Baran's synthesis.

Pipercyclobutanamide A (2) has been isolated from the powdered fruits of Piper nigrum (black pepper) and it has been recognized as a potent mechanism-based inhibitor of cytochrome P450 2D6 (CYP2D6) by recent studies.9 Pipercyclobutanamide A (2) is a heterodimeric cyclobutane natural product and it has a transtranstrans configuration with aryl and olefin functional groups on the opposite sides. The Baran synthesis of the proposed structure of pipercyclobutanamide A (2) demonstrated another elegant example of C–H functionalization in scalable synthesis (Scheme 2).10 In the synthesis amide 16 was prepared from methyl coumalate (8) in a three-step sequence with 8-aminoquinoline amide as a directing group.7 Although the C–H olefination resulted in an undesired bis-olefination product (not shown), the all cis cyclobutane 20 was achieved by a sequential arylation and olefination under optimized conditions in moderate yield with highly stereocontrolled selectivity. Further epimerization and functionality manipulations led to the completion of the total synthesis on a 100 mg scale. It is worth mentioning that data of the synthetic sample 2 were mismatched with reported data of isolated pipercyclobutanamide A, probably due to the unpredictable NMR chemical shift of the cyclobutane ring system, which originates from the rapid ring flipping character.

image file: c7qo00668c-s2.tif
Scheme 2 Selected key steps in the total synthesis of pipercyclobutanamide A (2, proposed structure) in Baran's synthesis.

Scopariusicide A (4) was isolated from the aerial parts of Isodon scoparius by Pu and Sun and showed a weak immunosuppressive activity (T cell, IC50 = 20.7 μM).11 The cyclobutane skeleton might originate from a crossed head-to-head dimerization of the parent olefins. Inspired by this biosynthetic hypothesis, the same group completed a concise total synthesis of scopariusicide A, featuring a crossed intermolecular [2 + 2]-photocycloaddition and a late-stage C–H functionalization on the cyclobutane ring (Scheme 3). Irradiation of the advanced intermediate 21 and methyl acrylate at λ = 313 nm gave a major head-to-head product in 68% yield, together with two regioisomers. Saponification and sequential coupling with 2-aminothioanisole (9) led to the precursor 22. Under optimized conditions, the requisite aryl group was installed smoothly utilizing a directed C–H activation reaction and the cyclobutane 23 was isolated in 82% yield. Subsequently, a hydrolysis reaction and an esterification reaction completed the synthesis of scopariusicide A (4) uneventfully.

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Scheme 3 Selected key steps in the total synthesis of scopariusicide A (4) in Pu's synthesis.

Hippolachnin A (5) has been isolated from South China Sea sponges Hippospongia lachne and exhibited a potent antifungal activity against three pathogenic fungi, Cryptococcus neoformans, Trichophyton rubrum and Microsporum gypseum, with an MIC value of 0.41 μM for each fungus.12 The structure of hippolachnin A possesses a highly substituted cyclobutane ring and six contiguous stereocenters. Carreira and co-workers envisioned that the core skeleton could be forged via functionalization of a highly strained cyclobutene (Scheme 4).13 The synthesis started with intermolecular [2 + 2]-photocycloaddition followed by irradiation of the enone 24 and hex-3-yne at λ > 270 nm and subsequent basic treatment with K2CO3 provided the desired cyclobutene 25 in 54% overall yield. The advanced intermediate 26 was synthesized via a scalable three-step route and its cyclization was studied. Two approaches were investigated to establish the requisite stereochemical assembly of the tricyclic system. The first approach, using the hydrometallation of cyclobutene and subsequent addition to the unsaturated ester, failed to install the correct C10 stereocenter. After optimization of the second approach, it was found that Lewis acid mediated ene-cyclization gave the desired congested structure 27 in high yield and good diastereoselectivity. The judicious selection of the BF3·2HOAc complex was key to the success of the reaction. Using Pearlman's catalyst (Pd(OH)2), the exo-selective hydrogenation of the exocyclic C[double bond, length as m-dash]C bond in 27 gave the tricyclic product 28 in high yield.

image file: c7qo00668c-s4.tif
Scheme 4 Selected key steps in the total synthesis of hippolachnin A in Carreira's synthesis (5).

As well as through photo-induced cycloaddition, the cyclobutane ring can also be synthesized through thermo- or Lewis acid-mediated cycloadditions. Recently, the Wood and Brown groups independently completed the concise synthesis of hippolachnin A (5), both featuring a quadricyclane cycloaddition and a late-stage C–H functionalization (Scheme 5).14 In Brown's synthesis, the [2π + 2σ + 2σ] cycloaddition of quadricyclane and the acid chloride 29 led to the cyclobutane 30 in 74% yield with 5[thin space (1/6-em)]:[thin space (1/6-em)]1 dr under microwave irradiation at 140 °C. Treatment of the advanced intermediate 31 under the Suárez conditions (I2, PhI(OAc)2, )15 led to the formation of the tricyclic product 32, which was further oxidized with DMDO (dimethyldioxirane) to afford the desired core skeleton 33 in 77% yield. In Wood's synthesis, a catalytic amount of TiCl4 efficiently promoted the [2π + 2σ + 2σ] cycloaddition of quadricyclane and the alkene 34 at 0 °C to provide the cyclobutane 35 in 73% yield with 4.4[thin space (1/6-em)]:[thin space (1/6-em)]1 diastereoselectivity. On treatment of the advanced intermediate 36 with modified White conditions (Pd(OAc)2·(CH2SO2Ph)2, Cr(salen)Cl, 1,4-benzoquinone)16 the desired C–H oxidation was achieved in 51% yield. Notably, the presence of excess water is crucial to the success of this transformation. Installation of the remaining vinylogous carbonate moiety completed the synthesis of hippolachnin A (5). In the same paper, studies based on a collaborative union of these two strategies were also described.

image file: c7qo00668c-s5.tif
Scheme 5 Key steps in the total synthesis of hippolachnin A in the Brown and Wood routes (5).

Lewis acid catalyzed enantioselective [2 + 2] cycloaddition is also a powerful method to synthesize chiral cyclobutane derivatives. In 2016, Tang and Xie reported a concise synthesis of (+)-piperarborenine B ((+)-1) which was enabled by an enantioselective construction of a cyclobutane ring in the presence of a catalytic amount of Lewis acid and chiral ligand (Scheme 6).17 In the forward sense, the Cu/Sabox-catalyzed [2 + 2]-cycloaddition of the methylidenemalonate 38 and the aryl alkene 39 produced the cyclobutane 40 as a single isomer in 68% yield and 99% ee. Exposure of the advanced intermediate 41 under C–H functionalization conditions afforded the fully substituted cyclobutane 42 in high yield. A further 5-step transformation completed the total synthesis uneventfully.

image file: c7qo00668c-s6.tif
Scheme 6 Selected key steps in the total synthesis of (+)-piperarborenine B ((+)-1) in Xie and Tang's synthesis.

Construction of the cyclobutane ring other than through cycloaddition

In addition to cycloadditions, there has been a number of other reports in the field of catalytic enantioselective synthesis of cyclobutanes in the last decade. Interestingly, among them diazo compounds were chosen as precursors to assemble four-membered carbon rings in most cases.

Piperchabamide G (3) was isolated from the fruit of Piper chaba in 2009 and exhibited hepatoprotective activity by inhibition of the D-GalN/TNF-α-induced death of hepatocytes.18 Like pipercyclobutanamide A (2), piperchabamide G (3) is also a tetrasubstituted cyclobutane, and has a transtranstrans relative configuration. Tang and co-workers envisioned that the tetrasubstituted cyclobutane core could be synthesized from a cyclobutenoate, which was formed from the silver-catalyzed ring-expansion of a cyclopropyl diazo compound (Scheme 7).19 In the synthesis the cyclopropyl diazo compound 43 underwent a smooth ring expansion to afford the cyclobutenoate 44 in 95% yield in the presence of a catalytic amount of silver triflate. Rhodium-catalyzed conjugate addition of the arylboronic acid 45 to the cyclobutenoate 44 followed by epimerization provided the cyclobutane core skeleton 46 in 65% overall yield with all desired stereocenters set. Further functionality manipulations led to completion of the total synthesis of the proposed structures of pipercyclobutanamide A (2) and piperchabamide G (3). It is of note that the synthetic spectra did not match with the reported data. In the same paper, the authors modified the structures of pipercyclobutanamide A and piperchabamide G to six-membered ring isomers, i.e. chabamide and nigramide F, respectively.

image file: c7qo00668c-s7.tif
Scheme 7 Selected key steps in the total synthesis of pipercyclobutanamide A (2, proposed structure) and piperchabamide G (3) in Tang's synthesis.

In 2016, Fox and co-workers reported an elegant total synthesis of piperarborenine B (1) featuring their previously developed enantioselective bicyclobutanation/homoconjugate addition of a β-vinyl diazo compound (Scheme 8).20 In the forward sense, exposure of the diazoester 47 to 0.1 mol% of a mixed-ligand rhodium catalyst, Rh2(S-NTTL)3(dCPA), afforded the bicyclobutane intermediate 48 in 79% yield and 92% ee. Subsequent copper-mediated Grignard nucleophilic addition and kinetic protonation using BHT led to the formation of the cyclobutane product 50 in 69% yield and 92% ee with 4[thin space (1/6-em)]:[thin space (1/6-em)]1 dr. The advanced intermediate 51 was then treated under palladium-catalyzed C–H functionalization conditions to provide the densely substituted cyclobutane 52 in high yield. The (+)-piperarborenine B was synthesised in 10 steps and in 8% overall yield on a 0.4 g scale.

image file: c7qo00668c-s8.tif
Scheme 8 Selected key steps in the total synthesis of (+)-piperarborenine B (1) in Fox's synthesis.

(+)-Psiguadial B (6) has been isolated from the leaves of Psidium guajava and exhibits a potent inhibitory effect on the growth of HepG2 cells with an IC50 value of 45.62 nM.21 The structure of (+)-psiguadial B (6) has a central bicyclo[4.3.1]decane which is trans-fused to a cyclobutane. Reisman and co-workers hypothesized that a tandem Wolff rearrangement/catalytic asymmetric ketene addition and subsequent C–H functionalization would install the stereocenters on the cyclobutane ring (Scheme 9).22 Thus irradiation of the diazoketone 53 at λ = 254 nm together with 8-aminoquinoline (15) and 10 mol% (+)-cinchonine provided the cyclobutane 54 in 62% yield and 79% ee on a 4-gram scale. Treatment of 54 with the vinyl iodide 55 smoothly afforded the expected cis product 56 in 72% yield under C–H functionalization conditions. Epimerization at C5 gave the required correct stereocenters on the cyclobutane ring, which led to the completion of the synthesis.

image file: c7qo00668c-s9.tif
Scheme 9 Selected key steps in the total synthesis of (+)-psiguadial B (6) in Reisman's synthesis.

Phainanoids were isolated by Yue and co-workers from Phyllanthus hainanesis and exhibited potent immunosuppressive activities.23 The most potent one, phainanoid F (7), showed activities against the proliferation of T cells with an IC50 value of 2.04 ± 0.01 nM and B cells with an IC50 value of <1.60 ± 0.01 nM. Phainanoids have a complex polycyclic structure including two strained rings, cyclopropane and cyclobutane rings, and two spirocycles. As work towards the total synthesis, Dong and co-workers recently reported an efficient palladium-catalyzed cross-coulping reaction to construct the core cyclobutane skeleton (Scheme 10).24 Treatment of the advanced intermediate 57 with 5 mol% Pd(OAc)2, 10 mol% QPhos and 1.5 eq. LiOt-Bu afforded the desired 4,5-spirocycle 58 as a single diastereomer in 57% yield. The authors attributed this high stereoselectivity in the cross-coupling reaction to a favorable coordinative interaction between the carbonyl group in 3-coumaranone and the palladium catalyst.

image file: c7qo00668c-s10.tif
Scheme 10 Selected key steps towards the total synthesis of the phainanoid skeleton in Dong's synthesis.


In conclusion, we summarized here recent advances in the total synthesis of cyclobutane-containing natural products, featuring novel functionalization on four-membered rings and new assemblies of enantiomerically enriched cyclobutane or cyclobutene rings. With unceasing methodological development, we would expect that new disconnection strategies will be continuously utilized to access complex cyclobutane ring systems in complex molecule synthesis.

Conflicts of interest

There are no conflicts to declare.


We thank the 1000-Youth Talents Plan and Fudan University (for the start-up grant) for financial support.


  1. (a) Y.-Y. Fan, X.-H. Gao and J.-M. Yue, Sci. China: Chem., 2016, 59, 1126–1141 CrossRef CAS ; (b) M. A. Beniddir, L. Evanno, D. Joseph, A. Skiredj and E. Poupon, Nat. Prod. Rep., 2016, 33, 820–842 RSC ; (c) V. M. Dembitsky, Phytomedicine, 2014, 21, 1559–1581 CrossRef CAS PubMed .
  2. (a) S. Poplata, A. Troester, Y.-Q. Zou and T. Bach, Chem. Rev., 2016, 116, 9748–9815 CrossRef CAS PubMed ; (b) Y. Xu, M. L. Conner and K. M. Brown, Angew. Chem., Int. Ed., 2015, 54, 11918–11928 CrossRef CAS PubMed ; (c) C. M. Rasik and K. M. Brown, Synlett, 2014, 760–765 CAS .
  3. (a) Y. Qiu and S. Gao, Nat. Prod. Rep., 2016, 33, 562–581 RSC ; (b) D. Y.-K. Chen and S. W. Youn, Chem. – Eur. J., 2012, 18, 9452–9474 CrossRef CAS PubMed ; (c) P. B. Brady and V. Bhat, Eur. J. Org. Chem., 2017, 5179–5190 CrossRef CAS .
  4. I.-L. Tsai, F.-P. Lee, C.-C. Wu, C.-Y. Duh, T. Ishikawa, J.-J. Chen, Y.-C. Chen, H. Seki and I.-S. Chen, Planta Med., 2005, 71, 535–542 CrossRef CAS PubMed .
  5. W. R. Gutekunst and P. S. Baran, J. Am. Chem. Soc., 2011, 133, 19076–19079 CrossRef CAS PubMed .
  6. (a) F. Frebault, M. Luparia, M. T. Oliveira, R. Goddard and N. Maulide, Angew. Chem., Int. Ed., 2010, 49, 5672–5676 CrossRef CAS PubMed ; (b) E. J. Corey and J. Streith, J. Am. Chem. Soc., 1964, 86, 950–951 CrossRef CAS .
  7. (a) V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am. Chem. Soc., 2005, 127, 13154–13155 CrossRef CAS PubMed ; (b) D. Shabashov and O. Daugulis, J. Am. Chem. Soc., 2010, 132, 3965–3972 CrossRef CAS PubMed .
  8. F. Frébault and N. Maulide, Angew. Chem., Int. Ed., 2012, 51, 2815–2817 CrossRef PubMed .
  9. (a) Y. Fujiwara, K. Naithou, T. Miyazaki, K. Hashimoto, K. Mori and Y. Yamamoto, Tetrahedron Lett., 2001, 42, 2497–2499 CrossRef CAS ; (b) Subehan, T. Usia, S. Kadota and Y. Tezuka, Planta Med., 2006, 72, 527–532 CAS .
  10. W. R. Gutekunst, R. Gianatassio and P. S. Baran, Angew. Chem., Int. Ed., 2012, 51, 7507–7510 CrossRef CAS PubMed .
  11. M. Zhou, X.-R. Li, J.-W. Tang, Y. Liu, X.-N. Li, B. Wu, H.-B. Qin, X. Du, L.-M. Li, W.-G. Wang, J.-X. Pu and H.-D. Sun, Org. Lett., 2015, 17, 6062–6065 CrossRef CAS PubMed .
  12. (a) S.-J. Piao, Y.-L. Song, W.-H. Jiao, F. Yang, X.-F. Liu, W.-S. Chen, B.-N. Han and H.-W. Lin, Org. Lett., 2013, 15, 3526–3529 CrossRef CAS PubMed ; (b) A. Butts and D. J. Krysan, PLoS Pathog., 2012, 8, e1002870 CAS ; (c) T. Roemer and D. J. Krysan, Cold Spring Harbor Perspect. Med., 2014, 4, a019703 CrossRef PubMed .
  13. S. A. Ruider, T. Sandmeier and E. M. Carreira, Angew. Chem., Int. Ed., 2015, 54, 2378–2382 CrossRef CAS PubMed .
  14. M. E. McCallum, C. M. Rasik, J. L. Wood and M. K. Brown, J. Am. Chem. Soc., 2016, 138, 2437–2442 CrossRef CAS PubMed .
  15. J. I. Concepcioń, C. G. Francisco, R. Hernańdez and E. Suaŕez, Tetrahedron Lett., 1984, 25, 1953–1956 CrossRef .
  16. (a) T. J. Osberger and M. C. White, J. Am. Chem. Soc., 2014, 136, 11176–11181 CrossRef CAS PubMed ; (b) S. E. Ammann, G. T. Rice and M. C. White, J. Am. Chem. Soc., 2014, 136, 10834–10837 CrossRef CAS PubMed .
  17. J.-L. Hu, L.-W. Feng, L. Wang, Z. Xie, Y. Tang and X. Li, J. Am. Chem. Soc., 2016, 138, 13151–13154 CrossRef CAS PubMed .
  18. H. Matsuda, K. Ninomiya, T. Morikawa, D. Yasuda, I. Yamaguchi and M. Yoshikawa, Bioorg. Med. Chem., 2009, 17, 7313 CrossRef CAS PubMed .
  19. R. Liu, M. Zhang, T. P. Wyche, G. N. Winston-McPherson, T. S. Bugni and W. Tang, Angew. Chem., Int. Ed., 2012, 51, 7503–7506 CrossRef CAS PubMed .
  20. R. A. Panish, S. R. Chintala and J. M. Fox, Angew. Chem., Int. Ed., 2016, 55, 4983–4987 CrossRef CAS PubMed .
  21. M. Shao, Y. Wang, Z. Liu, D.-M. Zhang, H.-H. Cao, R.-W. Jiang, C.-L. Fan, X.-Q. Zhang, H.-R. Chen, X.-S. Yao and W.-C. Ye, Org. Lett., 2010, 12, 5040–5043 CrossRef CAS PubMed .
  22. L. M. Chapman, J. C. Beck, L. Wu and S. E. Reisman, J. Am. Chem. Soc., 2016, 138, 9803–9806 CrossRef CAS PubMed .
  23. Y.-Y. Fan, H. Zhang, Y. Zhou, H.-B. Liu, W. Tang, B. Zhou, J.-P. Zuo and J.-M. Yue, J. Am. Chem. Soc., 2015, 137, 138–141 CrossRef CAS PubMed .
  24. J. Xie, J. Wang and G. Dong, Org. Lett., 2017, 19, 3017–3020 CrossRef CAS PubMed .

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