Development of Tandem Metal-Mediated Cyclization Reactions for the Total Synthesis of Alkaloid Natural Products

40725-GB1
Development of Tandem Metal-Mediated Cyclization Reactions for the Total Synthesis of Alkaloid Natural Products

Erin Pelkey, Hobart and William Smith Colleges

A major component of our research program at Hobart and William Smith Colleges involves developing synthetic methodology that targets the aristolactam alkaloids. These compounds are of interest due to the combination of their structural complexity (highly oxygenated phenanthrene lactams) and inherent biological activity (anti-cancer activity).¹ Our strategy involves the use of a tandem metal-mediated coupling-cyclization sequence. The tandem sequence includes the addition of a carboxylate nucleophile² onto a proximate alkyne that is activated by coordination of a Pd(II)-arene complex (generated in situ). This is the final report detailing our progress to date. During our first year, we worked out the synthesis of the o-ethynylbenzoic acid 1. During our second year, we explored the key tandem reaction sequence of 1 leading to isozbenzofuran-1-ones 2 and discovered an unexpected stereochemical outcome (major product = (syn)-2). During this past year, we confirmed the structural identity of the tandem reaction products through independent syntheses of the corresponding desilylated isobenzofuran-1-ones 3. Overall, we have made good progress and we believe that compounds 2 and 3 represent potentially useful intermediates for completing the total synthesis of the aristolactam alkaloids (e.g., 4).

We investigated the key tandem coupling-cyclization reaction of 1 (Scheme 1).² In the event, treatment of 1 and p-iodoanisole with Pd(0) and potassium carbonate led to a mixture that seemed to include the expected product (anti)-2. Utilizing careful column chromatography, two isomeric isobenzofuran-1-ones 2 were separated (~6:1 ratio), although at this point, we were not able to unequivocally assign their alkene stereochemistry. We decided to distinguish between the "anti-addition" product (anti)-2 and the "syn-addition" product (syn)-2 by independent synthesis of the corresponding desilylated materials. In two separate reactions, desilylation of (anti)-2 and (syn)-2 with TBAF led to formation of (anti)-3 and (syn)-3, respectively.

The independent synthesis (anti)-3 was accomplished in three steps utilizing methodology developed by Larock and co-workers (Scheme 2).³ Treatment of o-ethynylbenzoate 5 with iodine monochloride gave isobenzofuran-1-one 6 via an electrophile-mediated 5-exo-dig cyclization. Subsequent Suzuki-Miyaura cross-coupling of 6 with p-methoxyphenylboronic acid gave 7, which was smoothly desilylated giving (anti)-3. To our surprise, (anti)-3 turned out to match the desilylation product derived from the minor stereoisomer of the tandem coupling-cyclization product. This meant that our tandem cyclization-coupling reaction gave 6:1 ratio of (anti)-2 to (syn)-2, and the desired product (syn)-2 was the minor product.

To further the stereochemistry of our isobenzofuran-1-one products 2, we investigated the independent synthesis of (syn)-3 utilizing the ring-closure methodology reported by Terada and Kanazawa (Scheme 3).⁴ Alkyne 9 was prepared by a Sonogashira cross-coupling reaction between iodobenzoate 8. Mild hydrolysis of 9 with lithium hydroxide gave o-ethynylbenzoic acid 10. A DBU-mediated 5-exo-dig cyclization of 10 then produced (syn)-3, which as expected, matched the desilylation product of the major stereoisomer of the tandem coupling-cyclization product.

In conclusions, upon achieving both independent syntheses, we are now very confident in the structural assignments of our tandem coupling-cyclization products as a 6:1 ratio of (syn)-2 and (anti)-2, respectively. We plan to investigate the endgame reactions (e.g., oxidative cyclization) of (anti)-2 and/or (anti)-3 leading to the aristolactam alkaloids.

The project has provided an excellent training ground for six undergraduate research students: Michael Liquori ('05), Matthew Garman ('06), Brian Ohman ('07), Michael DePersis ('07), Kailey Voellinger ('08), and Christian Moore ('09). Liquori, Garman, and DePersis are currently in medical school. Ohman is pursuing a Ph.D. in chemistry at U. Rochester, and Voellinger will soon enter the Ph.D. in chemistry at U. Minnesota. Our research progress has been communicated at five regional, national, and international conferences including: (1) ACS National Meeting, Philadelphia (Aug 2004); (2) International Conference of Heterocyclic Chemistry, Palermo, Italy (Aug 2005); (3) ACS Rochester Section-Undergraduate Research Symposium, SUNY-Brockport (Apr 2006); (4) CU-Roche Symposium, Boulder, CO (Jun 2006); and (5) ACS National Meeting, Boston (Aug 2007). We remain grateful to the Petroleum Research Fund for their continued support of basic research in chemistry.

<>References

(1) Couture, A.; Deniau, E.; Grandclaudon, P.; Rybalko-Rosen, H.; LŽonce, S.; Pfeiffer, B.; Renard, P. Synthesis and biological evaluation of aristolactams. Bioorg. Med. Chem. Lett. 2002, 12, 3557-3559.

(2) Rossi, R.; Bellina, F.; Biagetti, M.; Catanese, A.; Mannina, L. Palladium-Catalyzed Synthesis of Stereodefined 3-[1,1-unsymmetrically disubstituted)-methylidene]isobenzofuran-1(3H)-ones and Stereodefined 5-[1,1-unsymmetrically disubstituted]furan-2(5H)-ones. Tetrahedron Lett. 2000, 41, 5281-5286.

(3) Yao, T.; Larock, R.C. Regio- and Stereoselective Synthesis of Isoindolin-1-ones via Electrophilic Cyclization. J. Org. Chem. 2005, 70, 1432-1437.

(4) Kanazawa, C.; Terada, M. Organic-base-catalyzed synthesis of phthalides via highly regioselective intramolecular cyclization reaciton. Tetrahedron Lett. 2007, 48, 933-935.

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Home > Reports Back to Table of Contents 40725-GB1 Development of Tandem Metal-Mediated Cyclization Reactions for the Total Synthesis of Alkaloid Natural Products Erin Pelkey, Hobart and William Smith Colleges A major component of our research program at Hobart and William Smith Colleges involves developing synthetic methodology that targets the aristolactam alkaloids. These compounds are of interest due to the combination of their structural complexity (highly oxygenated phenanthrene lactams) and inherent biological activity (anti-cancer activity).¹ Our strategy involves the use of a tandem metal-mediated coupling-cyclization sequence. The tandem sequence includes the addition of a carboxylate nucleophile² onto a proximate alkyne that is activated by coordination of a Pd(II)-arene complex (generated in situ). This is the final report detailing our progress to date. During our first year, we worked out the synthesis of the o-ethynylbenzoic acid 1. During our second year, we explored the key tandem reaction sequence of 1 leading to isozbenzofuran-1-ones 2 and discovered an unexpected stereochemical outcome (major product = (syn)-2). During this past year, we confirmed the structural identity of the tandem reaction products through independent syntheses of the corresponding desilylated isobenzofuran-1-ones 3. Overall, we have made good progress and we believe that compounds 2 and 3 represent potentially useful intermediates for completing the total synthesis of the aristolactam alkaloids (e.g., 4). We investigated the key tandem coupling-cyclization reaction of 1 (Scheme 1).² In the event, treatment of 1 and p-iodoanisole with Pd(0) and potassium carbonate led to a mixture that seemed to include the expected product (anti)-2. Utilizing careful column chromatography, two isomeric isobenzofuran-1-ones 2 were separated (~6:1 ratio), although at this point, we were not able to unequivocally assign their alkene stereochemistry. We decided to distinguish between the "anti-addition" product (anti)-2 and the "syn-addition" product (syn)-2 by independent synthesis of the corresponding desilylated materials. In two separate reactions, desilylation of (anti)-2 and (syn)-2 with TBAF led to formation of (anti)-3 and (syn)-3, respectively. The independent synthesis (anti)-3 was accomplished in three steps utilizing methodology developed by Larock and co-workers (Scheme 2).³ Treatment of o-ethynylbenzoate 5 with iodine monochloride gave isobenzofuran-1-one 6 via an electrophile-mediated 5-exo-dig cyclization. Subsequent Suzuki-Miyaura cross-coupling of 6 with p-methoxyphenylboronic acid gave 7, which was smoothly desilylated giving (anti)-3. To our surprise, (anti)-3 turned out to match the desilylation product derived from the minor stereoisomer of the tandem coupling-cyclization product. This meant that our tandem cyclization-coupling reaction gave 6:1 ratio of (anti)-2 to (syn)-2, and the desired product (syn)-2 was the minor product. To further the stereochemistry of our isobenzofuran-1-one products 2, we investigated the independent synthesis of (syn)-3 utilizing the ring-closure methodology reported by Terada and Kanazawa (Scheme 3).⁴ Alkyne 9 was prepared by a Sonogashira cross-coupling reaction between iodobenzoate 8. Mild hydrolysis of 9 with lithium hydroxide gave o-ethynylbenzoic acid 10. A DBU-mediated 5-exo-dig cyclization of 10 then produced (syn)-3, which as expected, matched the desilylation product of the major stereoisomer of the tandem coupling-cyclization product. In conclusions, upon achieving both independent syntheses, we are now very confident in the structural assignments of our tandem coupling-cyclization products as a 6:1 ratio of (syn)-2 and (anti)-2, respectively. We plan to investigate the endgame reactions (e.g., oxidative cyclization) of (anti)-2 and/or (anti)-3 leading to the aristolactam alkaloids. The project has provided an excellent training ground for six undergraduate research students: Michael Liquori ('05), Matthew Garman ('06), Brian Ohman ('07), Michael DePersis ('07), Kailey Voellinger ('08), and Christian Moore ('09). Liquori, Garman, and DePersis are currently in medical school. Ohman is pursuing a Ph.D. in chemistry at U. Rochester, and Voellinger will soon enter the Ph.D. in chemistry at U. Minnesota. Our research progress has been communicated at five regional, national, and international conferences including: (1) ACS National Meeting, Philadelphia (Aug 2004); (2) International Conference of Heterocyclic Chemistry, Palermo, Italy (Aug 2005); (3) ACS Rochester Section-Undergraduate Research Symposium, SUNY-Brockport (Apr 2006); (4) CU-Roche Symposium, Boulder, CO (Jun 2006); and (5) ACS National Meeting, Boston (Aug 2007). We remain grateful to the Petroleum Research Fund for their continued support of basic research in chemistry. <>References (1) Couture, A.; Deniau, E.; Grandclaudon, P.; Rybalko-Rosen, H.; LŽonce, S.; Pfeiffer, B.; Renard, P. Synthesis and biological evaluation of aristolactams. Bioorg. Med. Chem. Lett. 2002, 12, 3557-3559. (2) Rossi, R.; Bellina, F.; Biagetti, M.; Catanese, A.; Mannina, L. Palladium-Catalyzed Synthesis of Stereodefined 3-[1,1-unsymmetrically disubstituted)-methylidene]isobenzofuran-1(3H)-ones and Stereodefined 5-[1,1-unsymmetrically disubstituted]furan-2(5H)-ones. Tetrahedron Lett. 2000, 41, 5281-5286. (3) Yao, T.; Larock, R.C. Regio- and Stereoselective Synthesis of Isoindolin-1-ones via Electrophilic Cyclization. J. Org. Chem. 2005, 70, 1432-1437. (4) Kanazawa, C.; Terada, M. Organic-base-catalyzed synthesis of phthalides via highly regioselective intramolecular cyclization reaciton. Tetrahedron Lett. 2007, 48, 933-935. 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40725-GB1 Development of Tandem Metal-Mediated Cyclization Reactions for the Total Synthesis of Alkaloid Natural Products

40725-GB1
Development of Tandem Metal-Mediated Cyclization Reactions for the Total Synthesis of Alkaloid Natural Products