- Email: [email protected]
A biomimetic synthesis of homofascaplysin C from ditryptophans
Accepted Manuscript A biomimetic synthesis of homofascaplysin C from ditryptophans Mei Xu, Rui An, Tao Huang, Xiao-jiang Hao, Sheng Liu PII: DOI: Reference:
S0040-4039(16)30124-1 http://dx.doi.org/10.1016/j.tetlet.2016.02.014 TETL 47287
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
5 December 2015 28 January 2016 3 February 2016
Please cite this article as: Xu, M., An, R., Huang, T., Hao, X-j., Liu, S., A biomimetic synthesis of homofascaplysin C from ditryptophans, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.014
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.
1
Tetrahedron Letters
A biomimetic synthesis of homofascaplysin C from ditryptophans Mei Xua,b, Rui Ana, Tao Huanga, Xiao-jiang Haoa,b, Sheng Liua,b,* a b
The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang 550002, PR China The Key Laboratory of Chemistry for Natural Products, Guizhou Medcial University
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
A route for the biomimetic synthesis of homofascaplysin C has been established. The key strategy is based on the chemoselective and sequential oxidative cleavage of two side-chains of the ditryptophan precursor. 2009 Elsevier Ltd. All rights reserved .
Keywords: Homofascaplysin C Ditryptophan Biomimetic synthesis Transamination Oxidative cleavage
Alkaloids containing the 2,2¶-biindole core of ditryptophan cross-links are a topic of recent research because their members have varied structures, and many bisindole natural products possess diverse and important biological activities. From a mechanistic view, ditryptophan derivatives might serve as starting materials for synthesis of these natural products, which have been fully demonstrated by Movassaghi et al., Tambar et al., and our group in the construction of trigonoliimines alkaloids.1 Fascaplysin (1) and several related metabolites such as homofascaplysin A, B and C (2), were discovered from the marine sponge Fascaplysinopsis Bergquist sp.2 and Fijian sponge Fascaplysinopsis reticulate.3 These alkaloids exhibit a broad range of bioactivities,4 including antibacterial, antifungal, antiviral, antimalarial, anticancer and the novel 12H-pyrido[1,2a;3,4-E¶]diindole ring system make them become attractive targets of synthetic chemists. Amongst these studies, several reports have been established for the synthesis of homofascaplysin C.5 Vranken and co-workers reported the synthesis of homofascaplysin C from ditryptophan. Key transformations in their pioneer work involved the acid-catalyzed cyclization of a N-butylurea intermediate to generate the polycyclic aromatic framework and oxidative cleavage of the amino acid moiety to form the characteristic aldehyde group.5c
Figure 1. Fascaplysin (1) and homofascaplysin C (2)
Our approach toward homofascaplysin C originated from recent synthesis study toward indolo[3,2-a]carbazoles6, in which
we detailed a biomimetic transamination/aromatic cyclization sequence to construct indolo[3,2-a]carbazole. We observed that 2- ¶-indolyl) tryptophan derivative 3 could be converted into the corresponding D-keto ester 4 or aldehyde 5 alternatively with the adoption of different metal salts catalyst and conditions (Scheme 1). Moreover, our research showed copper(II) ions could effectively trigger an oxidative transformation, thus D-keto ester 4 was decomposed to aldehyde 5.
Scheme 1. Initial inspiration
As an interest concerning on the development of novel synthesis strategies for bisindole alkaloids, we envisioned that the chemselective and sequential oxidative cleavage of the side chain in 2-indolyl tryptophans might specifically suggest an alternative for biomimetic synthesis of homofascaplysin C. Scheme 2 depicts a novel retrosynthetic analysis, homofascaplysin C could be obtained by decarboxylation from ester 6. The aldehyde group of 6 could be generated through oxidative cleavage of the amino acid moiety in ditryptophan derivative 7. Intermediate 7 containing a latent indole 3-pyruvic acid ester unit might be produced via a transamination /cyclization sequence from ditryptophan 8. Further disconnection gave two basic tryptophan units 9 and 10.
2
Tetrahedron Thus the ester 12 was produced in 53% combined yield (2 steps). Notably, pentacycle 12 contains the complete core of the fascaplysins. Further the Cbz group of 12 was deprotected to deliver the amine 7. To the best of our knowledge, the oxidative CD-CE cleavage of tryptophan side chain to furnish the 3indolecarbaldehydes was both achieved by Y. MaKi8 using the pyrimido[5,4-g]pteridine N-oxide under irradiation with UVvisible light and Vranken using ferric chloride as an oxidant. According to previous observation, our efforts was focused on evaluating the oxidative condition using Cu(II) ions as catalyst. Compared to the adoption of air as oxidant, oxygen has been proved to be more effective. The key intermediate 6 was formed in 41% yield under optimized condition. Finally, substrate 6 was then hydrolyzed and subsequent decarboxylation of the corresponding acid happened at 200 oC yielding the desired product 1 uneventfully.
Scheme 2. Biomimetic retrosynthetic analysis towards homofascaplysin C
Intrigued by above considerations, synthesis study toward homofascaplysin C was initiated (Scheme 3). First, we sought conditions that enabled the union of two tryptophan subunits to form 2,2ƍ-bistryptophan 8. Heterodimerization reaction of Cbz protected tryptophan 9 and Phth protected tryptophan 10 under ionic conditions7 providing the desired ditryptophan 8 in 27% yield. Although the union of two indole subunits at their 2,2¶junction using a Pd-catalyzed cross-coupling reaction is more effective and well-precedented,1a-b,1f the procedure we adopted was step economic and the desired heterodimer 8 could be obtained on gram scale. Unveiling the amino group of imide 8 provided a free amine 11, which was subjected to the next transamination. It was found that combined with the adoption of sodium glyoxylate and zinc ions could promote the demanding transformation at room temperature smoothly. Intramolecular cyclization of the unstable keto ester intermediate was promoted by TFA in heat dioxane.
In conclusion, we have developed a biomimetic approach to construct the heteroaromatic system of natural 12H-pyrido[1,2a;3,4-b¶@GLLQGROHs with a near-biosynthetic view in mind. To some extent, these procedures seemed to be lack of efficiency, presumably as a result of mimicking the biogenesis. However, this work successfully demonstrated that fascaplysin and related metabolites could be delivered from ditryptophan intermediates via the chemselective and sequential oxidative cleavage of the side chains. The formation of polycyclic aromatics from ditryptophan may have broader applications in the synthesis of other indole alkaloids. Acknowledgments The work was financially supported by NSFC (No. 21462013), Qiankehe [2015] 2107 and West Light Foundation of The Chinese Academy of Sciences.
Scheme 3. Reagents and conditions: (a) (i) TFA, rt; (ii) DDQ, 1,4-dioxane, 0 oC to rt. (b) 80% Hydrazine hydrate, DCM/MeOH, rt. (c) (i) ZnSO4, CHOCOONa·H2O, MeCN/acetate buffer, rt. (ii) TFA, 1, 4-dioxane, 100 oC. (d) BF3·Et2O, EtSH, rt. (e) CuSO4, CHOCOONa·H2O, MeCN/acetate buffer, O2, rt. (f) (i) NaOH, MeOH/H2O/DMSO, 40 oC. (ii) 200 oC, neat.
3 References and notes 1.
2. 3. 4.
(a) Qi, X.; Bao, H.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133, 10050-10053; (b) Han, S.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 10768-10771. (c) Liu, S.; Hao, X. J. Tetrahedron Lett. 2011, 52, 5640-5642. (d) Qiu, J.; Zhang, J. X.; Liu, S.; Hao, X. J. Tetrahedron Lett. 2013, 54, 300-302. (e) Zhao, B.; Hao, X.-Y.; Zhang, J.-X.; Liu, S.; Hao, X.-J. Org. Lett. 2013, 15, 528-530. (f) Han, S.; Morrison, K. C.; Hergenrother, P. J.; Movassaghi, M. J. Org. Chem. 2014, 79, 473-486. Roll, D. M.; Ireland, C. M.; Lu, H. S. M.; Clardy, J. J. Org. Chem. 1988, 53, 3276-3278. Jemenez, C.; Quinoa, E.; Adamczeski, M.; Hunter, L. M.; Crews, P. J. Org. Chem. 1991, 56, 3403-3410. (a) Segraves, N. L.; Lopez, S.; Johnson, T. A.; Said, S. A.; Fu, X.; Schmitz, F. J.; Pietraszkiewicz, H.; Valeriotec, F. A.; Crewsa, P. Tetrahedron Lett. 2003, 44, 3471-3475; (b) Schmidt, E. W.; Faulkner, D. J. Tetrahedron Lett. 1996, 37, 3951-3954; (c) Kirsch, G.; Konig, G. M.; Wright, A. D.; Kaminsky, R. J. Nat. Prod. 2000, 63, 825-829; (d) Charan, R. D.; McKee, T. C.; Gustafson, K. R.; Pannell, L. K.; Boyd, M. R. Tetrahedron Lett. 2002, 43, 52015204; (e) Popov, A. M.; Stonik, V. A. Antibiot. Khimioter. 1991, 36, 12-14; (f) Hormann, A.; Chaudhuri, B.; Fretz, H. Bioorg. Med.
5.
6. 7.
8.
Chem. 2001, 9, 917-921; (g) Segraves, N. L.; Robinson, S. J.; Garcia, D.; Said, S. A.; Fu, X.; Schmitz, F. J.; Pietraszkiewicz, H.; Valeriote, F. A.; Crews, P. J. Nat. Prod. 2004, 67, 783-792. (a) Gribble, G. W.; Pelcman, B. J. Org. Chem. 1992, 57, 36363642. (b) Dubovitskii, S. V. Tetrahedron Lett. 1996, 37, 52075208; (c) Carter, D. S.; Van Vranken, D. L. J. Org. Chem. 1999, 64, 8537-8545; (d) Waldmann, H.; Eberhardt, L.; Wittstein, K.; Kumar, K. Chem. Commun. 2010, 4622-4624. (e) Dai, Y. S.; Zhang, W. X.; Wang, K. C.; Wang, W. X.; Zhang, W. Tetrahedron 2013, 69, 1912-1918. Liang, L. N.; Fan, T. Y.; Huang, T.; Yan, C.; Xu, M.; Liu, S. Tetrahedron Lett. 2015, 56, 434-436. (a) Bergman, J.; Koch, E.; Pelcman, B. Tetrahedron Lett. 1995, 36, 3945-3948; (b) Gilbert, E. J.; Ziller, J. W.; Van Vranken, D. L. Tetrahedron 1997, 53, 16553-16564. Sako, M.; Shimada, K.; Hirota, K. Maki, Y. Tetrahedron Lett. 1986, 27, 3877-3880.
Corresponding author. Tel./fax: +86 851 5416876 (S. Liu).
E-mail address: [email protected].
Click here to remove instruction text...
2. Experimental and Spectroscopic Data
Graphical Abstract To create your abstract, type over the instructions in the template box below.
A biomimetic synthesis of homofascaplysin C from ditryptophan Mei Xu, Rui An, Tao Huang, Xiao-jiang Hao, Sheng Liu*
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
S0040-4039(16)30124-1 http://dx.doi.org/10.1016/j.tetlet.2016.02.014 TETL 47287
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
5 December 2015 28 January 2016 3 February 2016
Please cite this article as: Xu, M., An, R., Huang, T., Hao, X-j., Liu, S., A biomimetic synthesis of homofascaplysin C from ditryptophans, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.014
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.
1
Tetrahedron Letters
A biomimetic synthesis of homofascaplysin C from ditryptophans Mei Xua,b, Rui Ana, Tao Huanga, Xiao-jiang Haoa,b, Sheng Liua,b,* a b
The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, Guiyang 550002, PR China The Key Laboratory of Chemistry for Natural Products, Guizhou Medcial University
A RT I C L E I N F O
A BS T RA C T
Article history: Received Received in revised form Accepted Available online
A route for the biomimetic synthesis of homofascaplysin C has been established. The key strategy is based on the chemoselective and sequential oxidative cleavage of two side-chains of the ditryptophan precursor. 2009 Elsevier Ltd. All rights reserved .
Keywords: Homofascaplysin C Ditryptophan Biomimetic synthesis Transamination Oxidative cleavage
Alkaloids containing the 2,2¶-biindole core of ditryptophan cross-links are a topic of recent research because their members have varied structures, and many bisindole natural products possess diverse and important biological activities. From a mechanistic view, ditryptophan derivatives might serve as starting materials for synthesis of these natural products, which have been fully demonstrated by Movassaghi et al., Tambar et al., and our group in the construction of trigonoliimines alkaloids.1 Fascaplysin (1) and several related metabolites such as homofascaplysin A, B and C (2), were discovered from the marine sponge Fascaplysinopsis Bergquist sp.2 and Fijian sponge Fascaplysinopsis reticulate.3 These alkaloids exhibit a broad range of bioactivities,4 including antibacterial, antifungal, antiviral, antimalarial, anticancer and the novel 12H-pyrido[1,2a;3,4-E¶]diindole ring system make them become attractive targets of synthetic chemists. Amongst these studies, several reports have been established for the synthesis of homofascaplysin C.5 Vranken and co-workers reported the synthesis of homofascaplysin C from ditryptophan. Key transformations in their pioneer work involved the acid-catalyzed cyclization of a N-butylurea intermediate to generate the polycyclic aromatic framework and oxidative cleavage of the amino acid moiety to form the characteristic aldehyde group.5c
Figure 1. Fascaplysin (1) and homofascaplysin C (2)
Our approach toward homofascaplysin C originated from recent synthesis study toward indolo[3,2-a]carbazoles6, in which
we detailed a biomimetic transamination/aromatic cyclization sequence to construct indolo[3,2-a]carbazole. We observed that 2- ¶-indolyl) tryptophan derivative 3 could be converted into the corresponding D-keto ester 4 or aldehyde 5 alternatively with the adoption of different metal salts catalyst and conditions (Scheme 1). Moreover, our research showed copper(II) ions could effectively trigger an oxidative transformation, thus D-keto ester 4 was decomposed to aldehyde 5.
Scheme 1. Initial inspiration
As an interest concerning on the development of novel synthesis strategies for bisindole alkaloids, we envisioned that the chemselective and sequential oxidative cleavage of the side chain in 2-indolyl tryptophans might specifically suggest an alternative for biomimetic synthesis of homofascaplysin C. Scheme 2 depicts a novel retrosynthetic analysis, homofascaplysin C could be obtained by decarboxylation from ester 6. The aldehyde group of 6 could be generated through oxidative cleavage of the amino acid moiety in ditryptophan derivative 7. Intermediate 7 containing a latent indole 3-pyruvic acid ester unit might be produced via a transamination /cyclization sequence from ditryptophan 8. Further disconnection gave two basic tryptophan units 9 and 10.
2
Tetrahedron Thus the ester 12 was produced in 53% combined yield (2 steps). Notably, pentacycle 12 contains the complete core of the fascaplysins. Further the Cbz group of 12 was deprotected to deliver the amine 7. To the best of our knowledge, the oxidative CD-CE cleavage of tryptophan side chain to furnish the 3indolecarbaldehydes was both achieved by Y. MaKi8 using the pyrimido[5,4-g]pteridine N-oxide under irradiation with UVvisible light and Vranken using ferric chloride as an oxidant. According to previous observation, our efforts was focused on evaluating the oxidative condition using Cu(II) ions as catalyst. Compared to the adoption of air as oxidant, oxygen has been proved to be more effective. The key intermediate 6 was formed in 41% yield under optimized condition. Finally, substrate 6 was then hydrolyzed and subsequent decarboxylation of the corresponding acid happened at 200 oC yielding the desired product 1 uneventfully.
Scheme 2. Biomimetic retrosynthetic analysis towards homofascaplysin C
Intrigued by above considerations, synthesis study toward homofascaplysin C was initiated (Scheme 3). First, we sought conditions that enabled the union of two tryptophan subunits to form 2,2ƍ-bistryptophan 8. Heterodimerization reaction of Cbz protected tryptophan 9 and Phth protected tryptophan 10 under ionic conditions7 providing the desired ditryptophan 8 in 27% yield. Although the union of two indole subunits at their 2,2¶junction using a Pd-catalyzed cross-coupling reaction is more effective and well-precedented,1a-b,1f the procedure we adopted was step economic and the desired heterodimer 8 could be obtained on gram scale. Unveiling the amino group of imide 8 provided a free amine 11, which was subjected to the next transamination. It was found that combined with the adoption of sodium glyoxylate and zinc ions could promote the demanding transformation at room temperature smoothly. Intramolecular cyclization of the unstable keto ester intermediate was promoted by TFA in heat dioxane.
In conclusion, we have developed a biomimetic approach to construct the heteroaromatic system of natural 12H-pyrido[1,2a;3,4-b¶@GLLQGROHs with a near-biosynthetic view in mind. To some extent, these procedures seemed to be lack of efficiency, presumably as a result of mimicking the biogenesis. However, this work successfully demonstrated that fascaplysin and related metabolites could be delivered from ditryptophan intermediates via the chemselective and sequential oxidative cleavage of the side chains. The formation of polycyclic aromatics from ditryptophan may have broader applications in the synthesis of other indole alkaloids. Acknowledgments The work was financially supported by NSFC (No. 21462013), Qiankehe [2015] 2107 and West Light Foundation of The Chinese Academy of Sciences.
Scheme 3. Reagents and conditions: (a) (i) TFA, rt; (ii) DDQ, 1,4-dioxane, 0 oC to rt. (b) 80% Hydrazine hydrate, DCM/MeOH, rt. (c) (i) ZnSO4, CHOCOONa·H2O, MeCN/acetate buffer, rt. (ii) TFA, 1, 4-dioxane, 100 oC. (d) BF3·Et2O, EtSH, rt. (e) CuSO4, CHOCOONa·H2O, MeCN/acetate buffer, O2, rt. (f) (i) NaOH, MeOH/H2O/DMSO, 40 oC. (ii) 200 oC, neat.
3 References and notes 1.
2. 3. 4.
(a) Qi, X.; Bao, H.; Tambar, U. K. J. Am. Chem. Soc. 2011, 133, 10050-10053; (b) Han, S.; Movassaghi, M. J. Am. Chem. Soc. 2011, 133, 10768-10771. (c) Liu, S.; Hao, X. J. Tetrahedron Lett. 2011, 52, 5640-5642. (d) Qiu, J.; Zhang, J. X.; Liu, S.; Hao, X. J. Tetrahedron Lett. 2013, 54, 300-302. (e) Zhao, B.; Hao, X.-Y.; Zhang, J.-X.; Liu, S.; Hao, X.-J. Org. Lett. 2013, 15, 528-530. (f) Han, S.; Morrison, K. C.; Hergenrother, P. J.; Movassaghi, M. J. Org. Chem. 2014, 79, 473-486. Roll, D. M.; Ireland, C. M.; Lu, H. S. M.; Clardy, J. J. Org. Chem. 1988, 53, 3276-3278. Jemenez, C.; Quinoa, E.; Adamczeski, M.; Hunter, L. M.; Crews, P. J. Org. Chem. 1991, 56, 3403-3410. (a) Segraves, N. L.; Lopez, S.; Johnson, T. A.; Said, S. A.; Fu, X.; Schmitz, F. J.; Pietraszkiewicz, H.; Valeriotec, F. A.; Crewsa, P. Tetrahedron Lett. 2003, 44, 3471-3475; (b) Schmidt, E. W.; Faulkner, D. J. Tetrahedron Lett. 1996, 37, 3951-3954; (c) Kirsch, G.; Konig, G. M.; Wright, A. D.; Kaminsky, R. J. Nat. Prod. 2000, 63, 825-829; (d) Charan, R. D.; McKee, T. C.; Gustafson, K. R.; Pannell, L. K.; Boyd, M. R. Tetrahedron Lett. 2002, 43, 52015204; (e) Popov, A. M.; Stonik, V. A. Antibiot. Khimioter. 1991, 36, 12-14; (f) Hormann, A.; Chaudhuri, B.; Fretz, H. Bioorg. Med.
5.
6. 7.
8.
Chem. 2001, 9, 917-921; (g) Segraves, N. L.; Robinson, S. J.; Garcia, D.; Said, S. A.; Fu, X.; Schmitz, F. J.; Pietraszkiewicz, H.; Valeriote, F. A.; Crews, P. J. Nat. Prod. 2004, 67, 783-792. (a) Gribble, G. W.; Pelcman, B. J. Org. Chem. 1992, 57, 36363642. (b) Dubovitskii, S. V. Tetrahedron Lett. 1996, 37, 52075208; (c) Carter, D. S.; Van Vranken, D. L. J. Org. Chem. 1999, 64, 8537-8545; (d) Waldmann, H.; Eberhardt, L.; Wittstein, K.; Kumar, K. Chem. Commun. 2010, 4622-4624. (e) Dai, Y. S.; Zhang, W. X.; Wang, K. C.; Wang, W. X.; Zhang, W. Tetrahedron 2013, 69, 1912-1918. Liang, L. N.; Fan, T. Y.; Huang, T.; Yan, C.; Xu, M.; Liu, S. Tetrahedron Lett. 2015, 56, 434-436. (a) Bergman, J.; Koch, E.; Pelcman, B. Tetrahedron Lett. 1995, 36, 3945-3948; (b) Gilbert, E. J.; Ziller, J. W.; Van Vranken, D. L. Tetrahedron 1997, 53, 16553-16564. Sako, M.; Shimada, K.; Hirota, K. Maki, Y. Tetrahedron Lett. 1986, 27, 3877-3880.
Corresponding author. Tel./fax: +86 851 5416876 (S. Liu).
E-mail address: [email protected].
Click here to remove instruction text...
2. Experimental and Spectroscopic Data
Graphical Abstract To create your abstract, type over the instructions in the template box below.
A biomimetic synthesis of homofascaplysin C from ditryptophan Mei Xu, Rui An, Tao Huang, Xiao-jiang Hao, Sheng Liu*
Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.