Letter pubs.acs.org/OrgLett
An Approach to the Core of Lactonamycin Philip J. Parsons,*,† Daniel R. Jones,† Lee J. Walsh,† Lewis A. T. Allen,† Ada Onwubiko,† Lewis Preece,‡ Johnathan Board,‡ and Andrew J. P. White† †
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, U.K. Department of Chemistry, University of Sussex, Falmer, Brighton BN1 9RH, U.K.
‡
S Supporting Information *
ABSTRACT: A cascade reaction has been developed for the synthesis of lactonamycin. In this paper, we demonstrate that a transition-metal-free thermal ene−diyne cyclization can be used for the construction of the entire core of the antibiotic lactonamycin and anticancer agent lactonamycin Z.
L
1 and 2).20−22 We have also demonstrated that highly substituted aromatic rings can be formed in one synthetic
actonamycin (1) was isolated from Streptomyces rishiriensis in 1996 by Matsumoto and co-workers and is an important addition to the armory of antibiotics that are active against the “superbugs” vancomycin-resistant Enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA).1,2 In 2003, Fiedler et al. reported the isolation of lactonamycin Z (2) from Stremptomyces sanglieri; it is of similar structure but also possesses anticancer activity (Figure 1).3
Scheme 1. Lactonamycin Model Studies
Scheme 2. Metal-Free Thermal Cyclization
Figure 1. Lactonamycin (1), lactonamycin Z (2), and lactonamycinone (3).
operation by a transition-metal-free cascade, which utilizes the ring opening of furans as a key step.23 Ley 24 and Danheiser25,26 have demonstrated that triynes can be cyclized thermally to afford aromatic rings. In this paper, we show how the core of lactonamycin (8) can be made using a thermal cascade reaction, which does not involve the use of transition metals, following our retrosynthetic strategy (Scheme 3). The aldehyde 9 was made from the commercially available alcohol 10 (Scheme 4).
This unique structure has attracted numerous synthetic efforts. The first synthetic study was undertaken by Danishefsky in 2000, who completed the total synthesis of lactonamycinone (3) in 2003.4−7 Subsequent studies by Deville and Behar,8 Kelly,9,10 Barrett,11−15 and Parrain and Commeiras16 have been undertaken. Only two groups have thus far completed the synthesis of lactonamycin; the first was Tatsuta et al. in 201017 and the second was Nakata and Saikawa et al. in 2013.18,19 In 2006, we reported that heterocycles could easily be synthesized using a transition-metal-free cyclization (Schemes © 2017 American Chemical Society
Received: March 27, 2017 Published: April 26, 2017 2533
DOI: 10.1021/acs.orglett.7b00902 Org. Lett. 2017, 19, 2533−2535
Letter
Organic Letters Scheme 3. Retrosynthesis of Lactonamycin
Scheme 5. Preparation of the Diynes
Scheme 4. Synthesis of the Cyclization Precursor
Scheme 6. Unexpected Synthesis of the Naphthalene
Lewis acid which coordinated to the aldehyde, instead of forming the zincated alkyne. This promotes an intramolecular cyclization by attack of the pendant alkene into the neighboring aldehyde. The resulting cation is stabilized by a mesomeric effect from the bromine and followed by proton loss. Elimination of the zinc species allows aromatization and affords the naphthalene product (20). Unsurprisingly, the reaction proceeds equally well in the absence of the alkyne. Studies are ongoing to investigate the scope of this novel naphthalene synthesis. When the diynes 19a and 19b were treated with the Knochel−Hauser base (TMPMgCl·LiCl) followed by addition of the aldehyde 9 at −10 °C to room temperature over 4 days, to our delight, the desired amides were formed in 55− 60% yields after workup with tert-butyl bromide.29 We discovered that the amides 21a,b cyclized in boiling toluene in the presence of epoxyhexane to afford the desired pentacycles after 6 h (8a) and (8b) (Scheme 7). The structure of 8a was confirmed by X-ray crystallography (Figure 2).
Treatment of the known alcohol 10 with butyllithium and then solid carbon dioxide followed by hydrochloric acid gave the lactone 11 in 77% yield. Demethylation of 12 was carried out using pyridinium hydrochloride in 86% yield.27 Selective alkylation with 2,3-dibromopropene in the presence of lithium hydroxide in methanol gave the desired ether 13 in 63% yield. When the ether was heated in water under microwave conditions at 195 °C, the rearranged product 14 was obtained in up to 98% yield. Hydroxymethylation of 14 with formaldehyde gave the triol 15 in 70% yield. Selective methylation of the triol with TMS-diazomethane gave the desired dimethyl ether 16 (79%), which was then oxidized to the aldehyde 9 with DMP (94%). With the key aldehyde in hand, we were in a position to construct the cyclization precursor (21). Our experiments began with the introduction of TIPS protected N-methylpropargylamine with the aim of subsequent deprotection and amide coupling to form the cyclization precursor, however, the addition and deprotection were capricious and all attempts for the amide coupling were unsuccessful. Disappointed by this failure, we elected to introduce the desired side chain (19) in one synthetic step. The diynes (19a−b) were prepared from N-methylpropargylamine and the TMS or DMPS propiolic acid (Scheme 5). When trying to replicate the conditions described by Downey et al.,28 in adding the diyne 19a into the aldehyde, the naphthalene 20 was unexpectedly formed in 86% yield (Scheme 6). It is postulated that the zinc species acted as a
Scheme 7. Formation of the Cyclization Precursor
Further, we were able to achieve a “one pot” addition− cyclization using toluene as the solvent (Scheme 8). An efficient synthesis of the ABCDE rings of lactonamycin and a late-stage intermediate in its synthesis has been presented. Studies on the total synthesis are ongoing as well as work on the versatility of the naphthalene synthesis. 2534
DOI: 10.1021/acs.orglett.7b00902 Org. Lett. 2017, 19, 2533−2535
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Organic Letters
(7) Siu, T.; Cox, C. D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 5629−5634. (8) Deville, J. P.; Behar, V. Org. Lett. 2002, 4, 1403−1405. (9) Kelly, T. R.; Xu, D.; Martínez, G.; Wang, H. Org. Lett. 2002, 4, 1527−1529. (10) Kelly, T. R.; Cai, X.; Tu, B.; Elliott, E. L.; Grossmann, G.; Laurent, P. Org. Lett. 2004, 6, 4953−4956. (11) Jacques, S. A.; Michaelis, S.; Gebhardt, B.; Blum, A.; Lebrasseur, N.; Larrosa, I.; White, A. J. P.; Barrett, A. G. M. Eur. J. Org. Chem. 2012, 2012, 107−113. (12) Henderson, D. A.; Collier, P. N.; Pavé, G.; Rzepa, P.; White, A. J. P.; Burrows, J. N.; Barrett, A. G. M. J. Org. Chem. 2006, 71, 2434−2444. (13) Wehlan, H.; Jezek, E.; Lebrasseur, N.; Pavé, G.; Roulland, E.; White, A. J. P.; Burrows, J. N.; Barrett, A. G. M. J. Org. Chem. 2006, 71, 8151−8158. (14) Le Vézouët, R.; White, A. J. P.; Burrows, J. N.; Barrett, A. G. M. Tetrahedron 2006, 62, 12252−12263. (15) Jacques, S. A.; Patel, B. H.; Barrett, A. G. M. Tetrahedron Lett. 2011, 52, 6072−6075. (16) Dubois, S.; Rodier, F.; Blanc, R.; Rahmani, R.; Heran, V.; Thibonnet, J.; Commeiras, L.; Parrain, J.-L. Org. Biomol. Chem. 2012, 10, 4712−4719. (17) Tatsuta, K.; Tanaka, H.; Tsukagoshi, H.; Kashima, T.; Hosokawa, S. Tetrahedron Lett. 2010, 51, 5546−5549. (18) Adachi, S.; Watanabe, K.; Iwata, Y.; Kameda, S.; Miyaoka, Y.; Onozuka, M.; Mitsui, R.; Saikawa, Y.; Nakata, M. Angew. Chem., Int. Ed. 2013, 52, 2087−2091. (19) Watanabe, K.; Iwata, Y.; Adachi, S.; Nishikawa, T.; Yoshida, Y.; Kameda, S.; Ide, M.; Saikawa, Y.; Nakata, M. J. Org. Chem. 2010, 75, 5573−5579. (20) Parsons, P. J.; Board, J.; Waters, A. J.; Hitchcock, P. B.; Wakenhut, F.; Walter, D. S. Synlett 2006, 2006, 3243−3246. (21) Parsons, P. J.; Waters, A. J.; Walter, D. S.; Board, J. J. Org. Chem. 2007, 72, 1395−1398. (22) Parsons, P. J.; Board, J.; Faggiani, D.; Hitchcock, P. B.; Preece, L.; Waters, A. J. Tetrahedron 2010, 66, 6526−6533. (23) Parsons, P. J.; Jones, D. R.; Padgham, A. C.; Allen, L. A. T.; Penkett, C. S.; Green, R. A.; White, A. J. P. Chem. - Eur. J. 2016, 22, 3981−3984. (24) Saaby, S.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 3365−3368. (25) Robinson, J. M.; Sakai, T.; Okano, K.; Kitawaki, T.; Danheiser, R. L. J. Am. Chem. Soc. 2010, 132, 11039−11041. (26) Sakai, T.; Danheiser, R. L. J. Am. Chem. Soc. 2010, 132, 13203−13205. (27) Schmid, C. R.; Beck, C. A.; Cronin, J. S.; Staszak, M. A. Org. Process Res. Dev. 2004, 8, 670−673. (28) Downey, C. W.; Mahoney, B. D.; Lipari, V. R. J. Org. Chem. 2009, 74, 2904−2906. (29) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 2958−2961.
Figure 2. X-ray crystal structure of the ABCDE rings of the lactonamycin core (8a).
Scheme 8. “One-Pot” Addition−Cyclization of the Lactonamycin Core
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00902. Experimental procedures and spectral data (PDF) X-ray crystallographic data for 8a (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Philip J. Parsons: 0000-0002-9158-4034 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Drs. Alfred and Isabel Bader are gratefully acknowledged for their very generous support of this work. An Imperial College studentship (EPSRC 1507589) to D.R.J. is also acknowledged. Professor Parsons awards to L.J.W. and L.A.T.A. and a Davox award are gratefully acknowledged. Peter Haycock and Dr. Lisa Haigh (Imperial College London) are acknowledged for their help with NMR and mass spectrometry, respectively.
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REFERENCES
(1) Matsumoto, N.; Tsuchida, T.; Maruyama, M.; Kinoshita, N.; Homma, Y.; Iinuma, H.; Sawa, T.; Hamada, M.; Takeuchi, T.; Heida, N.; Yoshioka, T. J. Antibiot. 1999, 52, 269−275. (2) Matsumoto, N.; Tsuchida, T.; Maruyama, M.; Sawa, R.; Kinoshita, N.; Homma, Y.; Takahashi, Y.; Iinuma, H.; Naganawa, H.; Sawa, T.; Hamada, M.; Takeuchi, T. J. Antibiot. 1996, 49, 953−954. (3) Holtzel, A.; Dieter, A.; Schmid, D. G.; Brown, R.; Goodfellow, M.; Beil, W.; Jung, G.; Fiedler, H. P. J. Antibiot. 2003, 56, 1058−61. (4) Cox, C.; Danishefsky, S. J. Org. Lett. 2000, 2, 3493−3496. (5) Cox, C.; Danishefsky, S. J. Org. Lett. 2001, 3, 2899−2902. (6) Cox, C. D.; Siu, T.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 5625−5629. 2535
DOI: 10.1021/acs.orglett.7b00902 Org. Lett. 2017, 19, 2533−2535
