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Review
. 2016 Jul 8;21(7):892.
doi: 10.3390/molecules21070892.

Marine Natural Products as Models to Circumvent Multidrug Resistance

Solida Long  1 , Emília Sousa  2   3 , Anake Kijjoa  4   5 , Madalena M M Pinto  6   7
Affiliations
Review

Marine Natural Products as Models to Circumvent Multidrug Resistance

Solida Long et al. Molecules. .

Abstract

Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

Keywords: ABC transporters; P-glycoprotein modulators; marine natural products; multidrug resistance (MDR); structure activity relationship (SAR); synthesis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of sipholane triterpenes 1–4 and their analogs 5–9. Dashed circles indicate SAR studies performed for MDR activities.
Scheme 1
Scheme 1
The semi-synthesis transformation of sipholenol A (1) into analogs 8 and 9. Reagents and conditions: (1) acid anhydride, MDAP, anhydrous CH2Cl2; (2) p-toluenesulfonic acid, CHCl3; (3) acid anhydride, MDAP, anhydrous CH2Cl2.
Figure 2
Figure 2
The structures of parguerene I (10) and II (11).
Figure 3
Figure 3
Structure of agosterol A (12) and 4-deacetoxyagosterol A (13). Dashed circles indicate the groups essential for reversing MDR activity.
Scheme 2
Scheme 2
The synthetic pathway of agosterol A (12). Reagents and conditions: (1) MOMCl, iPr2NEt, CH2Cl2; (2) phthalhydrazide, Pb(OAc)4, CH2Cl2, AcOH, two steps; (3) O3,CH2Cl2, pyridine, then Me2S; (4) 3-methylbutylmagnesium bromide, THF, two steps; (5) TMAD, PMe3, p-OCH3BzOH,THF; (6) LiAlH4, THF; (7) (S)-(−)-MTPA[(R)-(+)-MTPA], EDCl.HCl, DMAP, CH2Cl2; (8)TBSOTf, 2,6-lutidine, DMF-CH2Cl2; (9) Hg(OAc), EtOH/CHCl3/AcOH; (10) 4-phenyl-1,2,4-triazoline-3,5-dione, CH2Cl2; (11) mCPBA, CHCl3; (12) LiAlH4, THF; (13) TBSOTf, 2,6-lutidine, toluene; (14) Fe(CO)3, 1-(4-methyoxyphenyl)-4-pheynyl-1-azabuta-(E,E)-1,3-diene, PhCH3; (15) MgBr2-Et2O, Me2S, CH2Cl2; (16) TsCl, pyridine, quant.; (17) DBN, PhH, quant.; (18) OsO4, pyridine, then aq. NaHSO3; (19) TESOTf, pyridine, quant.; (20) Me3NO, PhH; (21) BH3Me2S, THF, then H2O2, aq. NaOH; (22) TBAF, THF; (23) Ac2O, pyridine; HF, pyridine, THF.
Scheme 2
Scheme 2
The synthetic pathway of agosterol A (12). Reagents and conditions: (1) MOMCl, iPr2NEt, CH2Cl2; (2) phthalhydrazide, Pb(OAc)4, CH2Cl2, AcOH, two steps; (3) O3,CH2Cl2, pyridine, then Me2S; (4) 3-methylbutylmagnesium bromide, THF, two steps; (5) TMAD, PMe3, p-OCH3BzOH,THF; (6) LiAlH4, THF; (7) (S)-(−)-MTPA[(R)-(+)-MTPA], EDCl.HCl, DMAP, CH2Cl2; (8)TBSOTf, 2,6-lutidine, DMF-CH2Cl2; (9) Hg(OAc), EtOH/CHCl3/AcOH; (10) 4-phenyl-1,2,4-triazoline-3,5-dione, CH2Cl2; (11) mCPBA, CHCl3; (12) LiAlH4, THF; (13) TBSOTf, 2,6-lutidine, toluene; (14) Fe(CO)3, 1-(4-methyoxyphenyl)-4-pheynyl-1-azabuta-(E,E)-1,3-diene, PhCH3; (15) MgBr2-Et2O, Me2S, CH2Cl2; (16) TsCl, pyridine, quant.; (17) DBN, PhH, quant.; (18) OsO4, pyridine, then aq. NaHSO3; (19) TESOTf, pyridine, quant.; (20) Me3NO, PhH; (21) BH3Me2S, THF, then H2O2, aq. NaOH; (22) TBAF, THF; (23) Ac2O, pyridine; HF, pyridine, THF.
Figure 4
Figure 4
The structures of polyoxygenated steroids 14–20, and SAR for polyoxygenated steroids with antitumor activity in overexpressing P-gp cells.
Scheme 3
Scheme 3
The synthesis of 3,16,20-polyoxygenated steroids 21–24. Reagents and conditions: (1) I: NH4Cl, pyridine, AcOH; II: CrO3, AcOH, H2O, (CH2Cl2)2; (2) 4-methylpentylmagnesium bromide, THF; (3) PCC, NaOAc, CH2Cl2; (4) Ph2Se2, m-iodomybenzoic acid, toluene, reflux.
Figure 5
Figure 5
The structures of bryostatin 1 (25) and merle 23 (26).
Scheme 4
Scheme 4
Synthesis of the methyl bryostatin 1 (25) analogs 27 (a) and 28 (b,c). Reagents and conditions: (a) (1) NaH, allybromide, THF, rt; (2) Dess-Martin periodinane, CH2Cl2, rt; (3) t-BuLi, Et2O, −78 °C, (recyclable 1:1 diastereomer mixture: Dess-Martin periodinane, CH2Cl2, rt, then NaBH4, CeCl3·7H2O, −40 °C; (4) t-BuOH, allyl bromide, THF, rt; (5) 9-BBN, THF, 66 °C, then NaOH, H2O2; (6) Dess-Martin periodinane, CH2Cl2, rt; (7) (−)-(lpc)BOMe, allylmagnesium bromide, CH2Cl2, −78 °C to rt; (8) TBSCl, imidazole, THF, rt; (9) catalytic KMnO4, NaIO4, rt; (10) 2,4,6-trichloro-benzoylchloride, Et3N, DMAP, CH2Cl2, rt; (11) HF·pyridine, CH3CN, rt; (12) Amberlyst-15 resin, CH2Cl2, rt; (13) Pd(OH)2, H2, EtOAc, 1 atm; (b) (1) 10 mol % of [CpRu(CH3CN)3]PF6, acetone, rt; (2) NBS, DMF then BF3-OEt2, 1,3-propanedithiol, CH2Cl2, 0 °C then PPTS, CH3OH, CH(OCH3)3, refux; (3) TESCl, DMAP, then pyridine, Ac2O; PPTS, MeOH, rt; DMSO, (COCl)2, Et3N, CH2Cl2 −78 °C; Ph3PCH3Br, n-BuLi; (4) TBAF, THF, rt; Me3SnOH, DCE, 140 °C, microwave; Pd(PPh3)4, CO, DMF/CH3OH, 85 °C; TESOTf, 2,6-lutidine, CH2Cl2; (c) (1) n-BuLi, methyl propionate, BF3·OEt2, THF, −78 °C; (2) Pd(OAc)2, tris(2,6-dimethoxyphenyl) phosphine, benzene, then Pd(O2CCF3)2, rt; (3) trifluoroperacetic acid, NaHPO4, CH2Cl2/CH3CN/ CH3OH, 0 °C; Dess-Martin oxidation; NaBH4, CeCl3·7H2O, −30o°C; Ac2O, pyridine, DMAP, CH2Cl2, rt; (4) CrCl2, CHI3, THF, rt; 26% (47% BRSM); Pd(PPh3)4, THF, rt; (5) AcOH/H2O; (6) TESCl, ETA, DMF, −35 to −15 °C; (7) Et3N, DMAP, 2-mehyl-6-nitrobenzoic acid anhydride, CH2Cl2; (8) benzene, 50–80 °C, 17 mol % of Grubbs-Hoveyda catalyst; (9) PPTS, MeOH, rt.
Scheme 4
Scheme 4
Synthesis of the methyl bryostatin 1 (25) analogs 27 (a) and 28 (b,c). Reagents and conditions: (a) (1) NaH, allybromide, THF, rt; (2) Dess-Martin periodinane, CH2Cl2, rt; (3) t-BuLi, Et2O, −78 °C, (recyclable 1:1 diastereomer mixture: Dess-Martin periodinane, CH2Cl2, rt, then NaBH4, CeCl3·7H2O, −40 °C; (4) t-BuOH, allyl bromide, THF, rt; (5) 9-BBN, THF, 66 °C, then NaOH, H2O2; (6) Dess-Martin periodinane, CH2Cl2, rt; (7) (−)-(lpc)BOMe, allylmagnesium bromide, CH2Cl2, −78 °C to rt; (8) TBSCl, imidazole, THF, rt; (9) catalytic KMnO4, NaIO4, rt; (10) 2,4,6-trichloro-benzoylchloride, Et3N, DMAP, CH2Cl2, rt; (11) HF·pyridine, CH3CN, rt; (12) Amberlyst-15 resin, CH2Cl2, rt; (13) Pd(OH)2, H2, EtOAc, 1 atm; (b) (1) 10 mol % of [CpRu(CH3CN)3]PF6, acetone, rt; (2) NBS, DMF then BF3-OEt2, 1,3-propanedithiol, CH2Cl2, 0 °C then PPTS, CH3OH, CH(OCH3)3, refux; (3) TESCl, DMAP, then pyridine, Ac2O; PPTS, MeOH, rt; DMSO, (COCl)2, Et3N, CH2Cl2 −78 °C; Ph3PCH3Br, n-BuLi; (4) TBAF, THF, rt; Me3SnOH, DCE, 140 °C, microwave; Pd(PPh3)4, CO, DMF/CH3OH, 85 °C; TESOTf, 2,6-lutidine, CH2Cl2; (c) (1) n-BuLi, methyl propionate, BF3·OEt2, THF, −78 °C; (2) Pd(OAc)2, tris(2,6-dimethoxyphenyl) phosphine, benzene, then Pd(O2CCF3)2, rt; (3) trifluoroperacetic acid, NaHPO4, CH2Cl2/CH3CN/ CH3OH, 0 °C; Dess-Martin oxidation; NaBH4, CeCl3·7H2O, −30o°C; Ac2O, pyridine, DMAP, CH2Cl2, rt; (4) CrCl2, CHI3, THF, rt; 26% (47% BRSM); Pd(PPh3)4, THF, rt; (5) AcOH/H2O; (6) TESCl, ETA, DMF, −35 to −15 °C; (7) Et3N, DMAP, 2-mehyl-6-nitrobenzoic acid anhydride, CH2Cl2; (8) benzene, 50–80 °C, 17 mol % of Grubbs-Hoveyda catalyst; (9) PPTS, MeOH, rt.
Figure 6
Figure 6
Structure of discodermolide (29) with highlighted subunits A, B, and C.
Scheme 5
Scheme 5
Total synthesis of subunits A, B, and C of (+)-discodermolide (29). Reagents and conditions: (a) (1) t-BuLi, Me2CuLi, LiCN, Et2O/DMS then n-Bu3SnCl; (2) TEMPO, BAIB; (b) (1) TBSOTf, 2,6-lutidine, O3, Sudan III then DMS; (2) TBSOTf, 2,6-lutidine; (3) Ni(acac)2, (CH2=CH4)Sn, MeLi; (4) DDQ, CH2Cl2/H2O, I2, PPh3; (c) (1) TBSCl, imidazole, DIBAL-H, CH2Cl2, (COCl)2, DMSO; (2) O3, Sudan III, (EtO)2P(O)CH2C(O)NMe, NaH; (3) PhCHO, KHMDS.
Scheme 5
Scheme 5
Total synthesis of subunits A, B, and C of (+)-discodermolide (29). Reagents and conditions: (a) (1) t-BuLi, Me2CuLi, LiCN, Et2O/DMS then n-Bu3SnCl; (2) TEMPO, BAIB; (b) (1) TBSOTf, 2,6-lutidine, O3, Sudan III then DMS; (2) TBSOTf, 2,6-lutidine; (3) Ni(acac)2, (CH2=CH4)Sn, MeLi; (4) DDQ, CH2Cl2/H2O, I2, PPh3; (c) (1) TBSCl, imidazole, DIBAL-H, CH2Cl2, (COCl)2, DMSO; (2) O3, Sudan III, (EtO)2P(O)CH2C(O)NMe, NaH; (3) PhCHO, KHMDS.
Figure 7
Figure 7
The structure of halichondrin B (30), eribulin (31), and the analogs 32–35.
Scheme 6
Scheme 6
Schematic approach for the total synthesis of eribulin (31).
Figure 8
Figure 8
The scaffold of lamellarins and their representatives 36–44. SAR studies for lamellarin D (37) and lamellarin O (41) regarding antitumor activity on BCRP overexpressing cells.
Scheme 7
Scheme 7
Synthesis of lamellarin O (41) and lamellarins type II. Reagents and conditions: (a) (1) H2O2, NaOH, EtOH/H2O; (2) BF3·Et2O, Et2O, reflux, then NH2OH·HCl, reflux, pyridine, EtOH; (3) H2, Pd/C, THF; (4) ClCOCO2Me, pyridine, THF; (5) Ti-graphide (TiCl:C8K = 1:2), DME, reflux; p-MeO-C6H4COCH2Br, K2CO3, acetone, reflux; (b) (1) NBS (3 eq), THF; (2) PhLi (1 eq), then ClCO2Me (1.05 eq); (3) Pd(PPh3)2Cl2 (10 mol%), 1,4-dioxane, p-TBOMSO-C4H6-SnMe3 (2 eq); (4) Bu4NF (1.1 eq), THF, then 0.5 M HCl; (5) Bu4NF (1.1 eq), THF then 0.5 M HCl; (6) PPd(PPh3)2Cl2 (10 mol %), 1,4-dioxane, p-TBOMSO-C4H6-SnMe3 (2 eq); (7) p-MeO-C4H6-COBr (3 eq), K2CO3 (5 eq), Bu4NCl (20 mol %), THF; (8) Bu4NF (1.1 eq), THF, then 0.5 M HCl; (c) (1) Pd(PP3)2Cl2 (3 mol %), CuI (6 mol %), Et3N; (2) dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate, toluene, reflux; (3) Zn, HOAc; (4) p-MeO-C4H6-COBr, K2CO3, DMF; (5) LiOH, THF/CH3OH/H2O (3:2:1); (6) TFA, CH2Cl2; (7) H2,Pd/C (0.1 wt %), EtOH.
Scheme 7
Scheme 7
Synthesis of lamellarin O (41) and lamellarins type II. Reagents and conditions: (a) (1) H2O2, NaOH, EtOH/H2O; (2) BF3·Et2O, Et2O, reflux, then NH2OH·HCl, reflux, pyridine, EtOH; (3) H2, Pd/C, THF; (4) ClCOCO2Me, pyridine, THF; (5) Ti-graphide (TiCl:C8K = 1:2), DME, reflux; p-MeO-C6H4COCH2Br, K2CO3, acetone, reflux; (b) (1) NBS (3 eq), THF; (2) PhLi (1 eq), then ClCO2Me (1.05 eq); (3) Pd(PPh3)2Cl2 (10 mol%), 1,4-dioxane, p-TBOMSO-C4H6-SnMe3 (2 eq); (4) Bu4NF (1.1 eq), THF, then 0.5 M HCl; (5) Bu4NF (1.1 eq), THF then 0.5 M HCl; (6) PPd(PPh3)2Cl2 (10 mol %), 1,4-dioxane, p-TBOMSO-C4H6-SnMe3 (2 eq); (7) p-MeO-C4H6-COBr (3 eq), K2CO3 (5 eq), Bu4NCl (20 mol %), THF; (8) Bu4NF (1.1 eq), THF, then 0.5 M HCl; (c) (1) Pd(PP3)2Cl2 (3 mol %), CuI (6 mol %), Et3N; (2) dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate, toluene, reflux; (3) Zn, HOAc; (4) p-MeO-C4H6-COBr, K2CO3, DMF; (5) LiOH, THF/CH3OH/H2O (3:2:1); (6) TFA, CH2Cl2; (7) H2,Pd/C (0.1 wt %), EtOH.
Scheme 8
Scheme 8
Synthesis of lamellarin D (37). Reagents and conditions: (a) (1) PdCl2(PPh3)2, PPh3, K2CO3, NaH, DMF; (2) PdCl2(PPh3)2, K2CO3, DMF; (3) NBS, THF; (4) DDQ, CHCl3, MW, AlCl3, CH2Cl2; (5) NaH, THF; (b) (1) Pd(PPh3)4, THF, reflux; (2) KOH-EtOH, reflux, then p-TsOH, CH2Cl2, reflux; (3) Cu2O, quinolone; (4) Pd(OAc)2, CH3CN, reflux; (5) BCl3, CH2Cl2.
Scheme 9
Scheme 9
Synthesis of lamellarin I (38) and K (39) via 1,3-dipolar cyclization of nitrones. Reagents and conditions: (1) NaBH4, MeOH, H2O2, Na2WO3, MeOH; (2) toluene, 120 °C, 18 h; (3) AlCl3.
Figure 9
Figure 9
Structures of ningalin B (45), analogs 46–55, and SAR studies for P-gp modulation.
Scheme 10
Scheme 10
Synthesis of ningalin B (45). Reagents and conditions: (a) (1) N2; (2) Zn, AcOH; (3) K2CO3; (b) (1) AgOAc, NaOAc, THF; (2) POCl3, DMF; (3) DMSO/H2O or THF: t-BuOH:H2O; (4) Pb(OAc)4, EtOAc; (5) BBr3, CH2Cl2.
Figure 10
Figure 10
Structures of welwitindolinones 56–58 and SAR studies. The dashed circle indicates the groups important for P-gp.
Scheme 11
Scheme 11
Synthesis of N-methylwelwitindolinone C isothiocyanate (57) by Gang’s approach (a) and Rawal’s approach (b). Reagents and conditions: (a) (1) iodine promoted bromination; (2) NaNH2, t-BuOH, THF; (3) trimethyethylstannane; (4) LiEt3B-D, THF, Cl3CCONCO, CH2Cl2, K2CO3, MeOH; AgOTf, PhI(OAc)2, CH3CN, bathophenantroline; (5) NaH, air, THF; (b) (1) TiCl4, toluene; (2) Pd(OAc)2, P-tBu3, KO-tBu, toluene; (3) NaBH(OMe)3, THF/EtOH then N2H2, AcOH, EtOH; NCS, pyridine; MMPP, TFA, AcOH; (4) Dess-Martin periodinane, NaHCO3, CH2Cl2; NH2OH.HCl, pyridine, MeOH; (5) NCS, DMF, THF, then Et3N.
Figure 11
Figure 11
Harmine (59) and analogs 60–62. The dashed circles indicate groups important for biological functions.
Figure 12
Figure 12
Structures of indolcarbazole derivatives 63–69.
Scheme 12
Scheme 12
Synthesis of indolcarbazole derivatives 63 and 70. Reagents and conditions: (a) (1) i. EtMgBr, THF, benzene, ii. N-methylmaleimide; (2) KOH, MeOH or dioxane; (3) NH4OAc; (4) DDQ, PTSA, toluene; (b) (1) Br2, HNO3; (2) CH3CH2Br, Mg, THF, indole, toluene; (3) DDQ, toluene.
Figure 13
Figure 13
Structures of trabectedin (71) and lurbinectedin (72).
Scheme 13
Scheme 13
Total synthesis of trabectedin (71). Reagents and conditions: (1) PhI(OAc)2, MeOH; (2) NaCN, DMF/H2O; (3) BnBr, K2CO3, DMF; (4) aq H2O2, K2CO3, DMSO; (5) PhI(OAc)2, KOH, MeOH; (6) LiOH, EtOH/H2O, reflux; (7) t-BuOK, THF, DBU, (8) Boc2O, DMAP, THF, (2 steps); (9) H2 (750 psi), Pd/C, EtOAc; (10) H2NNH2·H2O, THF, evaporation; NaBH4, MeOH, (2 steps); (11) TFA, CF3CH2OH; evaporation; PhNTf2, DMAP, Cs2CO3, MeCN; (12) trimethylboroxine, Pd(PPh3)4, K3PO4, 1,4-dioxane; (13) HCl, EtOAc; ClCO2Me, NaHCO3, H2O; (14) l-Selectride, THF; (15) CSA, toluene, reflux (2 steps); (16) aq KOH, 1,4-dioxane, rt, MOMCl.
Figure 14
Figure 14
Structure of nocardioazine A (73).
Scheme 14
Scheme 14
Total synthesis of nocardioazine A (73). Reagents and conditions: (1) (S)-BINOL, SnCl4, DCM; (2) OiPr-HG II, DCM, reflux; (3) NaBH4, CeCl3·7H2O, MeOH; (4) (+)-diethyl tartrate, Ti(OiPr)4, tBuOOH, 4Å MS, DMC; (5) MsCl, Et3N, THF; (6) TBAI, DIPEA, CH3CN; (7) Pd2(dba)3, dppb, DMBA, DEC; (8) LiOH, THF/H2O; (9) PyBrop, DIPEA, DMF.
Figure 15
Figure 15
Structures of fumitremorgin C (74) and derivatives 75–78 and SAR for BCRP inhibition.
Scheme 15
Scheme 15
Total synthesis of FTC derivatives, dimethoxy-FTC (78) and Ko143 (77). Reagents and conditions: (a) (1) CH(OMe)3; (2) Fmoc-HCl, pyridine, CH2Cl2; (3) piperidine, DMF; (4) Fmoc-l-pro-OH, CIP, DiPEA, MNP; (5) piperidine, THF; (b) (1) Hg(OOCCF3)2, KI, I2, CH2Cl2, then Boc2O, DMAP, MeCN; (2) Pd(OAc)2, Ag2CO3, toluene; (3) Mg(ClO4)2, MeCN; (c) (1) 1-benzyl-2-methyl-(S)-1,2-aziridinedicarboxylate, ytterbium triflate, CH2Cl2; (2) H2 balloon, MeOH, 10% Pd/C; (3) isovaleraldehyde, TFA, CH2Cl2; (4) N-Fmoc-5-t-butyl l-glutamic acid ester, diisopropylethylamine 2-chloro-1,3-dimethylimmidazolinium hexaflorophosphate, N-methylpyrrolidinone; (5) piperidine, THF.
Scheme 15
Scheme 15
Total synthesis of FTC derivatives, dimethoxy-FTC (78) and Ko143 (77). Reagents and conditions: (a) (1) CH(OMe)3; (2) Fmoc-HCl, pyridine, CH2Cl2; (3) piperidine, DMF; (4) Fmoc-l-pro-OH, CIP, DiPEA, MNP; (5) piperidine, THF; (b) (1) Hg(OOCCF3)2, KI, I2, CH2Cl2, then Boc2O, DMAP, MeCN; (2) Pd(OAc)2, Ag2CO3, toluene; (3) Mg(ClO4)2, MeCN; (c) (1) 1-benzyl-2-methyl-(S)-1,2-aziridinedicarboxylate, ytterbium triflate, CH2Cl2; (2) H2 balloon, MeOH, 10% Pd/C; (3) isovaleraldehyde, TFA, CH2Cl2; (4) N-Fmoc-5-t-butyl l-glutamic acid ester, diisopropylethylamine 2-chloro-1,3-dimethylimmidazolinium hexaflorophosphate, N-methylpyrrolidinone; (5) piperidine, THF.
Figure 16
Figure 16
Structure of plinabulin (79).
Figure 17
Figure 17
Structure of hapalosin (80) and analogs 81–88 highlighting the important domains for synthesis (A–C).
Scheme 16
Scheme 16
Synthesis of hapalosin (80) and derivatives. Reagents and conditions: (a) (1) Bu2BOTf, Et3N/CH2Cl2, then Me(CH2)6CHO; (2) n-BuLi, BnOH/THF; (3) Ref. [193]; (4) NaOH, DCC, DMAP/CH2Cl2; (5) H2, Pd(OH)2/EtOH, vinyl-2-hydroxy-3-methylbutanoate, DCC, DMAP/CH2Cl2; (6) TFA/CH2Cl2, DPPA, i-Pr2NEt/DMF; (b) (1) i. DCC, DMAP/CH2Cl2, ii. H2, Pd(OH)2/EtOH, (2) DCC, DMAP/CH2Cl2; (3) i. HF-pyridine, ii. (Ph3P)4Pd, morpholine, then TFA, iii. DPPA, EtNt-Pr.
Figure 18
Figure 18
Botryllamides 89–93 and SAR studies on BCRP inhibitory activity.
Scheme 17
Scheme 17
Synthesis of boryllamides G (91) and F (93). Reagents and conditions: (1) NaOMe, MeOH, reflux, overnight; (2) octopamine·HCl or bis-brominated octopamine, WSCl, HOBt, Et3N; (3) Ac2O, pyridine; (4) K2CO3, DMSO.
Figure 19
Figure 19
Structure of kendarimide A (94).
Scheme 18
Scheme 18
Synthesis of l-pyroMeGlu-l-Phe-OEt (a) and l,l-N-methylcysteinyl-N-methylcystein ring (b). Reagents and Conditions: (a) (1) H2O, 132 °C, 1.9 kg/cm2 (autoclave); (2) Na2HCO3, C2H5I, DMF; (3) TFA, CH2Cl2; (4) l-N-pyroMeGlu, DEPC, TEA, DMF, 0 °C; (b) (1) acetamidomethanol, conc. HCl, (Boc)2O, 1N NaOH; (2) (Boc)2O, 1N NaOH, Ac2O, pyridine; (3) TFA, CH2Cl2; (4) DEPC, Et3N, DMF; (5) TFA, CH2Cl2, quant.; (6) EDCI, HOAt, CH2Cl2/DMF; (7) I2, CH2Cl2/MeOH; (8) TFA, CH2Cl2, quant.
Figure 20
Figure 20
Structures of patellamides B (95), C (96), and D (97).
Scheme 19
Scheme 19
Synthesis of patellamide A (98). Reagents and conditions: (1) 20% piperidine/DMF, HOBt, HBTU, DIEA, Fmoc-aThr(Trt)-OH; (2) 20% piperidine/DMF, HOBt, HBTU, DIEA, Fmoc-Ile-OH; (3) Pd(PPh3)4, PhSiH3, CH2Cl2, 6 h and 20% piperidine/DMF; (4) HOBt, HBTU, DIEA, CH2Cl2, 2% TFA, PhSH, CH2Cl2; (5) Burgess reagent, THF, 55 °C, 1 h then 77 °C, 4 h; (6) Pd(PPh3)4, PhSiH3, CH2Cl2, 2 h.
Figure 21
Figure 21
Structure of ISA (99–101), ISA-B (102, 103), and deacyl ISA (104).
Scheme 20
Scheme 20
The total synthesis of ISA derivatives. Reagents and conditions: (1) n-BuLi, Et2AlCl, toluene; (2) KH; (3) TBS-Cl, imidazole, DMAP, DMF; (4) n-BuLi, Boc2O; (5) CuBr2.SMe2, MeLi, THF; (6) HF-pyridine; (7) TFA, CH2Cl2; (8) (COCl)2, DMF cat, CH2Cl2, toluene, reflux.
Scheme 21
Scheme 21
Total synthesis of secalonic acid D (105). Reagents and conditions: (1) 2,6-lutidine, iPrSi(OTf)2, CH2Cl2, then Et3N·3HF; (2) Rh/Al2O3, H2, MeOH; (3) NaH, THF; (4) CH2Cl2, then NaH, THF.
Scheme 22
Scheme 22
Synthesis of (+)-terrein (106). Reagents and conditions: (1) TBSCl, imidazole, DMF; (2) n-BuLi, MePO(OMe)2, THF, then benzene-H2O, reflux; (3) NaH, MeCHO, THF; (4) (Et4NCl), MeCN or HF·MeCN or TBAF, MeCN.
Figure 22
Figure 22
Structure of shornephine A (107).
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