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Total synthesis of actinophenanthroline A via double Doebner–Miller reaction
Accepted Manuscript Total synthesis of Actinophenanthroline A via double Doebner–Miller reaction Suman Kr Ghosh, Rajagopal Nagarajan PII: DOI: Reference:
S0040-4039(16)30720-1 http://dx.doi.org/10.1016/j.tetlet.2016.06.045 TETL 47772
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
25 May 2016 10 June 2016 12 June 2016
Please cite this article as: Ghosh, S.K., Nagarajan, R., Total synthesis of Actinophenanthroline A via double Doebner–Miller reaction, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.045
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 Actinophenanthroline A via double Doebner–Miller reaction Suman Kr Ghosh and Rajagopal Nagarajan*
Leave this area blank for abstract info.
1
Tetrahedron Letters
Total synthesis of Actinophenanthroline A via double Doebner–Miller reaction Suman Kr Ghosh and Rajagopal Nagarajan* a
School of chemistry, University of Hyderabad, Hyderabad- 500046, India (+) 91 40 23012460 [email protected]
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
Total synthesis of actinophenanthroline A, a marine actinomycete within the family of Streptomycetaceae (strain CNQ-149) is reported. Both the racemic and enantiopure actinophenanthroline A has been synthesized with good overall yields. Highlight of the synthesis contains the classical and economical double Doebner-Miller reaction to access the 1, 7phenanthroline core followed by a modified EDCI coupling.
Keywords: Total Synthesis Natural product 1,7-phenanthroline Double Doebner-Miller
In June 2015, Fenical et al. isolated1 some unprecedented alkaloids actinobenzoquinoline and actinophenanthroline A- C (Figure 1.) from a marine actinomycete within the family of streptomycetaceae (strain CNQ-149). The core structures of both the alkaloids were not known in the alkaloid literature previously. Actinophenanthrolines A−C are the elementary examples of natural products containing the 1,7-phenanthroline alkaloid core. The synthetic phenanthrolines are already well established in literature from ages, among them 1,7-, 1,10-, 4,7- are predominantly common. Synthetic 1, 7-phenanthrolines were the first phenanthroline to be prepared by Skarup et al. in 18822 and later on, studies revealed their activities to induce the biosynthesis of drug-metabolizing enzymes by binding to metals.3 1, 10-Phenanthrolines are most well studied among all the phenanthrolines as they exhibit properties like: inhibitors of zinc metallopeptidases,4 antimalarial activities5, metal binding capacity.6 Thus, the first naturally occurring alkaloids which contains 1,7- phenanthroline core were indeed important from a synthetic view point. This may open opportunity to reveal many important biological or pharmaceutical properties. As, our group is working on the total synthesis of different heterocyclic alkaloids,7 this alkaloid actinophenanthroline A enticed us to carry out the synthesis of it. Though there were many synthetic strategies available in literature for 1, 7- phenanthroline core8 but we planned our synthetic route for this alkaloid via the classic and economic Doebner-Miller method.9 Very recently Lindsley group reported the first total synthesis for this alkaloid starting from 8-hydroxy-2-methylquinoline. Although their synthetic route gave a good overall yield but it consists of isolation and purification problems in every steps as author mentioned in their manuscript.10 Thus, in this paper we report an easier and economical total synthesis of actinophenanthroline A via double Doebner-Miller reaction.
Figure. 1. Structures of Actinophenanthrolines
As depicted in scheme 1, our initial strategy for the synthesis of 9 hinged on the deprotection of the hydroxyl groups (aliphatic and aromatic) of compound 8 in two consecutive steps. Compound 8 could be stemmed from compound 7 via a coupling reaction with protected L-lactic acid. The amine (7) could be generated through nitration followed by reduction on compound 5. To achieve the exact 1, 7 phenanthroline core (5), a repeated Doebner-Miller reaction on 2-methoxy-5-nitroaniline would have been the best pathway.
2 Scheme 1. Retrosynthetic analysis
We commenced the forward synthesis with 2-methoxy-5nitroaniline (1a), where it was treated with crotonaldehyde in Doebner-Miller reaction conditions at 90 °C with mixed acid (AcOH and HCl) to produce the substituted 2-methylquinoline (3) in 61 % yield. Exposure of this nitroquinoline (3) to a reflux condition with Fe powder/NH4Cl, furnished the corresponding amine product (4) which has been subjected to second DoebnerMiller reaction with crotonaldehyde in same mixed acid condition for 2 h at 90 °C to achieve the desired 1, 7phenanthroline core (5) in 71% yield. Next, selective introduction of a nitro group at the C5 of the compound 5 can be achieved only with the o and p directing substitution at C6. Thus, we had an edge due to the methoxy group at C6 of compound 5. Hence, we treated compound 5 with HNO3-H2SO4 at 0 °C to obtain the corresponding nitro substituted compound (6) but unfortunately yield was very poor.
Scheme 2. Forward Synthesis
reached to compound 7, we were very eager to carry out the key coupling reaction between amine (7) and L-lactic acid using EDCI.HCl as coupling agents that has already been reported for benzene moieties,11 but unfortunately that was a failure. Thus, we tried variety of conditions with different coupling agents (EDCI.HCl, HBTU, HATU, TBTU, DCC, CID, CDI) along with activating agents (DMAP, HOBt) at varied temperatures even then we failed to obtain our desired coupled product 8 (see Supporting Information, Table 1). We envisaged that it is the free hydroxyl group of lactic acid which might be the culprit for these consecutive failures. Thus, we protected the free hydroxyl group of L-lactic acid with methoxy group. We prepared the (S)2-methoxypropanoic acid in three steps starting from L-lactic acid by following ref. 12.
Figure. 1. X-ray structure of 6-methoxy-2, 8-dimethyl-1,7-phenanthrolin-5amine (7)13
Next, we treated compound 7 and (S)-2-methoxypropanoic acid (12) with EDCI.HCl in DCM at 0 °C- rt for 72 h then at 50 °C for another 24 h but still we were not able to obtain the coupled product 13.
Scheme 3. Synthesis of enantiospecific Actinophenanthroline A
We presume that it is not only the hydroxyl group but there might be some other electronic or steric factors which plays a vital role for this reaction. It is possibly that C5 amine on this phenanthroline core that is less nucleophilic (in comparison with simple benzene core) due to the presence of two electron withdrawing pyridine rings. Hence, its nucleophilicity might not be enough to displace the O-acyl lactic acid intermediate (which forms in situ with EDCI and lactic acid) to form the desired amide (8/13). Hence, we envisioned that, keeping an electron withdrawing group at the α-/β position of the L-lactic acid might increase the eletrophilicity of the lactic acid intermediate that might be sufficient to form the desired coupled product (8/ 13). Next, we tried to optimize the reaction using different conditions with other nitrating agents like NO2BF4, AcONO2 and NaNO3H2SO4 to improve the yield of compound 6. Among them NaNO3-H2SO4 condition at 0- 10 °C found to give a moderate yield of compound 6. This nitro group of compound 6 was reduced again to respective 5-amino-1, 7-phenanthroline (7) in quantitative yields with Fe powder under reflux condition. As we
From this perspective, we primarily started the venture for synthesis of racemic actinophenanthroline A. We carried out the reaction between compound 7 and pyruvic acid with coupling agent EDCI. HCl in DCM at 0 °C for 1 h, followed by 30 mins at rt to get the desired coupled product 14 with an excellent yield. The keto group of compound 13 was next reduced to alcohol using sodium borohydride in methanol at 0 °C which led to a racemic compound 15. The methoxy deprotection of compound
3 15 was then achieved using BBr3 in DCM at -78 °C to rt in a highly diluted condition after 24 h. The NMR spectrum of synthetic racemic actinophenanthroline A exactly matches with the reported actinophenanthroline A. Thus, we successfully completed the total synthesis of racemic actinophenanthroline A.
Scheme 4. Synthesis of racemic Actinophenanthroline A
natural product along with the synthetic product (see Supporting Information). In conclusion, we have successfully achieved the synthesis of both enantiopure actinophenanthroline A as well as the racemic version. The easier, classical and economical methods had been utilized to synthesize this alkaloid. This synthetic strategy administers an easier route to synthesize the other analogue alkaloids.
Acknowledgments We thank DST for financial support. S.K.G. also thanks UGC for senior research fellowship. Supplementary Material Experimental procedure, NMR, HRMS and Crystallographic data are available in supporting information. References and notes 1.
After a successful synthetic execution of racemic actinophenanthroline A we diverted our focus again towards the enantiopure actinophenanthroline A. Thus, we protected the hydroxyl group of L-lactic acid with acetyl group which indeed became an electron withdrawing group to α of the acid group. (S)-2-acetoxypropanoic acid was prepared via three steps, where the acid group was first protected with benzyl group using benzyl bromide in basic condition. Next, the acetoxylation was achieved using acetic anhydride with DMAP (cat.) followed by deprotection of the benzyl group using hydrogenation led to the (S)-2-acetoxypropanoic acid (see Supporting Information).
2. 3.
4.
5.
Scheme 5. Synthesis of enantiospecific Actinophenanthroline A 6.
7.
8.
With desired acid in hand, we carried out the key coupling reaction between the amine (7) and (S)-2-acetoxypropanoic acid with EDCI. HCl in DCM. The reaction was very sluggish, after 72 h also it did not reach completion. Hence, we interrupted the reaction and isolated the pure coupled product 19 along with some unreacted starting amine (7). The cleavage of O-acetate group of compound 19 was performed selectively using K2CO3 in MeOH solvent at 0 °C, within 10 mins the reaction was completed to give compound 20 in quantitative yields. On treatment of compound 20 with BBr3 in DCM the deprotection of methoxy group was achieved in 72 % yield to obtain the enantiopure actinophenanthroline A. We accomplished the total synthesis of racemic as well as enantiopure actinophenanthroline A with overall 5.11% and 4.8% yields respectively. All spectral data and HRMS data is consistent with the data of isolated
9.
10.
11. 12. 13.
Nam, S- J.; Kauffman, C. A.; Jensen, P. R.; E. M. Curtis; Rheingold, A. L.; Fenical W. Org. Lett. 2015, 17, 3240–3243. Skraup, H.; Vortmann, G. Monatsh. Chem. 1882, 3, 572. a) Felber, J. P.; Coombs, T. L.; Vallee, B. L. Biochemistry 1962, 1, 231−238. b) Salvesen, G. S.; Nagase, H. Proteolytic Enzymes: A Practica Approach, 2nd ed.; Oxford University Press: Oxford, U.K., 2001; 1, 105−130. (a) Wang, S.; Hartley, D. P.; Ciccotto, S. L.; Vincent, S. H.; Franklin, R. B.; Kim, M. S. Drug Metab. Dispos. 2003, 31, 773−775. (b) Carr, B. A.; Franklin, M. R. J. Biochem. Mol. Toxicol. 1999, 13, 77−82. (c) Carr, B. A.; Franklin, M. R. Xenobiotica 1998, 28, 949−956. a) Yapi, A. D.; Mustof, M.; Chaviqnon, O.; Teulade, J. C.; Mallie, M.; Chapat, J. P.; Blache, Y. Chem. Pharm. Bull. 2000, 48, 1886−1889. b) Eqan, T. J.; Koch, K. R.; Swan, P. L.; Clarkson, C.; Van Schalkwyk, D. A.; Smith, P. J. J. Med. Chem. 2004, 47, 2926−2934. c) Yapi, A.D.; Valentin, A.; Chezal, J.-M.; Chavignon, O.; Chaillot, B.; Gerhardt, R.; Teulade, J.- C.; Blache, Y. Arch. Pharm. Chem. Life Sci. 2006, 339, 201−206. a) Sammes, P. G.; Yahioglu, G. Chem. Soc. Rev. 1994, 23, 327-334. b) Brand, R. M.; Hannah, T. L. AAPS Pharmsci. 2000, 35, 1- 5. c) Song, G.; Zhang, Y.; Su, Y.; Deng, W.; Han, K.; Li, X. Organometallics 2008, 27, 6193–6201. a) Prakash K. S.; Nagarajan, R. Org. Lett. 2014, 16, 244–246. b) Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2013, 78, 2802–2807. c) Ramesh, S.; Nagarajan, R. J. Org. Chem. 2013, 78, 545–558. d) Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2014, 79, 736–741. e) Ghosh, S. K.; Nagarajan, R. RSC Adv. 2014, 4, 63147. f) Ghosh, S. K.; Nagarajan, R. RSC Adv. 2016, 6, 27378. a) Graf, G. I.; Hastreiter, D.; da Silva, E. L.; Rebelo, R. A.; Montalbanb, A. G.; McKillopc, A. Tetrahedron 2002, 58, 9095–9100. b) Symeonidis, T. S.; Lykakis, I. N.; Litinas, K. E. Tetrahedron, 2013, 69, 4612- 4616. c) Summers, L. A. Adv. Heterocycl. Chem. 1978, 22, 1–69. d) Su, Q.; Li, P.; He, M.; Wu, Q.; Ye, L.; Mu, Y. Org. Lett. 2014, 16, 18−21. e) Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004, 3, 0449–0452. a) Doebner, O.; Miller, W. V. Ber. Dtsch. Chem. Ges. 1881, 14, 2812. b) Choi, H. Y.; Srisook, E.; Jang, K. S.; Chi, D. Y. J. Org. Chem. 2005, 70,1222–1226. c) Yamashkin, S. A.; Oreshkina, E. A. Chem. Heterocycl. Compd. 2006, 42, 701-718. While compiling our manuscript the first synthesis of this alkaloid has appeared in the following journal. Garcia-Barrantes, P. M.; Harp, J. R.; Lindsley, C. W. Tetrahedron Lett. 2016, 57, 2194–2196. Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 5630–5631. Hongen, T.; Taniguchi, T.; Nomura, S.; Kadokawa, J.; Monde, K. Macromolecules 2014, 47, 5313−5319. Molecular formula: C15H15N3O, unit cell parameters: a 12.1928(9), b 12.9524(10), c 16.6378(13); CCDC 1445332.
4
Highlights: Total synthesis of a marine actinomycete Actinophenanthroline A is achieved. Both racemic and enantiopure actinophenanthroline A has been synthesized. The classical and economical double Doebner-Miller reaction is used as Key step.
S0040-4039(16)30720-1 http://dx.doi.org/10.1016/j.tetlet.2016.06.045 TETL 47772
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
25 May 2016 10 June 2016 12 June 2016
Please cite this article as: Ghosh, S.K., Nagarajan, R., Total synthesis of Actinophenanthroline A via double Doebner–Miller reaction, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.045
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 Actinophenanthroline A via double Doebner–Miller reaction Suman Kr Ghosh and Rajagopal Nagarajan*
Leave this area blank for abstract info.
1
Tetrahedron Letters
Total synthesis of Actinophenanthroline A via double Doebner–Miller reaction Suman Kr Ghosh and Rajagopal Nagarajan* a
School of chemistry, University of Hyderabad, Hyderabad- 500046, India (+) 91 40 23012460 [email protected]
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
Total synthesis of actinophenanthroline A, a marine actinomycete within the family of Streptomycetaceae (strain CNQ-149) is reported. Both the racemic and enantiopure actinophenanthroline A has been synthesized with good overall yields. Highlight of the synthesis contains the classical and economical double Doebner-Miller reaction to access the 1, 7phenanthroline core followed by a modified EDCI coupling.
Keywords: Total Synthesis Natural product 1,7-phenanthroline Double Doebner-Miller
In June 2015, Fenical et al. isolated1 some unprecedented alkaloids actinobenzoquinoline and actinophenanthroline A- C (Figure 1.) from a marine actinomycete within the family of streptomycetaceae (strain CNQ-149). The core structures of both the alkaloids were not known in the alkaloid literature previously. Actinophenanthrolines A−C are the elementary examples of natural products containing the 1,7-phenanthroline alkaloid core. The synthetic phenanthrolines are already well established in literature from ages, among them 1,7-, 1,10-, 4,7- are predominantly common. Synthetic 1, 7-phenanthrolines were the first phenanthroline to be prepared by Skarup et al. in 18822 and later on, studies revealed their activities to induce the biosynthesis of drug-metabolizing enzymes by binding to metals.3 1, 10-Phenanthrolines are most well studied among all the phenanthrolines as they exhibit properties like: inhibitors of zinc metallopeptidases,4 antimalarial activities5, metal binding capacity.6 Thus, the first naturally occurring alkaloids which contains 1,7- phenanthroline core were indeed important from a synthetic view point. This may open opportunity to reveal many important biological or pharmaceutical properties. As, our group is working on the total synthesis of different heterocyclic alkaloids,7 this alkaloid actinophenanthroline A enticed us to carry out the synthesis of it. Though there were many synthetic strategies available in literature for 1, 7- phenanthroline core8 but we planned our synthetic route for this alkaloid via the classic and economic Doebner-Miller method.9 Very recently Lindsley group reported the first total synthesis for this alkaloid starting from 8-hydroxy-2-methylquinoline. Although their synthetic route gave a good overall yield but it consists of isolation and purification problems in every steps as author mentioned in their manuscript.10 Thus, in this paper we report an easier and economical total synthesis of actinophenanthroline A via double Doebner-Miller reaction.
Figure. 1. Structures of Actinophenanthrolines
As depicted in scheme 1, our initial strategy for the synthesis of 9 hinged on the deprotection of the hydroxyl groups (aliphatic and aromatic) of compound 8 in two consecutive steps. Compound 8 could be stemmed from compound 7 via a coupling reaction with protected L-lactic acid. The amine (7) could be generated through nitration followed by reduction on compound 5. To achieve the exact 1, 7 phenanthroline core (5), a repeated Doebner-Miller reaction on 2-methoxy-5-nitroaniline would have been the best pathway.
2 Scheme 1. Retrosynthetic analysis
We commenced the forward synthesis with 2-methoxy-5nitroaniline (1a), where it was treated with crotonaldehyde in Doebner-Miller reaction conditions at 90 °C with mixed acid (AcOH and HCl) to produce the substituted 2-methylquinoline (3) in 61 % yield. Exposure of this nitroquinoline (3) to a reflux condition with Fe powder/NH4Cl, furnished the corresponding amine product (4) which has been subjected to second DoebnerMiller reaction with crotonaldehyde in same mixed acid condition for 2 h at 90 °C to achieve the desired 1, 7phenanthroline core (5) in 71% yield. Next, selective introduction of a nitro group at the C5 of the compound 5 can be achieved only with the o and p directing substitution at C6. Thus, we had an edge due to the methoxy group at C6 of compound 5. Hence, we treated compound 5 with HNO3-H2SO4 at 0 °C to obtain the corresponding nitro substituted compound (6) but unfortunately yield was very poor.
Scheme 2. Forward Synthesis
reached to compound 7, we were very eager to carry out the key coupling reaction between amine (7) and L-lactic acid using EDCI.HCl as coupling agents that has already been reported for benzene moieties,11 but unfortunately that was a failure. Thus, we tried variety of conditions with different coupling agents (EDCI.HCl, HBTU, HATU, TBTU, DCC, CID, CDI) along with activating agents (DMAP, HOBt) at varied temperatures even then we failed to obtain our desired coupled product 8 (see Supporting Information, Table 1). We envisaged that it is the free hydroxyl group of lactic acid which might be the culprit for these consecutive failures. Thus, we protected the free hydroxyl group of L-lactic acid with methoxy group. We prepared the (S)2-methoxypropanoic acid in three steps starting from L-lactic acid by following ref. 12.
Figure. 1. X-ray structure of 6-methoxy-2, 8-dimethyl-1,7-phenanthrolin-5amine (7)13
Next, we treated compound 7 and (S)-2-methoxypropanoic acid (12) with EDCI.HCl in DCM at 0 °C- rt for 72 h then at 50 °C for another 24 h but still we were not able to obtain the coupled product 13.
Scheme 3. Synthesis of enantiospecific Actinophenanthroline A
We presume that it is not only the hydroxyl group but there might be some other electronic or steric factors which plays a vital role for this reaction. It is possibly that C5 amine on this phenanthroline core that is less nucleophilic (in comparison with simple benzene core) due to the presence of two electron withdrawing pyridine rings. Hence, its nucleophilicity might not be enough to displace the O-acyl lactic acid intermediate (which forms in situ with EDCI and lactic acid) to form the desired amide (8/13). Hence, we envisioned that, keeping an electron withdrawing group at the α-/β position of the L-lactic acid might increase the eletrophilicity of the lactic acid intermediate that might be sufficient to form the desired coupled product (8/ 13). Next, we tried to optimize the reaction using different conditions with other nitrating agents like NO2BF4, AcONO2 and NaNO3H2SO4 to improve the yield of compound 6. Among them NaNO3-H2SO4 condition at 0- 10 °C found to give a moderate yield of compound 6. This nitro group of compound 6 was reduced again to respective 5-amino-1, 7-phenanthroline (7) in quantitative yields with Fe powder under reflux condition. As we
From this perspective, we primarily started the venture for synthesis of racemic actinophenanthroline A. We carried out the reaction between compound 7 and pyruvic acid with coupling agent EDCI. HCl in DCM at 0 °C for 1 h, followed by 30 mins at rt to get the desired coupled product 14 with an excellent yield. The keto group of compound 13 was next reduced to alcohol using sodium borohydride in methanol at 0 °C which led to a racemic compound 15. The methoxy deprotection of compound
3 15 was then achieved using BBr3 in DCM at -78 °C to rt in a highly diluted condition after 24 h. The NMR spectrum of synthetic racemic actinophenanthroline A exactly matches with the reported actinophenanthroline A. Thus, we successfully completed the total synthesis of racemic actinophenanthroline A.
Scheme 4. Synthesis of racemic Actinophenanthroline A
natural product along with the synthetic product (see Supporting Information). In conclusion, we have successfully achieved the synthesis of both enantiopure actinophenanthroline A as well as the racemic version. The easier, classical and economical methods had been utilized to synthesize this alkaloid. This synthetic strategy administers an easier route to synthesize the other analogue alkaloids.
Acknowledgments We thank DST for financial support. S.K.G. also thanks UGC for senior research fellowship. Supplementary Material Experimental procedure, NMR, HRMS and Crystallographic data are available in supporting information. References and notes 1.
After a successful synthetic execution of racemic actinophenanthroline A we diverted our focus again towards the enantiopure actinophenanthroline A. Thus, we protected the hydroxyl group of L-lactic acid with acetyl group which indeed became an electron withdrawing group to α of the acid group. (S)-2-acetoxypropanoic acid was prepared via three steps, where the acid group was first protected with benzyl group using benzyl bromide in basic condition. Next, the acetoxylation was achieved using acetic anhydride with DMAP (cat.) followed by deprotection of the benzyl group using hydrogenation led to the (S)-2-acetoxypropanoic acid (see Supporting Information).
2. 3.
4.
5.
Scheme 5. Synthesis of enantiospecific Actinophenanthroline A 6.
7.
8.
With desired acid in hand, we carried out the key coupling reaction between the amine (7) and (S)-2-acetoxypropanoic acid with EDCI. HCl in DCM. The reaction was very sluggish, after 72 h also it did not reach completion. Hence, we interrupted the reaction and isolated the pure coupled product 19 along with some unreacted starting amine (7). The cleavage of O-acetate group of compound 19 was performed selectively using K2CO3 in MeOH solvent at 0 °C, within 10 mins the reaction was completed to give compound 20 in quantitative yields. On treatment of compound 20 with BBr3 in DCM the deprotection of methoxy group was achieved in 72 % yield to obtain the enantiopure actinophenanthroline A. We accomplished the total synthesis of racemic as well as enantiopure actinophenanthroline A with overall 5.11% and 4.8% yields respectively. All spectral data and HRMS data is consistent with the data of isolated
9.
10.
11. 12. 13.
Nam, S- J.; Kauffman, C. A.; Jensen, P. R.; E. M. Curtis; Rheingold, A. L.; Fenical W. Org. Lett. 2015, 17, 3240–3243. Skraup, H.; Vortmann, G. Monatsh. Chem. 1882, 3, 572. a) Felber, J. P.; Coombs, T. L.; Vallee, B. L. Biochemistry 1962, 1, 231−238. b) Salvesen, G. S.; Nagase, H. Proteolytic Enzymes: A Practica Approach, 2nd ed.; Oxford University Press: Oxford, U.K., 2001; 1, 105−130. (a) Wang, S.; Hartley, D. P.; Ciccotto, S. L.; Vincent, S. H.; Franklin, R. B.; Kim, M. S. Drug Metab. Dispos. 2003, 31, 773−775. (b) Carr, B. A.; Franklin, M. R. J. Biochem. Mol. Toxicol. 1999, 13, 77−82. (c) Carr, B. A.; Franklin, M. R. Xenobiotica 1998, 28, 949−956. a) Yapi, A. D.; Mustof, M.; Chaviqnon, O.; Teulade, J. C.; Mallie, M.; Chapat, J. P.; Blache, Y. Chem. Pharm. Bull. 2000, 48, 1886−1889. b) Eqan, T. J.; Koch, K. R.; Swan, P. L.; Clarkson, C.; Van Schalkwyk, D. A.; Smith, P. J. J. Med. Chem. 2004, 47, 2926−2934. c) Yapi, A.D.; Valentin, A.; Chezal, J.-M.; Chavignon, O.; Chaillot, B.; Gerhardt, R.; Teulade, J.- C.; Blache, Y. Arch. Pharm. Chem. Life Sci. 2006, 339, 201−206. a) Sammes, P. G.; Yahioglu, G. Chem. Soc. Rev. 1994, 23, 327-334. b) Brand, R. M.; Hannah, T. L. AAPS Pharmsci. 2000, 35, 1- 5. c) Song, G.; Zhang, Y.; Su, Y.; Deng, W.; Han, K.; Li, X. Organometallics 2008, 27, 6193–6201. a) Prakash K. S.; Nagarajan, R. Org. Lett. 2014, 16, 244–246. b) Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2013, 78, 2802–2807. c) Ramesh, S.; Nagarajan, R. J. Org. Chem. 2013, 78, 545–558. d) Ramkumar, N.; Nagarajan, R. J. Org. Chem. 2014, 79, 736–741. e) Ghosh, S. K.; Nagarajan, R. RSC Adv. 2014, 4, 63147. f) Ghosh, S. K.; Nagarajan, R. RSC Adv. 2016, 6, 27378. a) Graf, G. I.; Hastreiter, D.; da Silva, E. L.; Rebelo, R. A.; Montalbanb, A. G.; McKillopc, A. Tetrahedron 2002, 58, 9095–9100. b) Symeonidis, T. S.; Lykakis, I. N.; Litinas, K. E. Tetrahedron, 2013, 69, 4612- 4616. c) Summers, L. A. Adv. Heterocycl. Chem. 1978, 22, 1–69. d) Su, Q.; Li, P.; He, M.; Wu, Q.; Ye, L.; Mu, Y. Org. Lett. 2014, 16, 18−21. e) Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004, 3, 0449–0452. a) Doebner, O.; Miller, W. V. Ber. Dtsch. Chem. Ges. 1881, 14, 2812. b) Choi, H. Y.; Srisook, E.; Jang, K. S.; Chi, D. Y. J. Org. Chem. 2005, 70,1222–1226. c) Yamashkin, S. A.; Oreshkina, E. A. Chem. Heterocycl. Compd. 2006, 42, 701-718. While compiling our manuscript the first synthesis of this alkaloid has appeared in the following journal. Garcia-Barrantes, P. M.; Harp, J. R.; Lindsley, C. W. Tetrahedron Lett. 2016, 57, 2194–2196. Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 5630–5631. Hongen, T.; Taniguchi, T.; Nomura, S.; Kadokawa, J.; Monde, K. Macromolecules 2014, 47, 5313−5319. Molecular formula: C15H15N3O, unit cell parameters: a 12.1928(9), b 12.9524(10), c 16.6378(13); CCDC 1445332.
4
Highlights: Total synthesis of a marine actinomycete Actinophenanthroline A is achieved. Both racemic and enantiopure actinophenanthroline A has been synthesized. The classical and economical double Doebner-Miller reaction is used as Key step.