HETEROCYCLES

Communication | Special issue | Vol. 80, No. 2, 2010, pp. 841-846
Received, 31st July, 2009, Accepted, 4th September, 2009, Published online, 14th September, 2009.
DOI: 10.3987/COM-09-S(S)100

■ Divergent Synthesis of Lamellarin α 13-Sulfate, 20-Sulfate, and 13,20-Disulfate

Tsutomu Fukuda, Takeshi Ohta, Sho Saeki, and Masatomo Iwao*

Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan

Abstract

A divergent synthesis of three sulfate derivatives of lamellarin α, namely, lamellarin α 13-sulfate (2), 20-sulfate (1), and 13,20-disulfate (4) has been achieved via a common intermediate (6) in which 13-OH and 20-OH of the lamellarin core are differentially protected by MOM and benzyl groups, respectively. Compound (6) in turn was prepared using sequential Suzuki-Miyaura coupling of 3,4-dihydroxypyrrole bistriflate (7) as a key reaction.

Lamellarins and the related marine pyrrole alkaloids have attracted considerable attention due to their unique structures and highly useful biological activities.1 Lamellarin α 20-sulfate (1) was isolated from the unidentified ascidian collected from the Arabian Sea near Trivandrum, India, by Faulkner and co-workers.2 They demonstrated that 1 inhibits HIV-1 integrase selectively and growth of the HIV-1 virus in cell culture.2 Because cytotoxicity of 1 is quite low, this natural product has been regarded as a new type of lead compound for development of anti-HIV agents. An attempted synthesis of lamellarin α 20-sulfate (1) and 13-sulfate (2) from lamellarin α (3) by titration with DMF-SO3 complex was reported by Faulkner and coworkers in 2002. 3 Unfortunately, however, they obtained only lamellarin 13,20-disulfate (4) in low yield. Recently, we reported the first total synthesis of lamellarin α 20-sulfate (1) from the differentially protected lamellarin α (5).4 The selective introduction of sulfate group at

20-OH was effected by a sequence involving selective debenzylation of 20-OBn, 2,2,2-trichloroethylsulfonation of the resulting 20-OH, deprotection of 13-Oi-Pr, and final reductive cleavage of the 2,2,2-trichloroethyl ester moiety.5,6 For the structure-activity relationship studies concerning integrase inhibition and anti-HIV activity, we needed to prepare lamellarin α 13-sulfate (2) and 13,20-disulfate (4) also. It was revealed, however, the synthesis of 2 from 5 was difficult because debenzylation at 20-OBn occurred simultaneously during deprotection at 13-Oi-Pr under the standard BCl3 conditions. Thus, we designed a new lamellarin α derivative (6) in which 13-OH was protected by a more labile methoxymethyl (MOM) group. In this communication, we report a divergent synthesis of lamellarin α sulfate derivatives (1), (2), and (4) from the common intermediate (6) which in turn can be obtained from 3,4-dihydroxypyrrole bistriflate (7) and arylboronic acids (8), (9) using the previously established procedure developed in our laboratories (Scheme 1).4,5

The synthesis of arylboronic acid (8) is shown in Scheme 2. Isovanillin (10) was benzylated with benzyl bromide to give O-benzylisovanillin (11) in 86% yield.7 Baeyer-Villiger oxidation of 11 with m-chloroperbenzoic acid (mCPBA) followed by methanolysis afforded the phenol (12) in 90% yield. After MOM protection of the phenolic hydroxy group, the resulting 13 was regioselectively brominated by N-bromosuccinimide (NBS) to give 14 in 97% yield. Bromine–lithium exchange of 14 with tert-butyllithium followed by treatment with trimethyl borate afforded the desired arylboronic acid (8).
Another arylboronic acid (9) was prepared according to the procedure shown in Scheme 3. C-2-

selective bromine–lithium exchange of commercially available 2,4-dibromoanisole (15) followed by boration and oxidation gave the phenol (16) in 78% yield.8 After MOM protection of the phenolic hydroxy group, the resulting 17 was converted into the arylboronic acid (9) via bromine–lithium exchange with tert-butyllithium followed by treatment with trimethyl borate.

The synthesis of lamellarin α 13-sulfate (3) was shown in Scheme 4. Suzuki-Miyaura coupling of the

bistriflate (7) with 1.2 equiv of an arylboronic acid (8) under the standard conditions [Pd(PPh3)4 (2 mol%), Na2CO3, water, THF, reflux, 3 h]9 gave the mono-arylated pyrrole (18) in 74% yield. Compound (18) was converted into the lactone (19) by treatment with hydrochloric acid in methanol followed by acid-catalyzed lactonization in 93% yield. The second cross-coupling of 19 with an arylboronic acid (9) (2.0 equiv) using 8 mol% of Pd(PPh3)4 afforded 20 in 95% yield. Compound (20) was converted into the acid (21) by alkaline hydrolysis followed by acid-catalyzed relactonization in 61% yield. Decarboxylation of 21 in hot quinoline in the presence of copper(I) oxide produced 22.10 Intramolecular oxidative biaryl coupling of 22 under Kita’s conditions11 using phenyliodine bis(trifluoroacetate) (PIFA)-boron trifluoride etherate afforded the cyclized product (23) in 62% yield. Treatment of 23 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in refluxing dichloromethane produced the common intermediate (6). Deprotection of the MOM group by treatment with hydrochloric acid in methanol afforded 24, which was reacted with 2,2,2-trichloroethyl chlorosulfate in dichloromethane to give the mixed sulfate (25) in 89% yield.6 Hydrogenolysis of 25 over palladium on charcoal for 4 h at room temperature afforded debenzylated 26 in 61% yield. Final reductive deprotection of the 2,2,2-trichloroethyl ester with Zn/HCO2NH4 followed by ion exchange over Amberlite IRC-50 (Na+ form) and Sephadex purification produced lamellarin α 13-sulfate (2)12 in 61% yield.
The syntheses of lamellarin α 20-sulfate (1) and lamellarin α 13,20-disulfate (4) are shown in Scheme 5. Compound (6) was debenzylated by hydrogenolysis over palladium on charcoal to give 27 in 99% yield. 2,2,2-Trichloroethylsulfonation of 27 in a similar manner as described above provided 28 in 69% yield. Selective removal of MOM protecting group provided 29 in 81% yield. Treatment of 29 with Zn/HCO2NH4 followed by ion exchange over Amberlite IRC-50 (Na+ form) and Sephadex purification produced lamellarin α 20-sulfate (1)13 in 85% yield. Deprotection of MOM group from 27 with

hydrochloric acid in methanol produced lamellarin α (3) in 99% yield. Treatment of 3 with pyridine-SO3 complex in DMF-pyridine followed by ion exchange over Amberlite IRC-50 (Na+ form) and Sephadex purification afforded lamellarin α 13,20-disulfate (4)14 in 69% yield. The spectroscopic data of 1 and 4 are identical with those previously reported.3,4
In conclusion, we have succeeded in a divergent synthesis of lamellarin α 20-sulfate (1), 13-sulfate (2), and 13,20-disulfate (4) using 6 as a common intermediate. The synthesis of the other lamellarin sulfate derivatives and their structure-activity relationship studies are in progress.

ACKNOWLEDGEMENTS
The authors wish to thank the president’s discretionary fund of Nagasaki University and the Naito Foundation for financial support.

References

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12. Lamellarin α 13-sulfate (2). Mp 265-280 °C (dec.) (sealed capillary); IR (KBr): 3422, 1684, 1432, 1267, 1049 cm–1; 1H NMR (400 MHz, 8 mg of 2 in 0.7 mL of DMSO-d6): δ 3.31 (s, 3H), 3.37 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 6.39 (s, 1H), 6.46 (s, 1H), 7.07 (s, 1H), 7.16 (dd, J= 2.0 and 8.3 Hz, 1H), 7.19 (d, J= 7.3 Hz, 1H), 7.26 (d, J= 8.3 Hz, 1H), 7.36 (s, 1H), 7.71 (d, J= 2.0 Hz, 1H), 9.03 (d, J= 7.3 Hz, 1H); 13C NMR (100 MHz, 8 mg of 2 in 0.7 mL of DMSO-d6): δ 54.4, 54.5, 55.5, 56.2, 103.2, 103.8, 104.9, 105.5, 107.9, 109.3, 111.4, 113.9, 118.2, 122.2, 123.3, 124.2, 126.0, 127.2, 130.9, 133.5, 143.8, 147.2, 148.4, 148.8, 149.7, 150.3, 154.9. HRFABMS m/z. Calcd for C29H22NNa2O11S [(M+Na)+]: 638.0709. Found: 638.0662.
13. Lamellarin α 20-sulfate (1). Mp 258-268 °C (dec.) (sealed capillary) [lit.4, mp 263-269 °C (dec.) (sealed capillary)]; IR (KBr): 3422, 1698, 1485, 1418, 1273, 1047 cm–1; 1H NMR (400 MHz, 17 mg of 1 in 0.7 mL of DMSO-d6): δ 3.34 (s, 3H), 3.37 (s, 3H), 3.84 (s, 3H), 3.87 (s, 3H), 6.82 (s, 1H), 6.86 (dd, J= 1.9 and 8.2 Hz, 1H), 7.02 (d, J= 1.9 Hz, 1H), 7.16 (d, J= 8.2 Hz, 1H), 7.18 (s, 1H), 7.26 (d, J= 7.4 Hz, 1H), 7.34 (s, 1H), 7.57 (s, 1H), 9.02 (d, J= 7.4 Hz, 1H); 13C NMR (100 MHz, 17 mg of 1 in 0.7 mL of DMSO-d6): δ 54.4, 55.0, 55.5, 55.9, 104.7, 105.8, 106.9, 108.0, 108.7, 111.4, 111.5, 112.8, 113.4, 118.2 (118.16), 118.2 (118.24), 120.7, 122.0, 124.2, 127.0, 127.9, 133.4, 143.2, 145.1, 146.6, 148.3, 148.8, 149.0, 149.8, 154.1. HRFABMS m/z. Calcd for C29H22NNa2O11S [(M+Na)+]: 638.0709. Found: 638.0750.
14. Lamellarin α 13,20-disulfate (4). Mp 205-210 °C (dec.) (sealed capillary) [lit.3, mp > 260 °C (chars)]; IR (KBr): 1699, 1486, 1419, 1272, 1050 cm–1; 1H NMR (400 MHz, DMSO-d6): δ 3.37 (s, 3H), 3.39 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 6.73 (s, 1H), 7.12 (s, 1H), 7.21 (dd, J= 2.1 and 8.3 Hz, 1H), 7.29 (d, J= 8.3 Hz, 1H), 7.34 (d, J= 7.4 Hz, 1H), 7.42 (s, 1H), 7.58 (s, 1H), 7.75 (d, J= 2.1 Hz, 1H), 9.08 (d, J= 7.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 54.5, 55.0, 55.6, 56.2, 104.8, 105.6, 107.0, 108.1, 108.6, 111.0, 111.5, 112.9, 114.0, 118.3, 122.0, 123.1, 124.2, 125.9, 126.3, 128.2, 133.6, 143.1, 143.9, 145.0, 146.7, 149.1, 150.0, 150.6, 154.2. HRFABMS m/z. Calcd for C29H21NNa3O14S2 [(M+Na)+]: 740.0097. Found: 740.0145.