Synthesis of a Diastereomer of the Marine Macrolide Lytophilippine A

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Synthesis of a Diastereomer of the Marine Macrolide Lytophilippine A Andre ́ Klüppel, Annika Gille, Ceren Ester Karayel, and Martin Hiersemann* Fakultät für Chemie und Chemische Biologie, Technische Universität Dortmund, 44227 Dortmund, Germany

Org. Lett. Downloaded from pubs.acs.org by UNIV OF FLORIDA on 03/22/19. For personal use only.

S Supporting Information *

ABSTRACT: The synthesis of a diastereomer of lytophilippine A required 22 longest linear steps using known building blocks. Cross-metathesis/asymmetric aldol addition and regioselective esterification/ring-closing metathesis served as efficient combi tools for scaffold construction. Detailed NMR investigations in different solvent (systems) provide evidence for a deep-seated configurational misassignment of the molecule named lytophilippine A.

I

ensemble including a chlorine-substituted stereogenic carbon atom C25.6 In 2010, some of us reported the synthesis of a C1−C18 building block featuring the originally reported absolute configuration of 1a.7 The synthesis of a smaller tetrahydrofuran segment was published by Hodgson and Salik in 2012.8 In 2011, Lee et al. published the total synthesis of 1a;9 however, the NMR data (CD3OD) for synthetic 1a and the NMR data (unknown solvent) reported by Rezanka for the molecule named lytophilipine A did not match. Chemical correlation, derivatization, as well as NMR studies were originally used to assign the constitution and configuration of 1a.1 However, the solvent (system) used for the NMR experiments was not revealed, and primary data are apparently not available. Fascinated by the competitiveness of Macrorhynchia philippina in its natural habitat, and the resulting implications for its natural product chemistry, we initiated efforts to contribute to the unfinished quest for structural assignment of lytophilippine A by total synthesis. Because the credibility of the isolation report is compromised by an ambiguous discussion of the results, particularly with respect to the configurational assignment of the tetrahydrofuran section, we embarked on a research project aimed at the total synthesis of all possible diastereomers with respect to the C11−C15 region. Thus, a stereodivergent synthetic route offering the potential for full control over the absolute configuration of the C11− C15 segment was required. Herein, we report the total synthesis of (11R,13S,14R,15R)-lytophilippine A (1b) as one possible configurational match for the natural product. We provide a transparent comparison of our analytical data for 1b with those published by Lee for 1a and by Rezanka for the molecule named lytophilippine A. We emphasize the transparent 1H and 13C NMR assignment and solvent effects on chemical shifts.

n 2004, Rezanka and co-workers reported the isolation and structural characterization of the [14]macrolide lytophilippine A (1a) from a sample of the sessile marine animal Macrorhynchia philippina (alias Lytocarpus philippinus).1 The stinging hydroid is widely distributed and sometimes considered invasive.2 However, its natural product chemistry has been only sparsely investigated.3 The intricate structure of lytophilippine A is distinguished by the large number of stereogenic carbon atoms (17) relative to the overall chain length (27) (Figure 1).4,5 Thus,

Figure 1. Lytophilippine A from Macrorhynchia philippina.

lytophilippine A represents a substantial contest for configurational elucidation on one hand and for asymmetric total synthesis on the other hand. The two sites of unsaturation at C7/C8 and C18/C19 separate three sections presenting distinct structural characteristics: the southern C1−C6 γ-keto ester section is highlighted by a vicinal methyl branching, the northern C9−C17 section features a skipped and bridged polyol segment, and the eastern C19−C27 side chain is decorated by a methylene-separated stereotetrad−stereodyad © XXXX American Chemical Society

Received: February 26, 2019

A

DOI: 10.1021/acs.orglett.9b00722 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Our synthesis of the C15−C27 building block 7 commenced with an aldol reaction between the propionic acid ester 2 of the Abiko auxiliary10 and the known aldehyde 39,11 (86% de) to deliver the corresponding anti-β-hydroxy ester contaminated with inseparable 3 (Scheme 1). The contaminated β-hydroxy

Scheme 2. Elaboration of the C15−C27 Section

Scheme 1. Assemblage of the C15−C27 Section

yield over three steps; the minor diastereomer from the upstream aldol reaction could be separated by chromatography. In terms of structural assignment, it was useful to access the 20,22-syn aldol 9 by external hydride transfer under Luche conditions18 to the Re face of the C20 ketone carbonyl group and, subsequently, the enone 11 as a single diastereomer by cross-metathesis with methyl vinyl ketone (MVK-CM) in the presence of catMETium RF3 (10).19 With the alcohol 9 in hand, we opted for Mosher’s configurational correlation method20 to assign the absolute configuration of C20.21 Interestingly, reacting the MOM ether with AlCl3 in anisole22 triggered formation of the 1,3-dioxane 12 by intramolecular transacetalization. Interpretation of NOE experiments on the methylene acetal 12 supports the assignment of the relative configuration of the C20−C22 stereotriad.21 The synthesis of 1b was continued by an MVK-CM of 8 to deliver the C15−C27 building block 13 in 90% yield. Diastereoface-differentiating aldol reaction of the lithium enolate of 13 to the Re face of the carbonyl carbon atom of the aldehyde 1423 followed by diastereoface-differentiating external hydride transfer24 to the Re face of the C13 ketone carbonyl carbon atom of the chelated β-hydroxy ketone delivered the 11,13-diol 15 in 75% yield (dr = 95:5) (Scheme 3).25 With the northern building block 15 available, we advanced the synthesis by constructing the tetrahydrofuran moiety within the skipped and bridged polyol C9−C15 segment (Scheme 4). Thus, subjecting the triene 15 to a regioselective and stereodiverging Sharpless asymmetric epoxidation (SAE)26 in the presence of (−)-D-diisopropyl tartrate (DIPT) followed by Brønsted acid mediated diastereomer-differentiating acetalization7 delivered the tetrakisacetal 16 in 24% yield (dr = 94:6) as well as the diol 17 in 49% yield (dr = 95:5) after separation by chromatography.27

ester was subjected to MOM protection, and a succeeding DIBAL-H reduction afforded the primary alcohol 4 in 55% yield (3.23 g isolated mass) and with a moderate diastereoselectivity (82:18); auxiliary recovery was accomplished with 48% yield. The mixture of diastereomers was carried downstream until separation by chromatography was possible. Treatment of the alcohol 4 with 2-iodoxybenzoic acid (IBX)12 delivered the aldehyde 5 in 93% yield. Chain elongation in western direction was accomplished by treatment of 5 with lithiated diethyl ethylphosphonate to yield the corresponding β-hydroxy phosphonate that was oxidized according to Swern13 to deliver the corresponding β-keto phosphonate. Disappointingly, the subsequent condensation14 of the β-keto phosphonate with the α-branched aldehyde 615 proceeded very slowly and sluggishly to afford the α,β-enone 7 in meager yields and still as a mixture of diastereomers (82:18) from the aldol reaction. Several attempts to enable improvement proved futile. After passing the bottleneck, we continued with the structural elaboration of the building block 7 (Scheme 2). After some experimentation, we found that the removal of the MOM protecting group could be accomplished using an excess of ZnBr2 in butanethiol16 as an auxiliary nucleophile; various alternative conditions were either noneffective or triggered decomposition. Succeeding substrate-directed internal hydride transfer by tetrabutylammonium triacetoxyborohydride to the Si face of the C20 ketone carbonyl group proceeded as expected to provide the corresponding 20,22-anti-diol.17 Subsequent introduction of the acetonide protecting group delivered the elaborated C15−C27 building block 8 in 66% B

DOI: 10.1021/acs.orglett.9b00722 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 3. Section Fusion by CM and Aldol Addition

Scheme 5. Assemblage of the [14]Macrolactone and Conclusion of the Total Synthesis

Scheme 4. SAE and Diastereomer Differentiation

full conversion of the starting triene 19; attempts to scale (120 mg) the RCM, however, were hampered by slow and finally incomplete conversion. In practice at larger scale, two cycles of RCM were required to achieve complete conversion, and given the late-stage nature of the RCM, we refrained from further optimization. In order to achieve global deprotection, we adapted conditions previously reported for the total synthesis of 1a.9 Hence, fluoride-mediated cleavage of the TBS ether was followed by ketal hydrolysis to deliver (11R,13S,14R,15R)lytophilippine A (1b) in 45% from the triene 19 as a white solid which, in our hands, could not be crystallized to deliver crystals suitable for X-ray crystal structure analysis. Overall, 84 mg of 1b was made available during our total synthesis campaign. Aiming to contribute to the quest for structural assignment, we were well equipped for extensive NMR investigations. When comparing our NMR data for (11R,13S,14R,15R)-1b (CD3OD) to those reported by Lee for (11S,13R,14S,15S)-1a (CD3OD),21 we observed a very good fit of chemical shifts for protons of the side chain past C18 (Δδ ≤ 0.03 ppm); also in line with our expectations, major deviations (Δδ) were detected for protons from the skipped and bridged polyol region with the notable exception of H13 (Δδ = 0.01 ppm). When turning to NMR data comparison with the natural product named lytophilippine A reported by Rezanka, we had to deal with an unknown solvent system. Thus, a selection of deuterated solvents was used for NMR measurements. For CD3CN, CDCl3, C6D6, and D2O, we observed insufficient solubility of 1b. 1H and 13C NMR data were then collected in CD3OD, (CD3)2CO,31 (CD3)2SO,32 C5D5N,33 and C5D5N−CD3OD (1:1)34 and compared to the

With the protected C8−C27 segment 17 accessible, we progressed by assembling the [14]macrolactone of lytophilippine A (Scheme 5). Building on previous work,7 we deployed a remarkably regioselective Shiina esterification28 of the diol 17 with the acid 18.29 Further following the lead of our group, the ester was equipped with a TBS ether at C15 in order to facilitate the envisioned downstream ring-closing metathesis (RCM). Removal of the PMB protecting group and succeeding IBX oxidation12 of the corresponding lactonizationprone γ-hydroxy ester finally delivered the RCM competent γketo ester 19 in 59% yield from 17. At smaller scale (20 mg of 19), the decisive RCM of 19 proceeded uneventfully in the presence of the second-generation Grubbs precatalyst 2030 (0.2 equiv) to deliver the corresponding [14]macrolide with C

DOI: 10.1021/acs.orglett.9b00722 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

available NMR data basis, a global rather than regional configurational misassignment of the marine macrolide named lytopilippine A must be concluded.

data reported by Rezanka for the molecule named lytophilippine A (Figure 2). From this comparison, it is

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00722. Experimental procedures, configurational assignment, and comparison of NMR data for 1a and 1b (PDF) NMR spectra (PDF) Elemental analyses, MS spectra, and IR spectra (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Martin Hiersemann: 0000-0003-4743-5733 Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS Financial support by the DFG (HI628/12-2) and the TU Dortmund is gratefully acknowledged. REFERENCES

(1) Rezanka, T.; Hanus, L. O.; Dembitsky, V. M. Tetrahedron 2004, 60, 12191. The C27 palmitic acid and the C27 oleic acid esters were also isolated and named lytophilippines B and C. Weak antibacterial activity against Escherichia coli and Agrobacterium tumefaciens was reported for the molecule named lytophilippine A. (2) Cinar, M. E.; Bilecenoglu, M.; Ö ztürk, B.; Can, A. Aquat. Invasions 2006, 1, 84. (3) (a) Zlotkowski, K.; Hewitt, W. M.; Yan, P.; Bokesch, H. R.; Peach, M. L.; Nicklaus, M. C.; O’Keefe, B. R.; McMahon, J. B.; Gustafson, K. R.; Schneekloth, J. S. Org. Lett. 2017, 19, 1726. (b) Yan, P.; Ritt, D. A.; Zlotkowski, K.; Bokesch, H. R.; Reinhold, W. C.; Schneekloth, J. S.; Morrison, D. K.; Gustafson, K. R. J. Nat. Prod. 2018, 81, 1666. (4) For a review on tetrahydrofuran-containing macrolides from marine producers, see: Lorente, A.; Lamariano-Merketegi, J.; Albericio, F.; Alvarez, M. Chem. Rev. 2013, 113, 4567. (5) For selected recent synthetic work on constitutionally related marine [14]macrolides, see: (a) Gil, A.; Lamariano-Merketegi, J.; Lorente, A.; Albericio, F.; Alvarez, M. Org. Lett. 2016, 18, 4485. (b) Lorente, A.; Gil, A.; Fernandez, R.; Cuevas, C.; Albericio, F.; Alvarez, M. Chem. - Eur. J. 2015, 21, 150. (c) Schomaker, J. M.; Borhan, B. J. Am. Chem. Soc. 2008, 130, 12228. (d) Ueda, M.; Yamaura, M.; Ikeda, Y.; Suzuki, Y.; Yoshizato, K.; Hayakawa, I.; Kigoshi, H. J. Org. Chem. 2009, 74, 3370. (6) For examples of polyketides featuring chlorine-substituted stereogenic sp3 carbon atoms, see: (a) Wyche, T. P.; Piotrowski, J. S.; Hou, Y.; Braun, D.; Deshpande, R.; McIlwain, S.; Ong, I. M.; Myers, C. L.; Guzei, I. A.; Westler, W. M.; Andes, D. R.; Bugni, T. S. Angew. Chem., Int. Ed. 2014, 53, 11583. (b) Du, L.; King, J. B.; Cichewicz, R. H. J. Nat. Prod. 2014, 77, 2454. (7) Gille, A.; Hiersemann, M. Org. Lett. 2010, 12, 5258. (8) Hodgson, D. M.; Salik, S. Org. Lett. 2012, 14, 4402. (9) Jang, K. P.; Choi, S. Y.; Chung, Y. K.; Lee, E. Org. Lett. 2011, 13, 2476 For a modified synthetic procedure to 3, see the Supporting Information. . (10) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc. 1997, 119, 2586.

Figure 2. Comparison of 13C NMR data.

immediately evident that extensive global and solventindependent deviations between the measured 1H and 13C chemical shifts of synthetic 1b and those reported for the molecule named lytophilippine A by Rezanka exist. Furthermore, our extensive NMR studies reveal that Δδ(solvent) is generally far less pronounced than Δδ(1aRezanka−1b). Hence, the already reported chemical shift differences for synthetic and natural 1a Δδ(Rezanka−Lee) are probably not caused by NMR solvent effects. Consequently, a deep-seated global configurational misassignment of lytophilippine A by Rezanka et al. must be concluded. Hence, future attempts to assign the configuration of lytophilippine A by total synthesis have probably no prospect of success, and we refrained from converting 16 to a 11,14-trans-configured tetrahydrofuran diastereomer of the natural product.35 In conclusion, the total synthesis (11R,13S,14R,15R)lytophilippine A (1b), a diastereomer of a [14]macrolide originally isolated from a sample of the marine animal M. philippina (alias L. philippinus), was accomplished. A longest linear sequence consisting of 22 steps from known aldehyde 3 was established. Efforts were made to formulate a robust and reliable total synthesis, and the sequence consisting of crossmetathesis−aldol addition−diasteroface-differentiating β-hydroxy ketone reduction nicely embodies the agenda. We provide extensive NMR data for 1b in different solvents and a transparent chemical shift assignment. According to the thusD

DOI: 10.1021/acs.orglett.9b00722 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters (11) (a) Jaschinski, T. Diploma Thesis, TU Dortmund, 2008. (b) Stiasni, N. Ph.D. Dissertation, TU Dortmund, 2010. (12) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019. (13) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (14) Paterson, I.; Yeung, K.-S.; Smaill, J. N. Synlett 1993, 1993, 774. (15) Lin, N.; Overman, L. E.; Rabinowitz, M. H.; Robinson, L. A.; Sharp, M. J.; Zablocki, J. J. Am. Chem. Soc. 1996, 118, 9062. (16) Han, J. H.; Kwon, Y. E.; Sohn, J.-H.; Ryu, D. H. Tetrahedron 2010, 66, 1673. (17) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560. (18) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226. (19) Kadyrov, R.; Azap, C.; Weidlich, S.; Wolf, D. Top. Catal. 2012, 55, 538. (20) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (21) See the Supporting Information for details. (22) Terayama, N.; Yasui, E.; Mizukami, M.; Miyashita, M.; Nagumo, S. Org. Lett. 2014, 16, 2794. (23) Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron: Asymmetry 2002, 13, 1189. (24) Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro, M. Chem. Lett. 1987, 16, 1923. (25) The configurational assignment of C11 and C13 rests on Mosher’s configurational correlation method for C11 and Rychnovsky’s [13C]acetonide analysis for C13 in a 20S-configured derivative of 15 accessible from 9 by a sequence consisting of MOM protection, MVK−CM, aldol reaction with 14, and reduction; see: Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945. Also see the Supporting Information for details. (26) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974. (27) The ratio 16/17 mirrors the mismatched-enforced weak diastereofacial differentiation of the SAE using (−)-D-DIPT. NOE studies on 16 and 17 support the assignment of the relative configuration; see the Supporting Information for details. (28) Shiina, I.; Kubota, M.; Ibuka, R. Tetrahedron Lett. 2002, 43, 7535. In our hands, Steglich esterification failed and Yamaguchi esterification was lower yielding. (29) The constitution was assigned based on NMR−HMBC experiments. (30) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (31) 1H NMR Δδ [(CD3)2CO−CD3OD] in the range from −0.05 to +0.10 ppm. (32) 1H NMR Δδ [(CD3)2SO−CD3OD] in the range from −0.30 to −0.01 ppm; general upfield shift. (33) 1H NMR Δδ [C5D5N−CD3OD] in the range from 0 to +0.85 ppm. With one exception (6′-CH3), significant and general downfield shift. (34) Previously used as NMR solvent system by Rezanka et al.; see: Rezanka, T.; Hanus, L.; Dembitsky, V. M. Eur. J. Org. Chem. 2003, 2003, 4073. (35) Access to the primary data would be vital to unambiguously assign the true configuration of the marine polyketide. If indeed it is not available, reisolation from the natural source appears to be unavoidable.

E

DOI: 10.1021/acs.orglett.9b00722 Org. Lett. XXXX, XXX, XXX−XXX