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Total synthesis of naturally occurring (+)-psychotriasine and the related tetrahydro-β-carboline, dimeric tryptamines with NC connectivities
Accepted Manuscript Total synthesis of naturally occurring (+)-psychotriasine and the related tetrahydro-β-carboline, dimeric tryptamines with N–C connectivities Samuel Gallego, Paula Lorenzo, Rosana Alvarez, Angel R. de Lera PII: DOI: Reference:
S0040-4039(16)31629-X http://dx.doi.org/10.1016/j.tetlet.2016.12.003 TETL 48415
To appear in:
Tetrahedron Letters
Received Date: Accepted Date:
25 November 2016 2 December 2016
Please cite this article as: Gallego, S., Lorenzo, P., Alvarez, R., de Lera, A.R., Total synthesis of naturally occurring (+)-psychotriasine and the related tetrahydro-β-carboline, dimeric tryptamines with N–C connectivities, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Total synthesis of naturally occurring (+)psychotriasine and the related tetrahydro-carboline, dimeric tryptamines with N–C connectivities
Leave this area blank for abstract info.
Samuel Gallego, Paula Lorenzo, Rosana Álvarez and Ángel R. de Lera Departamento de Química Orgánica, Facultade de Química, CINBIO and IIS Galicia Sur, Universidade de Vigo, 36310 Vigo, Spain.
1
Tetrahedron Letters
Total synthesis of naturally occurring (+)-psychotriasine and the related tetrahydro-carboline, dimeric tryptamines with N–C connectivities Samuel Gallego,a Paula Lorenzo,a Rosana Alvarez,a, and Angel R. de Leraa, a
Departamento de Química Orgánica, Universidade de Vigo, CINBIO and IIS Galicia Sur, Lagoas-Marcosende, 36310 Vigo, Spain
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
Naturally occurring (+)-psychotriasine (+)-1 and congener tetrahydro--carboline (+)-3, which are dimeric tryptophan-derived alkaloids with tryptamine and carboline units connected by the indole nitrogen to the quaternary carbon atom of the pyrrolidinoindoline core, have been synthesized for the first time and their absolute configurations confirmed.
Keywords: Keyword_1 Keyword_2 Keyword_3 Keyword_4 Keyword_5 Keywords: alkaloids, synthesis, tryptamines
——— Corresponding author. Tel.: +34-986-812316; fax: +34-986-811940; e-mail: [email protected]
2009 Elsevier Ltd. All rights reserved.
2
Tetrahedron Letters 1. Introduction
Secondary metabolites derived from tryptophan are ubiquitous in Nature.1,2 Plants of the genus Psychotria (Rubiaceae), which grow mainly in tropical and subtropical areas, are rich in multimeric indole alkaloids.3 The heterodimeric (+)-psychotriasine (+)-1 was isolated from Psychotria calocarpa by Hao et al. and assigned structure 1, which is composed of two tryptophan-derived subunits, namely methyltryptamine and a hexahydropyrrolo[2,3b]indole, connected to each other through the C3a–N1' bond.4 Alkaloid (+)-3 differs in the N-connected component and this compound was isolated, together with (+)-2, from P. henryi, a plant used in traditional Chinese medicine.5 Based on an analysis of the spectroscopic data, the stereostructure of (+)-3 was proposed to be composed of hexahydropyrrolo[2,3b]indole and tetrahydropyrido[3,4-b]indole subunits connected by a C3’a–N1 bond. Comparison of the DFTcomputed and experimental ECD spectra for compounds (+)-2 and (+)-3 suggested the same absolute configuration, denoted as 3'aS,8'aR for 3 (note the change of descriptor for compound 2 at C8'a, which is S).5 We recently reported the total synthesis and structural revision of the C3–N heterodimeric pestalazine B (+)-4 (Figure 1),6 a diketopiperazine isolated from the pathogenic fungus Pestalotiopsis theae. The connection of the subunits was based on the displacement of exo-3a-bromo-2methylcarboxylate-hexahydropyrrolo[2,3-b]indole 57,8 (Scheme 1) by the indole nitrogen following the procedure reported by Rainier.9,10 The same strategy appears well suited to access the structurally related alkaloids 1 and 3, and thus determine their absolute stereostructures.
respectively. The mechanism of these C–N bond formation processes has been demonstrated by Rainier to involve a transient cyclopropylazetoindoline formed by intramolecular displacement of the bromine by the initially formed ester enolate, which is then trapped by the corresponding deprotected indole nitrogen. Subsequent kinetic protonation of the ester enolate results in the endo isomer of the substituted indoline.10 The expected inversion of configuration at C2’ was confirmed in both cases by 1H-NMR spectroscopy on the basis of the characteristic chemical shift of the endo methyl ester at ~3.2 ppm. Once the expedient construction of these dimeric tryptophan compounds had been completed, the decarboxylation of the original D-tryptophan esters that served to control the absolute configuration at the fusion atoms of the pyrrolidinoindoline core was carried out by the classical Barton’s reductive procedure. Saponification of the methyl esters 7 and 9 to the carboxylic acids and formation of the PTOC esters by treatment with isobutylchloroformate and thiopyridine N-oxide 10 was followed by photochemicallyinduced radical decarboxylation to afford 11 and 12, respectively.14 Deprotection of the BOC carbamates was effected by treatment with TMSI in CH3CN and final reduction of the methylcarbamates with RedAl® at 110 ºC15 afforded the desired products 1 and 3, respectively. As anticipated, the spectroscopic data (including the optical rotation, for 1, [α]D24.5 +106.1 (c 0.2, MeOH); lit.4: [α]D19.2 +104.2 (c 0.1, MeOH); for 3, [α]D22.5 +189.5 (c 0.2, MeOH); lit.5: [α]D23 +179.5 (c 0.16, MeOH)) of 1 and 3 matched those of the natural products4,5 and therefore the first total synthesis of these naturally occurring C3a-N1-linked tryptamine dimers was completed. Both racemic and unnatural (–)-psychotriasine have been synthesized previously. In 2009 Baran carried out the total synthesis of rac-psychotriasine during his comprehensive work on multimeric indole alkaloids and predicted, in the same year it was isolated from a natural source,4 that “it would not be surprising if non-selective oxidation pathways of methyl tryptamine in Nature would result in the formation of this product….”.15 Recently two synthesis of (–)psychotriasine have been reported.16 The first is based on a BINOL-catalyzed azo coupling-iminium cyclization strategy that was also applied to (+)-pestalazine B (4),16a and the second on a copper-catalyzed asymmetric dearomative amination of tryptamines.16b In the three cases, the indole ring was constructed by Pd-catalyzed Larock cyclization15 following the functionalization at C3a with an aniline.16 An additional synthesis of rac-psychotriasine is somehow related to that described here, since the C–N connection step is based on the displacement of an intermediate sulfonium ion by the protected tryptamine.17
Figure 1. Representative pyrrolidinoindoline-containing alkaloids with C3’a–N1 connections.
In the event, enantiopure exo-5,11 obtained by stereoselective bromocyclization of the appropriately protected D-tryptophan,7,8 was treated under basic conditions (KO-tBu in CH3CN) with either N-protected tryptamine 612 or N-protected tetrahydro--carboline 813 to afford the corresponding adducts 7 and 9 in 57 and 77% yields,
In summary, the absolute configuration of the purported structure of the natural products (+)-psychotriasine (1)4 and (+)-35 has been corroborated by their first total synthesis. The two stereocenters of these compounds were set up on intermediate 5 obtained by diastereoselective bromocyclization of protected D-tryptophan, as previously reported.7,8 The sacrificial chiral center of the starting amino acid was removed in the ensuing decarboxylation step.
3
Scheme 1. Reagents and conditions: (a) KO-tBu, CH3CN –10 to 25 ºC, 1 h; (b) 1. KOH, MeOH, 25 ºC, 30 min; 2. i-BuOCOCl, NMM, CH3CN/THF, 10; 2-methyl-2-propanethiol, Et3N, h, 0 to 25 ºC; (c) 1. TMSI, CH3CN, 0 ºC; 2. Red-Al®, 110 ºC, 5 min. Supplementary Material
Acknowledgments This work was supported by funds from the Spanish MINECO (SAF2013-48397-R-FEDER), Xunta de Galicia (Grant 08CSA052383PR from DXI+D+i; Consolidación 2013/007 from DXPCTSUG; INBIOMED-FEDER “Unha maneira de facer Europa”).
Conflict of interest The authors declare no conflict of interest.
References and notes 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
17.
Ishikawa, Y.; Morimoto, K.; Hamasaki, T. J. Am. Chem. Oil Soc. 1984, 61, 1864. Slack, G. J.; Puniani, E.; Frisvad, J. C.; Samson, R. A.; Miller, J. D. Mycol. Res. 2009, 113, 480. Zhang, C. X.; Peng, G. T.; He, X. X.; Zhu, C. C.; Deng, J. W.; Wei, Y. L. Nat. Prod. Res. Dev. 2011, 23, 571. Zhou, H.; He, H.-P.; Wang, Y.-H.; Hao, X.-J. Helv. Chim. Acta 2010, 93, 1650. Liu, Y.; Wang, J.-S.; Wang, X.-B.; Kong, L.-Y. Fitoterapia 2013, 86, 178. Pérez-Balado, C.; de Lera, A. R. Org. Biomol. Chem. 2010, 8, 5179. Pérez-Balado, C.; de Lera, A. R. Org. Lett. 2008, 10, 3701. Pérez-Balado, C.; Rodríguez-Graña, P.; de Lera, A. R. Chem. Eur. J. 2009, 15, 9928. Espejo, V. R.; Rainier, J. D. J. Am. Chem. Soc. 2008, 130, 12894 Espejo, V. R.; Li, X.-B.; Rainier, J. D. J. Am. Chem. Soc. 2010, 132, 8282. Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2009, 131, 8756. Snell, R. H.; Woodward, R. L.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50, 9116. Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1444. Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S. Angew. Chem. Int. Ed. 2011, 50, 2716. Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 7119. (a) Li, Q.; Xia, T.; Yao, L.; Deng, H.; Liao, X. Chem. Sci. 2015, 6, 3599. (b) Liu, C.; Yi, J.-C.; Zheng, Z.-B.; Tang, Y.; Dai, L.-X.; You, S.-L. Angew. Chem. Int. Ed. 2016, 55, 751-754. Tayu, M.; Ishizaki, T.; Higuchi, K.; Kawasaki, T. Org. Biomol. Chem. 2015, 13, 3863.
Detailed experimental part with spectroscopic data and copies of H-NMR and 13C-NMR spectra for all compounds described in the text. 1
HIGHLIGHTS
(+)-psychotriasine, isolated from Psychotria calocarpa, and the unnamed tryptoline analogue isolated from P. henryi, have been synthesized for the first time, and the structures of the natural specimens have been confirmed.
S0040-4039(16)31629-X http://dx.doi.org/10.1016/j.tetlet.2016.12.003 TETL 48415
To appear in:
Tetrahedron Letters
Received Date: Accepted Date:
25 November 2016 2 December 2016
Please cite this article as: Gallego, S., Lorenzo, P., Alvarez, R., de Lera, A.R., Total synthesis of naturally occurring (+)-psychotriasine and the related tetrahydro-β-carboline, dimeric tryptamines with N–C connectivities, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.
Total synthesis of naturally occurring (+)psychotriasine and the related tetrahydro-carboline, dimeric tryptamines with N–C connectivities
Leave this area blank for abstract info.
Samuel Gallego, Paula Lorenzo, Rosana Álvarez and Ángel R. de Lera Departamento de Química Orgánica, Facultade de Química, CINBIO and IIS Galicia Sur, Universidade de Vigo, 36310 Vigo, Spain.
1
Tetrahedron Letters
Total synthesis of naturally occurring (+)-psychotriasine and the related tetrahydro-carboline, dimeric tryptamines with N–C connectivities Samuel Gallego,a Paula Lorenzo,a Rosana Alvarez,a, and Angel R. de Leraa, a
Departamento de Química Orgánica, Universidade de Vigo, CINBIO and IIS Galicia Sur, Lagoas-Marcosende, 36310 Vigo, Spain
ARTICLE INFO
ABSTRACT
Article history: Received Received in revised form Accepted Available online
Naturally occurring (+)-psychotriasine (+)-1 and congener tetrahydro--carboline (+)-3, which are dimeric tryptophan-derived alkaloids with tryptamine and carboline units connected by the indole nitrogen to the quaternary carbon atom of the pyrrolidinoindoline core, have been synthesized for the first time and their absolute configurations confirmed.
Keywords: Keyword_1 Keyword_2 Keyword_3 Keyword_4 Keyword_5 Keywords: alkaloids, synthesis, tryptamines
——— Corresponding author. Tel.: +34-986-812316; fax: +34-986-811940; e-mail: [email protected]
2009 Elsevier Ltd. All rights reserved.
2
Tetrahedron Letters 1. Introduction
Secondary metabolites derived from tryptophan are ubiquitous in Nature.1,2 Plants of the genus Psychotria (Rubiaceae), which grow mainly in tropical and subtropical areas, are rich in multimeric indole alkaloids.3 The heterodimeric (+)-psychotriasine (+)-1 was isolated from Psychotria calocarpa by Hao et al. and assigned structure 1, which is composed of two tryptophan-derived subunits, namely methyltryptamine and a hexahydropyrrolo[2,3b]indole, connected to each other through the C3a–N1' bond.4 Alkaloid (+)-3 differs in the N-connected component and this compound was isolated, together with (+)-2, from P. henryi, a plant used in traditional Chinese medicine.5 Based on an analysis of the spectroscopic data, the stereostructure of (+)-3 was proposed to be composed of hexahydropyrrolo[2,3b]indole and tetrahydropyrido[3,4-b]indole subunits connected by a C3’a–N1 bond. Comparison of the DFTcomputed and experimental ECD spectra for compounds (+)-2 and (+)-3 suggested the same absolute configuration, denoted as 3'aS,8'aR for 3 (note the change of descriptor for compound 2 at C8'a, which is S).5 We recently reported the total synthesis and structural revision of the C3–N heterodimeric pestalazine B (+)-4 (Figure 1),6 a diketopiperazine isolated from the pathogenic fungus Pestalotiopsis theae. The connection of the subunits was based on the displacement of exo-3a-bromo-2methylcarboxylate-hexahydropyrrolo[2,3-b]indole 57,8 (Scheme 1) by the indole nitrogen following the procedure reported by Rainier.9,10 The same strategy appears well suited to access the structurally related alkaloids 1 and 3, and thus determine their absolute stereostructures.
respectively. The mechanism of these C–N bond formation processes has been demonstrated by Rainier to involve a transient cyclopropylazetoindoline formed by intramolecular displacement of the bromine by the initially formed ester enolate, which is then trapped by the corresponding deprotected indole nitrogen. Subsequent kinetic protonation of the ester enolate results in the endo isomer of the substituted indoline.10 The expected inversion of configuration at C2’ was confirmed in both cases by 1H-NMR spectroscopy on the basis of the characteristic chemical shift of the endo methyl ester at ~3.2 ppm. Once the expedient construction of these dimeric tryptophan compounds had been completed, the decarboxylation of the original D-tryptophan esters that served to control the absolute configuration at the fusion atoms of the pyrrolidinoindoline core was carried out by the classical Barton’s reductive procedure. Saponification of the methyl esters 7 and 9 to the carboxylic acids and formation of the PTOC esters by treatment with isobutylchloroformate and thiopyridine N-oxide 10 was followed by photochemicallyinduced radical decarboxylation to afford 11 and 12, respectively.14 Deprotection of the BOC carbamates was effected by treatment with TMSI in CH3CN and final reduction of the methylcarbamates with RedAl® at 110 ºC15 afforded the desired products 1 and 3, respectively. As anticipated, the spectroscopic data (including the optical rotation, for 1, [α]D24.5 +106.1 (c 0.2, MeOH); lit.4: [α]D19.2 +104.2 (c 0.1, MeOH); for 3, [α]D22.5 +189.5 (c 0.2, MeOH); lit.5: [α]D23 +179.5 (c 0.16, MeOH)) of 1 and 3 matched those of the natural products4,5 and therefore the first total synthesis of these naturally occurring C3a-N1-linked tryptamine dimers was completed. Both racemic and unnatural (–)-psychotriasine have been synthesized previously. In 2009 Baran carried out the total synthesis of rac-psychotriasine during his comprehensive work on multimeric indole alkaloids and predicted, in the same year it was isolated from a natural source,4 that “it would not be surprising if non-selective oxidation pathways of methyl tryptamine in Nature would result in the formation of this product….”.15 Recently two synthesis of (–)psychotriasine have been reported.16 The first is based on a BINOL-catalyzed azo coupling-iminium cyclization strategy that was also applied to (+)-pestalazine B (4),16a and the second on a copper-catalyzed asymmetric dearomative amination of tryptamines.16b In the three cases, the indole ring was constructed by Pd-catalyzed Larock cyclization15 following the functionalization at C3a with an aniline.16 An additional synthesis of rac-psychotriasine is somehow related to that described here, since the C–N connection step is based on the displacement of an intermediate sulfonium ion by the protected tryptamine.17
Figure 1. Representative pyrrolidinoindoline-containing alkaloids with C3’a–N1 connections.
In the event, enantiopure exo-5,11 obtained by stereoselective bromocyclization of the appropriately protected D-tryptophan,7,8 was treated under basic conditions (KO-tBu in CH3CN) with either N-protected tryptamine 612 or N-protected tetrahydro--carboline 813 to afford the corresponding adducts 7 and 9 in 57 and 77% yields,
In summary, the absolute configuration of the purported structure of the natural products (+)-psychotriasine (1)4 and (+)-35 has been corroborated by their first total synthesis. The two stereocenters of these compounds were set up on intermediate 5 obtained by diastereoselective bromocyclization of protected D-tryptophan, as previously reported.7,8 The sacrificial chiral center of the starting amino acid was removed in the ensuing decarboxylation step.
3
Scheme 1. Reagents and conditions: (a) KO-tBu, CH3CN –10 to 25 ºC, 1 h; (b) 1. KOH, MeOH, 25 ºC, 30 min; 2. i-BuOCOCl, NMM, CH3CN/THF, 10; 2-methyl-2-propanethiol, Et3N, h, 0 to 25 ºC; (c) 1. TMSI, CH3CN, 0 ºC; 2. Red-Al®, 110 ºC, 5 min. Supplementary Material
Acknowledgments This work was supported by funds from the Spanish MINECO (SAF2013-48397-R-FEDER), Xunta de Galicia (Grant 08CSA052383PR from DXI+D+i; Consolidación 2013/007 from DXPCTSUG; INBIOMED-FEDER “Unha maneira de facer Europa”).
Conflict of interest The authors declare no conflict of interest.
References and notes 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
17.
Ishikawa, Y.; Morimoto, K.; Hamasaki, T. J. Am. Chem. Oil Soc. 1984, 61, 1864. Slack, G. J.; Puniani, E.; Frisvad, J. C.; Samson, R. A.; Miller, J. D. Mycol. Res. 2009, 113, 480. Zhang, C. X.; Peng, G. T.; He, X. X.; Zhu, C. C.; Deng, J. W.; Wei, Y. L. Nat. Prod. Res. Dev. 2011, 23, 571. Zhou, H.; He, H.-P.; Wang, Y.-H.; Hao, X.-J. Helv. Chim. Acta 2010, 93, 1650. Liu, Y.; Wang, J.-S.; Wang, X.-B.; Kong, L.-Y. Fitoterapia 2013, 86, 178. Pérez-Balado, C.; de Lera, A. R. Org. Biomol. Chem. 2010, 8, 5179. Pérez-Balado, C.; de Lera, A. R. Org. Lett. 2008, 10, 3701. Pérez-Balado, C.; Rodríguez-Graña, P.; de Lera, A. R. Chem. Eur. J. 2009, 15, 9928. Espejo, V. R.; Rainier, J. D. J. Am. Chem. Soc. 2008, 130, 12894 Espejo, V. R.; Li, X.-B.; Rainier, J. D. J. Am. Chem. Soc. 2010, 132, 8282. Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2009, 131, 8756. Snell, R. H.; Woodward, R. L.; Willis, M. C. Angew. Chem. Int. Ed. 2011, 50, 9116. Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1444. Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S. Angew. Chem. Int. Ed. 2011, 50, 2716. Newhouse, T.; Lewis, C. A.; Eastman, K. J.; Baran, P. S. J. Am. Chem. Soc. 2010, 132, 7119. (a) Li, Q.; Xia, T.; Yao, L.; Deng, H.; Liao, X. Chem. Sci. 2015, 6, 3599. (b) Liu, C.; Yi, J.-C.; Zheng, Z.-B.; Tang, Y.; Dai, L.-X.; You, S.-L. Angew. Chem. Int. Ed. 2016, 55, 751-754. Tayu, M.; Ishizaki, T.; Higuchi, K.; Kawasaki, T. Org. Biomol. Chem. 2015, 13, 3863.
Detailed experimental part with spectroscopic data and copies of H-NMR and 13C-NMR spectra for all compounds described in the text. 1
HIGHLIGHTS
(+)-psychotriasine, isolated from Psychotria calocarpa, and the unnamed tryptoline analogue isolated from P. henryi, have been synthesized for the first time, and the structures of the natural specimens have been confirmed.