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A new route to platencin via decarboxylative radical cyclization† Gamal A. I. Moustafa, Yuki Saku, Hiroshi Aoyama and Takehiko Yoshimitsu*
Received 16th September 2014, Accepted 23rd October 2014 DOI: 10.1039/c4cc07316a www.rsc.org/chemcomm
A new approach to platencin, a potent antibiotic isolated from Streptomyces platensis, has been established. The highly congested tricyclic core of the natural product was successfully constructed by decarboxylative radical cyclization of an alkynyl silyl ester with Pb(OAc)4 in the presence of pyridine in refluxing 1,4-dioxane. The key decarboxylation, which likely takes place via lead(IV) esterification followed by carbon-centered radical generation and subsequent capture of the radical with a triple bond, allows the rapid construction of the twisted polycyclic system.
Platencin (1), a novel natural terpenoid molecule produced by Streptomyces platensis, has gained considerable attention as an attractive drug lead for antibiotic therapy in recent years (Fig. 1).1,2 The significant and broad-spectrum antibiotic activity of platencin stems from the dual inhibition of fatty acid synthetases, FabF and FabH, two essential enzymes for the survival of bacteria. Our laboratory has recently revealed that platencin exerts potent inhibitory activity toward multi- and extensively multi-drugresistant strains of Mycobacterium tuberculosis.3 However, despite the potent antibiotic activity of platencin, the improvement of its poor pharmacokinetic properties remains a problem. As such, intensive efforts to develop new platencin analogues with suitable pharmacokinetic properties by biosynthetic and chemical synthetic means are being exerted in many laboratories.4,5 We have been engaged in the total synthesis of this natural antibiotic, and have succeeded in establishing a synthetic route that features Ti(III)-mediated radical cyclization and homoallyl– homoallyl radical rearrangement to access the highly congested polycyclic skeleton.6 In the present study, we devised a new radical decarboxylation approach to the unique molecular architecture, which led to the formal total synthesis of platencin (1). Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: [email protected]; Fax: +81-6-6879-8214; Tel: +81-6-6879-8213 † Electronic supplementary information (ESI) available: Experimental protocols, spectroscopic and analytical data, and copies of 1H & 13C NMR. CCDC 1022475. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc07316a
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Fig. 1
Structure and atom numbering of platencin (1).
Our retrosynthesis of platencin (1) could be traced back to the known enone 2 that has been already converted into the natural product (Scheme 1). We envisioned that the enone would be derived from polycyclic compound 3, and that the key intermediate 3 would be obtained from alkynyl TBS ester 4 (or a corresponding carboxylic acid) by a decarboxylative radical cyclization. The functionalized bicyclo[2.2.2]octane system found in 4 would be readily constructed by the stereoselective sequential Michael reaction of enone 6 with ethyl acrylate. With this synthesis plan in mind, we endeavored to explore a new approach to platencin (1) (Scheme 2). Enone 6 was prepared in 55% yield by adding Grignard reagent 87 to 3-methoxy-2cyclohexenone 7 followed by facile dehydration of the resultant tertiary alcohol. Then, enone 6 was assembled with ethyl acrylate under conventional sequential Michael reaction8 conditions to provide bicyclo[2.2.2]octane derivative 5 in 61% yield. The introduction of an oxygen functionality at C5 (platencin numbering), which would eventually be transformed into the enone carbonyl of 2, was carried out by SeO2-mediated propargylic oxidation in slightly warmed MeCN (ca. 40 1C),9 leading to alcohol 9 in 64% yield (dr = 1 : 1). Ketalization of the carbonyl group of 9 under azeotropic dehydration conditions furnished ketal 10 in 80% yield. The hydrolysis of 10 with LiOH in refluxing aqueous EtOH led to the concomitant removal of both ethoxy and trimethylsilyl groups to afford hydroxy carboxylic acid (structure not shown). The hydroxy carboxylic acid was subjected to silylation with TBSCl/imidazole in DMF to give rise to disilylated material 4,
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Scheme 3
Scheme 1 A decarboxylative radical cyclization route to platencin (1): retrosynthetic analysis.
Scheme 2
Synthesis of alkynyl silyl ester 4.
which was isolable but somewhat unstable during silica gel chromatography due to the hydrolysis of the TBS ester functionality. With compound 4 in hand, we investigated the formation of another ring on the bicyclic system by elaborating the silyl ester functionality as a carbon radical precursor. In general, radical
Chem. Commun.
Hypothetical cascade of decarboxylative radical cyclization of 4.
decarboxylations are best performed by using Barton ester and related derivatives with a common radical mediator, such as n-Bu3SnH10 or free carboxylic acids with oxidants.11 We expected that the relatively labile TBS ester 4 would readily provide carboxylic acid in situ by desilylation followed by lead(IV) ester formation, or would directly react with lead(IV) tetraacetate to generate the mixed lead(IV) ester i, which would further undergo decarboxylation to produce carbon radical intermediate ii (Scheme 3). Then, radical ii would react with the triple bond to generate highly reactive alkenyl radical iii. It should also be emphasized that in our working hypothesis for the radical cyclization, the efficient hydrogen transfer onto transient alkenyl radical iii would be crucial. We envisioned that such a radical termination process would be operative via hydrogen atom abstraction from the ethereal solvent (iii to 3). Therefore, we decided to use ester 4 as the substrate in combination with lead(IV) tetraacetate as the oxidant in 1,4-dioxane as the ethereal solvent buffered with pyridine.12 Under the aforementioned conditions, to our delight, the decarboxylative radical cyclization of 4 took place to produce the desired compound 3 (30%; dr = 2 : 1) along with diastereomers 11 (30%; dr = 2 : 1).13 Although the determination of the stereochemistry was a highly challenging task, we were pleased to find that compound 12 derived from the major isomer of 11 gave crystals suitable for X-ray analysis (Fig. 2).14,15 We also noted that the 1H NMR spectra of each major isomer of 3 and 11 shown in Scheme 3 revealed some similarities, particularly the signals in the allylic and olefinic regions, and are distinct from those of each minor isomer, indicating that they likely have topological similarity in their molecular architectures.16 Based on those data, we assigned the stereochemistry at C5 of the major isomer of compound 3 to be a configuration, which only differed in the position of the ketal compared to the major isomer of 11. Compound 3 was hydrogenated with PtO2 in the presence of triethylamine in EtOAc under hydrogen atmosphere to furnish a saturated product as a single diastereomer favoring
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Notes and references
Fig. 2 X-ray crystallographic structure of alcohol 12 derived from the major isomer of 11.
Scheme 4
Synthesis of enone 2.
an a-configurational methyl group (Scheme 4). The high degree of facial selectivity observed for the hydrogenation was attributable to the presence of the bulky OTBS group that retards access of the reagent from the a-face. Then, the ketal and the silyl ether were sequentially cleaved by using 1 N HCl in THF followed by TBAF in THF to provide hydroxyketone 13 in 98% overall yield from 3. Hydroxyketone 13 was then subjected to Tebbe olefination (94% yield) followed by Parikh–Doering oxidation (74% yield; 82% based on recovered alcohol) to produce ketone 14. Conventional phenylselenylation of ketone 14 with LDA/PhSeCl followed by oxidative elimination with H2O2 allowed us to successfully access enone 2. The spectroscopic and analytical data of enone 2 synthesized by the aforementioned route were identical in all respects with those of authentic data reported in previous studies.5h,i,o,r In conclusion, we have accomplished a new formal synthesis of platencin (1) by devising a decarboxylative radical cyclization of alkynyl silyl ester 4 with lead(IV) tetraacetate/pyridine in 1,4-dioxane. The key transformation that uses a labile silyl ester as the carbon radical precursor is expected to find further application in decarboxylative radical chemistry. Investigations targeting platencin analogues synthesized using the present route for biological studies are ongoing, and the results will be reported in due course. G.A.I.M. acknowledges a scholarship awarded by the Egyptian Ministry of Higher Education for his graduate study. This work was supported by a grant generously provided by The Tokyo Biochemical Research Foundation (TBRF), and partially supported by a
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1 (a) J. Wang, S. Kodali, S. H. Lee, A. Galgoci, R. Painter, K. Dorso, F. Racine, M. Motyl, L. Hernandez, E. Tinney, S. Colletti, K. Herath, R. Cummings, O. Salazar, I. Gonzalez, A. Basilio, F. Vicente, O. Genilloud, F. Pelaez, H. Jayasuriya, K. Young, D. Cully and S. B. Singh, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 7612–7616; (b) H. Jayasuriya, K. B. Herath, C. Zhang, D. L. Zink, A. Basilio, O. Genilloud, M. T. Diez, F. Vicente, I. Gonzalez, O. Salazar, F. Pelaez, R. Cummings, S. Ha, J. Wang and S. B. Singh, Angew. Chem., Int. Ed., 2007, 46, 4684–4688. 2 For reviews, see: (a) A. M. Allahverdiyev, M. Bagirova, E. S. Abamor, S. C. Ates, R. C. Koc, C. Rabia, M. Miraloglu, S. Elcicek, S. Yaman and G. Unal, Infect. Drug Resist., 2013, 6, 99–114; (b) E. Martens and A. L. Demain, J. Antibiot., 2011, 64, 705–710; (c) X. Lu and Q. You, Curr. Med. Chem., 2010, 17, 1139–1155. 3 G. A. I. Moustafa, S. Nojima, Y. Yamano, A. Aono, M. Arai, S. Mitarai, T. Tanaka and T. Yoshimitsu, Med. Chem. Commun., 2013, 4, 720–723. 4 For reviews on the synthesis of platencin and the related antibiotic platensimycin, see: (a) M. Saleem, H. Hussain, I. Ahmed, T. van Ree and K. Karsten, Nat. Prod. Rep., 2011, 28, 1534–1579; (b) D. Y.-K. Chen, Synlett, 2011, 2459–2481; (c) K. Palanichamy and K. P. Kaliappan, Chem. – Asian J., 2010, 5, 668–703; (d) K. C. Nicolaou, J. S. Chen, D. J. Edmonds and A. A. Estrada, Angew. Chem., Int. Ed., 2009, 48, 660–719; (e) K. Tiefenbacher and J. Mulzer, Angew. Chem., Int. Ed., 2008, 47, 2548–2555. 5 (a) V. Singh, B. Das and S. M. Mobin, Synlett, 2013, 1583–1587; (b) L. Zhu, C. Zhou, W. Yang, S. He, G.-J. Cheng, X. Zhang and C.-S. Lee, J. Org. Chem., 2013, 78, 7912–7929; (c) J. S. Yadav, R. Goreti, S. Pabbaraja and B. Sridhar, Org. Lett., 2013, 15, 3782–3785; (d) K. Palanichamy, A. V. Subrahmanyam and K. P. Kaliappan, Org. Biomol. Chem., 2011, 9, 7877–7886; (e) G. Y. Leung, H. Li, O.-Y. Toh, A. M.-Y. Ng, R. J. Sum, J. E. Bandow and D. Y.-K. Chen, Eur. J. Org. Chem., 2011, 183–196; ( f ) S. Hirai and M. Nakada, Tetrahedron, 2011, 67, 518–530; ( g) D. C. J. Waalboer, S. H. A. M. Leenders, T. Schuelin-Casonato, F. L. van Delft and F. P. J. T. Rutjes, Chem. – Eur. J., 2010, 16, 11233–11236; (h) K. C. Nicolaou, G. S. Tria and D. J. Edmonds, Angew. Chem., Int. Ed., 2008, 47, 1780–1783; (i) J. Hayashida and V. H. Rawal, Angew. Chem., Int. Ed., 2008, 47, 4373–4376; ( j) K. Tiefenbacher and J. Mulzer, Angew. Chem., Int. Ed., 2008, 47, 6199–6200; (k) S. Y. Yun, J.-C. Zheng and D. Lee, Angew. Chem., Int. Ed., 2008, 47, 6201–6203; (l ) D. C. J. Waalboer, M. C. Schaapman, F. L. Van Delft and F. P. J. T. Rutjes, Angew. Chem., Int. Ed., 2008, 47, 6576–6578; (m) K. C. Nicolaou, Q.-Y. Toh and D. Y.-K. Chen, J. Am. Chem. Soc., 2008, 130, 11292–11293; (n) K. A. B. Austin, M. G. Banwell and A. C. Willis, Org. Lett., 2008, 10, 4465–4468; (o) K. Tiefenbacher and J. Mulzer, J. Org. Chem., 2009, 74, 2937–2941; (p) G. N. Varseev and M. E. Maier, Angew. Chem., Int. Ed., 2009, 48, 3685–3688; (q) A. K. Ghosh and K. Xi, Angew. Chem., Int. Ed., 2009, 48, 5372–5375; (r) K. C. Nicolaou, G. S. Tria, D. J. Edmonds and M. Kar, J. Am. Chem. Soc., 2009, 131, 15909–15917; (s) S. Hirai and M. Nakada, Tetrahedron Lett., 2010, 51, 5076–5079; (t) S. Hirai and M. Nakada, Tetrahedron, 2011, 67, 518–530; (u) V. Singh, B. C. Sahu, V. Bansal and S. M. Mobin, Org. Biomol. Chem., 2010, 8, 4472–4481; (v) P. Li and H. Yamamoto, Chem. Commun., 2010, 46, 6294–6295. 6 T. Yoshimitsu, S. Nojima, M. Hashimoto and T. Tanaka, Org. Lett., 2011, 13, 3698–3701. 7 Y. Shishido and C. Kibayashi, J. Org. Chem., 1992, 57, 2876–2883. 8 M. Ihara and K. Fukumoto, Angew. Chem., Int. Ed. Engl., 1993, 32, 1010–1022 and references cited therein. 9 (a) B. Chabaud and K. B. Sharpless, J. Org. Chem., 1979, 44, 4202–4204; (b) N. Sonoda, Y. Yamamoto, S. Murai and S. Tsutsumi, Chem. Lett., 1972, 229–232. 10 (a) D. H. R. Barton, D. Crich and W. B. Motherwell, J. Chem. Soc., Chem. Commun., 1983, 939; (b) M. F. Saraiva, M. R. C. Couri, M. Le Hyaric and M. V de Almeida, Tetrahedron, 2009, 65, 3563–3572. 11 For selected instances on related radical chemistry, see: (a) X. Li, Z. Wang, X. Cheng and C. Li, J. Am. Chem. Soc., 2012, 134,
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ChemComm 14 The structure of compound 12 was unambiguously determined by X-ray crystallographic analysis. CCDC 1022475. The X-ray analysis suggests that the hydroxyl group of the major C5 isomer of 11 has an axial orientation, being free from allylic strain with the exo-methylene. In contrast, the minor isomer of 11, which bears an equatorial hydroxyl group, likely suffers from allylic strain. The difference in the energies of the transition states of the radical cyclization by which those two isomers were produced might reflect the selectivity. This rationale is also applicable to the preferential production of the major isomer of 3 over the corresponding minor C5 isomer of 3. 15 The Mitsunobu esterification of alcohol 12 followed by hydrolysis gave an alcohol that was identical with one of the minor isomers, allowing us to confirm the stereochemical relationships of the cyclized materials. For further details, see ESI†. 16 Compounds 3 and 11 (corresponding major isomers are shown) show topological similarity in their molecular architectures.
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A new route to platencin via decarboxylative radical cyclization† Gamal A. I. Moustafa, Yuki Saku, Hiroshi Aoyama and Takehiko Yoshimitsu*
Received 16th September 2014, Accepted 23rd October 2014 DOI: 10.1039/c4cc07316a www.rsc.org/chemcomm
A new approach to platencin, a potent antibiotic isolated from Streptomyces platensis, has been established. The highly congested tricyclic core of the natural product was successfully constructed by decarboxylative radical cyclization of an alkynyl silyl ester with Pb(OAc)4 in the presence of pyridine in refluxing 1,4-dioxane. The key decarboxylation, which likely takes place via lead(IV) esterification followed by carbon-centered radical generation and subsequent capture of the radical with a triple bond, allows the rapid construction of the twisted polycyclic system.
Platencin (1), a novel natural terpenoid molecule produced by Streptomyces platensis, has gained considerable attention as an attractive drug lead for antibiotic therapy in recent years (Fig. 1).1,2 The significant and broad-spectrum antibiotic activity of platencin stems from the dual inhibition of fatty acid synthetases, FabF and FabH, two essential enzymes for the survival of bacteria. Our laboratory has recently revealed that platencin exerts potent inhibitory activity toward multi- and extensively multi-drugresistant strains of Mycobacterium tuberculosis.3 However, despite the potent antibiotic activity of platencin, the improvement of its poor pharmacokinetic properties remains a problem. As such, intensive efforts to develop new platencin analogues with suitable pharmacokinetic properties by biosynthetic and chemical synthetic means are being exerted in many laboratories.4,5 We have been engaged in the total synthesis of this natural antibiotic, and have succeeded in establishing a synthetic route that features Ti(III)-mediated radical cyclization and homoallyl– homoallyl radical rearrangement to access the highly congested polycyclic skeleton.6 In the present study, we devised a new radical decarboxylation approach to the unique molecular architecture, which led to the formal total synthesis of platencin (1). Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: [email protected]; Fax: +81-6-6879-8214; Tel: +81-6-6879-8213 † Electronic supplementary information (ESI) available: Experimental protocols, spectroscopic and analytical data, and copies of 1H & 13C NMR. CCDC 1022475. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc07316a
This journal is © The Royal Society of Chemistry 2014
Fig. 1
Structure and atom numbering of platencin (1).
Our retrosynthesis of platencin (1) could be traced back to the known enone 2 that has been already converted into the natural product (Scheme 1). We envisioned that the enone would be derived from polycyclic compound 3, and that the key intermediate 3 would be obtained from alkynyl TBS ester 4 (or a corresponding carboxylic acid) by a decarboxylative radical cyclization. The functionalized bicyclo[2.2.2]octane system found in 4 would be readily constructed by the stereoselective sequential Michael reaction of enone 6 with ethyl acrylate. With this synthesis plan in mind, we endeavored to explore a new approach to platencin (1) (Scheme 2). Enone 6 was prepared in 55% yield by adding Grignard reagent 87 to 3-methoxy-2cyclohexenone 7 followed by facile dehydration of the resultant tertiary alcohol. Then, enone 6 was assembled with ethyl acrylate under conventional sequential Michael reaction8 conditions to provide bicyclo[2.2.2]octane derivative 5 in 61% yield. The introduction of an oxygen functionality at C5 (platencin numbering), which would eventually be transformed into the enone carbonyl of 2, was carried out by SeO2-mediated propargylic oxidation in slightly warmed MeCN (ca. 40 1C),9 leading to alcohol 9 in 64% yield (dr = 1 : 1). Ketalization of the carbonyl group of 9 under azeotropic dehydration conditions furnished ketal 10 in 80% yield. The hydrolysis of 10 with LiOH in refluxing aqueous EtOH led to the concomitant removal of both ethoxy and trimethylsilyl groups to afford hydroxy carboxylic acid (structure not shown). The hydroxy carboxylic acid was subjected to silylation with TBSCl/imidazole in DMF to give rise to disilylated material 4,
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Scheme 3
Scheme 1 A decarboxylative radical cyclization route to platencin (1): retrosynthetic analysis.
Scheme 2
Synthesis of alkynyl silyl ester 4.
which was isolable but somewhat unstable during silica gel chromatography due to the hydrolysis of the TBS ester functionality. With compound 4 in hand, we investigated the formation of another ring on the bicyclic system by elaborating the silyl ester functionality as a carbon radical precursor. In general, radical
Chem. Commun.
Hypothetical cascade of decarboxylative radical cyclization of 4.
decarboxylations are best performed by using Barton ester and related derivatives with a common radical mediator, such as n-Bu3SnH10 or free carboxylic acids with oxidants.11 We expected that the relatively labile TBS ester 4 would readily provide carboxylic acid in situ by desilylation followed by lead(IV) ester formation, or would directly react with lead(IV) tetraacetate to generate the mixed lead(IV) ester i, which would further undergo decarboxylation to produce carbon radical intermediate ii (Scheme 3). Then, radical ii would react with the triple bond to generate highly reactive alkenyl radical iii. It should also be emphasized that in our working hypothesis for the radical cyclization, the efficient hydrogen transfer onto transient alkenyl radical iii would be crucial. We envisioned that such a radical termination process would be operative via hydrogen atom abstraction from the ethereal solvent (iii to 3). Therefore, we decided to use ester 4 as the substrate in combination with lead(IV) tetraacetate as the oxidant in 1,4-dioxane as the ethereal solvent buffered with pyridine.12 Under the aforementioned conditions, to our delight, the decarboxylative radical cyclization of 4 took place to produce the desired compound 3 (30%; dr = 2 : 1) along with diastereomers 11 (30%; dr = 2 : 1).13 Although the determination of the stereochemistry was a highly challenging task, we were pleased to find that compound 12 derived from the major isomer of 11 gave crystals suitable for X-ray analysis (Fig. 2).14,15 We also noted that the 1H NMR spectra of each major isomer of 3 and 11 shown in Scheme 3 revealed some similarities, particularly the signals in the allylic and olefinic regions, and are distinct from those of each minor isomer, indicating that they likely have topological similarity in their molecular architectures.16 Based on those data, we assigned the stereochemistry at C5 of the major isomer of compound 3 to be a configuration, which only differed in the position of the ketal compared to the major isomer of 11. Compound 3 was hydrogenated with PtO2 in the presence of triethylamine in EtOAc under hydrogen atmosphere to furnish a saturated product as a single diastereomer favoring
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Notes and references
Fig. 2 X-ray crystallographic structure of alcohol 12 derived from the major isomer of 11.
Scheme 4
Synthesis of enone 2.
an a-configurational methyl group (Scheme 4). The high degree of facial selectivity observed for the hydrogenation was attributable to the presence of the bulky OTBS group that retards access of the reagent from the a-face. Then, the ketal and the silyl ether were sequentially cleaved by using 1 N HCl in THF followed by TBAF in THF to provide hydroxyketone 13 in 98% overall yield from 3. Hydroxyketone 13 was then subjected to Tebbe olefination (94% yield) followed by Parikh–Doering oxidation (74% yield; 82% based on recovered alcohol) to produce ketone 14. Conventional phenylselenylation of ketone 14 with LDA/PhSeCl followed by oxidative elimination with H2O2 allowed us to successfully access enone 2. The spectroscopic and analytical data of enone 2 synthesized by the aforementioned route were identical in all respects with those of authentic data reported in previous studies.5h,i,o,r In conclusion, we have accomplished a new formal synthesis of platencin (1) by devising a decarboxylative radical cyclization of alkynyl silyl ester 4 with lead(IV) tetraacetate/pyridine in 1,4-dioxane. The key transformation that uses a labile silyl ester as the carbon radical precursor is expected to find further application in decarboxylative radical chemistry. Investigations targeting platencin analogues synthesized using the present route for biological studies are ongoing, and the results will be reported in due course. G.A.I.M. acknowledges a scholarship awarded by the Egyptian Ministry of Higher Education for his graduate study. This work was supported by a grant generously provided by The Tokyo Biochemical Research Foundation (TBRF), and partially supported by a
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ChemComm 14 The structure of compound 12 was unambiguously determined by X-ray crystallographic analysis. CCDC 1022475. The X-ray analysis suggests that the hydroxyl group of the major C5 isomer of 11 has an axial orientation, being free from allylic strain with the exo-methylene. In contrast, the minor isomer of 11, which bears an equatorial hydroxyl group, likely suffers from allylic strain. The difference in the energies of the transition states of the radical cyclization by which those two isomers were produced might reflect the selectivity. This rationale is also applicable to the preferential production of the major isomer of 3 over the corresponding minor C5 isomer of 3. 15 The Mitsunobu esterification of alcohol 12 followed by hydrolysis gave an alcohol that was identical with one of the minor isomers, allowing us to confirm the stereochemical relationships of the cyclized materials. For further details, see ESI†. 16 Compounds 3 and 11 (corresponding major isomers are shown) show topological similarity in their molecular architectures.
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