Abstract
The pentacyclic base of the sponge-derived alkaloid lihouidine has been assembled from two quinoline fragments. The key step is a nitration-promoted cyclization to form the C–C bond between the two quinoline units.
The bright red Suberea sponge metabolite lihouidine (1) possesses a stereogenic center but was isolated as a racemate.1 A biosynthetic hypothesis, based on speculation by Bowden et al.,1 that accounts for this unusual observation is illustrated in 2, where spontaneous, successive Michael-type additions of the β-dicarbonyl’s (deprotonated) nucleophilic methylene carbon into the adjacent electrophililic orthoquinone moieties may occur outside of a chiral environment. A reduced (catecholic) version of 2 might be traced back to two molecules of aaptamine (4). We have initiated a synthesis project to test this premise. Our route passes through the pentacyclic platform 3, and the concise synthesis of this key intermediate is described below.
The synthesis strategy for 3 was predicated on intramolecularly forging the key C(15)–C(16) bond uniting the two quinoline units from a precursor bearing quinolines already linked through N(5). To implement this strategy, assembly of quinoline building blocks 10 and 13 was achieved as described in Scheme 2. The chloride 9 is a known compound, prepared from 6 and methyl propiolate,2 but substitution of the Meldrum’s acid derivative 73 for the alkyne electrophile led to isolated yields of 9 that were superior to those achieved with the earlier chemistry. Heating 9 and methylamine in a sealed tube effected nucleophilic aromatic substitution of NH(CH3) for Cl much more efficiently than with either lower temperature conditions or with microwave irradiation. With the quinoline 10 in hand, synthesis of the second quinoline coupling partner, 13, from isatin (11) was accomplished by modification of the method reported by Vargas.4
Scheme 2.
Preparation of the two quinoline building blocks.
A Buchwald-Hartwig-type coupling5 between amine 10 and chloride 13 proceeded after much optimization to furnish the desired bis quinoline cyclization substrate 14 in good yield. The original plan for inducing oxidative cyclization within 14 involved protonation of the “DMAP”-type moiety to generate, at least transiently, a cationic system 15 that might participate in a 6π electrocyclization followed by rearomatization via air oxidation. However, exhaustively screening acids in search of this reactivity was not rewarded – no evidence of C–C bond formation was detected under either thermal or photochemical conditions. These trials were met with either recovery of intact 14, or substrate destruction without formation or any characterizable products. In the course of these experiments, an attempt at substrate nitration with the classic reagent combination HNO3/H2SO4 led to a singular result; formation of discrete products upon consumption of 14 (Table 1, entry 1). Separation of three compounds from this reaction mixture and subsequent spectroscopic characterization6 led to the assignments 16, 17a, and 17b. A diagnostic proton signal Ha in the 1H NMR spectrum of 17a occurred as a singlet at δ7.54 ppm. This proton’s assignment was confirmed by an HMBC correlation to the carbons labeled b in 17, which in turn were identified by their HMBC correlations to the protons c of the methoxy units. The regiochemical assignment of the nitro group position in 17b was based upon the nOe’s shown in Scheme 3. The regiochemistry of 17a nitration then was assigned by default as the other possible isomer. Nitration of one of the quinoline rings occurred in each product, but for the first time, products featuring the key C(15)-C(16) bond were detected. Optimization studies (Table 1) led to the conclusion that the best yield of the cyclized material 17 could be achieved by treatment with undiluted fuming nitric acid (entry 6). The mechanistic course of this transformation remains a matter of speculation, as the central question of whether nitration precedes or follows C(15)–C(16) bond formation is unknown. The role of an electrocyclization (cf. 15) in this C–C bond formation cannot be ascertained at present.
Table 1.
Results of the nitration of bis quinoline 14. All yields reported are for chromatographically pure material.
| entry | conditions | 16 (%) | 17a (%) | 17b (%) |
|---|---|---|---|---|
| 1 | HNO3, H2SO4, 0 °C | 10 | 31 | 9 |
| 2 | KNO3, H2SO4, 0 °C | 8 | 14 | 5 |
| 3 | Bu4NNO3, (F3CCO)2O, 0 °C → rt | 71 | -- | -- |
| 4 | NO2BF4, sulfolane, rt | -- | -- | -- |
| 5 | fuming HNO3, CH3SO3H, rt | -- | 22 | 5 |
| 6 | fuming HNO3, 0 °C | 12 | 52 | -- |
Scheme 3.
Completion of the pentacycle 3 synthesis.
The desired pentacyclic target 3 could be derived from 17a, or equally efficiently, from 17a/17b mixtures, by two simple operations. Initial reduction of the nitro function with Fe metal led to an intermediate amine that was not isolated. This compound(s) immediately was converted to an intermediate diazonium product(s) en route to the parent hydrocarbon via H3PO2-mediated reductive cleavage of nitrogen. Thus, compound 3 was available in 10 steps from commercially available 5. Studies to convert 3 into a β-ketoamide precursor to bis orthoquinone 2, and thence to lihouidine, are ongoing.
Scheme 1.
Lihouidine biomimetic retrosynthesis.
Acknowledgments
Support from the National Institutes of Health, General medical Scienced Dividion (GM37681) is gratefully acknowledged.
Footnotes
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References
- 1.Bowden BF, McCool BJ, Willis RH. J Org Chem. 2004;69:7791–7793. doi: 10.1021/jo0498819. [DOI] [PubMed] [Google Scholar]
- 2.Kelly TR, Maguire MP. Tetrahedron. 1985;41:3033–3036. [Google Scholar]
- 3.Walz AJ, Sundberg RJ. J Org Chem. 2000;65:8001–8010. doi: 10.1021/jo001080s. [DOI] [PubMed] [Google Scholar]
- 4.Torres JC, Pilli RA, Vargas MD, Violante FA, Garden SJ, Pinto AC. Tetrahedron. 2002;58:4487–4492. [Google Scholar]
- 5.(a) Guram A, Rennels R, Buchwald S. Angew Chem Int Ed. 1995;34:1348–1350. [Google Scholar]; (b) Louie J, Hartwig J. Tetrahedron Lett. 1995;36:3609–3612. [Google Scholar]
- 6.orange solid. mp 116–118 °C; IR (CH2Cl2) 1726 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.01 (d, J = 4.6 Hz, 1H), 8.42 (dd, J = 8.5, 0.9 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.66 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.38 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.32 (d, J = 9.3 Hz, 1H), 7.23 (d, J = 4.6 Hz, 1H), 6.92 (s, 1H), 4.22 (s, 3H), 4.05 (s, 3H), 3.82 (s, 3H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.3, 156.7, 152.9, 152.4, 151.8, 149.3, 146.5, 144.4, 137.2, 130.8, 128.2, 126.1, 124.9, 122.4, 120.9, 119.7, 118.3, 116.5, 114.2, 62.6, 57.5, 53.2, 39.8; ESCI m/z (relative intensity) 404.2 (M + H, 100%), 426.1 (M + Na, 12%); HRMS calcd for C23H21N3O4 (M + H) 404.1610, found 404.1596.mp 161–164 °C; IR (thin film) 1727 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J = 4.6 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.30 (d, J = 4.6 Hz, 1H), 7.16 (s, 1H), 4.25 (s, 3H), 4.02 (s, 3H), 3.88 (s, 3H), 3.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 154.8, 152.5, 150.0, 149.9, 148.1, 146.3, 145.3, 142.3, 136.4, 129.8, 127.7, 125.3, 124.5, 120.7, 120.6, 114.8, 113.4, 112.1, 62.2, 57.1, 52.4, 39.2; ESCI m/z (relative intensity) 449.2 (M + H, 100%), 471.2 (M + Na, 12%); HRMS calcd for C23H19N3O4 (M + H) 449.1461, found 449.1440.mp 68–70 °C. IR (CH2Cl2) 1730 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.47 (d, J = 2.5 Hz, 1H), 9.03 (d, J = 4.5 Hz, 1H), 8.31 (dd, J = 9.2, 2.5 Hz, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.54 (s, 1H), 7.28 (d, J = 4.5 Hz, 1H), 4.22 (s, 3H), 3.95 (s, 3H), 3.85 (s, 3H), 3.63 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 165.4, 157.0, 152.7, 151.3, 150.3, 148.4, 146.7, 145.4, 143.8, 142.0, 137.5, 128.8, 123.9, 123.1, 121.2, 119.3, 114.9, 114.4, 112.6, 62.5, 57.3, 53.0, 39.4; ESI m/z (relative intensity) 447.1 (M + H, 100%), 404.2 (M − CO2, 34%); HRMS calcd for C23H18N4O6 (M + H) 447.1305, found 447.1291.mp 162 °C (dec.); IR (thin film) 1726 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J = 5.2 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 9.2, 2.4 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.58 (s, 1H), 6.69 (d, J = 5.3 Hz, 1H), 4.19 (s, 3H), 4.18 (s, 3H), 4.04 (s, 3H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.7, 152.5, 151.1, 148.9, 144.5, 144.3, 135.9, 130.0, 128.8, 127.7, 124.3, 121.5, 121.2, 121.1, 116.9, 115.5, 113.8, 109.8, 100.8, 61.7, 57.0, 53.7, 31.4; ESCI m/z (relative intensity) 447.1 (M + H, 100%); HRMS calcd for C23H18N4O6 (M + H) 447.1305, found 447.1308.IR (CH2Cl2) 1731 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 5.3 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.66 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 7.41 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 6.59 (d, J = 5.3 Hz, 1H), 4.14 (s, 3H), 4.13 (s, 3H), 4.03 (s, 3H), 3.87 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.9, 152.3, 152.0, 148.5, 146.3, 146.2, 143.7, 143.4, 135.1, 130.6, 127.7, 125.6, 124.3, 122.4, 122.3, 115.4, 114.7, 108.4, 99.8, 61.5, 56.9, 53.2, 31.0; ESCI m/z (relative intensity) 402.1 (M + H, 100%); HRMS calcd for C23H19N3O4 (M + H) 402.1454, found 402.1477.