Furans are highly electron-rich aromatic compounds and this structure is often found in natural products and medicines. Furans are also useful as a four-carbon unit with oxygen functionalities, and are used in organic syntheses as a building block.1, 2 In 2003, we reported the first total synthesis of nakadomarin A (1),3 a manzamine alkaloid containing a furan ring. In this synthesis, we first reported that a new type of furan-iminium cation cyclization (FIC)4, 5 through intermediate [A] was highly effective for constructing the central core of nakadomarin A (Figure 1). In the structure of intermediate [A], the 3-position of the furan ring was directly bound to a spiro-ring system, and cyclization occurred at the 2-position of the furan ring to give the tetracyclic core of nakadomarin A.
Furan-iminium cation cyclization (FIC) in the synthesis of manzamine alkaloids.
Since then, we have been studying a new version of FIC in which a furan ring is connected to the spiro-ring system at the 2-position with a two-carbon tether, shown as [B]. This intermediate also cyclized to give spiro-tetracyclic products 4 efficiently with complete regio- and stereoselectivity.6 The ABC tricyclic core of ircinal A (3), including a tetra-substituted stereogenic center, could be constructed by this procedure. Based on model studies, we started a total synthesis of manzamine A (2),7, 8, 9, 10, 11, 12, 13, 14 which shows potent biological activities, such as anticancer, antibacterial and antimalarial activities, and related alkaloids such as ircinal A, a key synthetic and biogenetic precursor for manzamine A.
Based on this strategy, a new synthetic route is shown in Scheme 1. Among the five rings in the structure of ircinal A, both 13- and 8-membered unsaturated rings should be constructed by ring closing metathesis (RCM) at a later stage in the synthesis. The disconnection of ring B gives the iminium cation intermediate 7, which should be simplified to the known spirolactam intermediate 8.
The Horner–Wadsworth–Emmons reaction of spirolactam 8, which was prepared according to a procedure described in supporting information, gave unsaturated ester in 80% yield (Scheme 2), which was stereoselectively reduced to saturated ester 9a by hydrogenation catalyzed by PtO2 in aqueous MeOH, along with 9b, which was obtained by partial ester exchange to methyl ester. A mixture of 9a and 9b was converted to their Weinreb amide without purification. The diastereomer ratio was determined to be 14:1 by 1H NMR. The Weinreb amide was then converted to furylketone 10 by reaction with 2-furyl lithium, and compound 10 was purified by crystallization to remove the minor diastereomeric isomer. The aldol reaction of 10 with formaldehyde in the presence of DBU gave hydroxymethylated 11 in a diastereomer ratio of 10:1.
Conditions for Scheme 2: a Ph3P=CHCO2Et, toluene, reflux, 12 h (80%), b H2, cat. PtO2, MeOH–H2O (5:1), rt, 24 h, c HNMe(OMe), iPrMgCl, tetrahydrofurane (THF), −20 °C, 2 h. d 2-furyl lithium, THF, −78 °C, 2 h (84%, 3 steps). e HCHO, DBU (74%). f NaBH4, MeOH, 0 °C, 1 h. g t-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), 2,6-lutidine, CH2Cl2, −78 °C, 2 h. h Li, NH3, −40 °C, 4.5 h. i benezenesulfonyl chloride (BsCl), NaHCO3, AcOEt–H2O, rt, 3 h (61%, 4 steps). j tetrabutylammoniumu fluoride (TBAF), THF, rt, 12 h. k Ac2O, pyridine, rt, 5.5 h. l p-TsOH, iPrOH–CH2Cl2, rt, 12 h, (88%, 3 steps). m MsCl, pyridine, rt, 2.5 h. n o-NO2PhSeCN, NaBH4, DMF, rt, 12 h. o 30% H2O2 aq, THF, rt, 2.5 h, (64%, 3 steps). p Boc2O, Et3N, cat. dimethylaminopyridine (DMAP), THF, rt, 4.5 h, (98%). q LiBH4, THF, rt, 2.5 h. r Ac2O, pyridine, rt, 4 h. s p-TsOH, acetone–H2O, rt, 48 h. t IBX, dimethylsulfoxide (DMSO), 50 °C, 6 h (4 steps, 70%).
The ketone carbonyl group in 11 was removed by stepwise reduction to methylene to increase the electron density of the furan group. Thus, 11 was converted to the secondary alcohol 12, which was protected as a silyl ether. Silyl ether 13 was further reduced by lithium–ammonia to give 14 after reprotection of the secondary amine by a benzenesulfonyl group. After conversion of the silyl ether to acetate 15, a tetrahydropyranyl (THP) group was removed and the primary alcohol 16 was converted to phenylselenoether 18 via mesylate 17.15 Oxidative elimination followed by Boc protection gave 19. Reduction of lactam carbonyl in 19 to N-Boc aminal followed by acetylation of the primary alcohol gave a cyclization precursor 20. A crucial FIC of 20 proceeded slowly to give hemiacetal 21, which was oxidized to lactone 22 by 2-iodoxybenzoic acid (IBX). No diastereomeric isomer was observed under this cyclization.
Conditions for Scheme 3: a NaBH4, cat. NiCl2, MeOH, rt, 1 min. b trifluoroacetic acid (TFA), CH2Cl2, 0 °C to rt. c 5-hexenoyl chloride, DMAP, Et3N, CH2Cl2, (83%, 3 steps). d Grubbs' second (10 mol%), CH2Cl2, reflux, 3.5 h, (90%). e KCN, MeOH–CH2Cl2, rt, 24 h. f Dess–Martin periodinane, CH2Cl2, 0 °C, 3.5 h, (91%, 2 steps). g TMSBr, Et3N, CH2Cl2, rt, h Pd(OAc)2, CH3CN, rt. i HC(OMe)3, p-TsOH–H2O, MeOH, rt, (78%, 3 steps). j diisobutylaluminum hydride (DIBAL), CH2Cl2, −78 °C, 1.5 h. k Ph3PCH3Br, potassium hexamethyldisilazane (KHMDS), THF, 0 °C to rt, 12 h, (65%, 2 steps). l Na, naphthalene, 1,2-dimethoxyethane (DME), −65 °C, 30 min. m 5-hexenoyl chloride, DMAP, Et3N, CH2Cl2, (88%, 2 steps). n Grubbs' first (20 mol%), CH2Cl2 (degassed), reflux, 24 h. o 1 N HCl, AcOEt, rt, 5 min, (63%, 2 steps). p DIBAL, CH2Cl2, −78 °C to rt. q Dess–Martin periodinane, CH2Cl2, 0 °C to rt (21%, 2 steps).
Chemoselective reduction of conjugated olefin in 22 (Scheme 3),16 followed by removal of a Boc group and acylation with 5-hexenoyl chloride, gave diene 23, a precursor for 8-membered ring formation. RCM using Grubbs’ second generation catalyst gave cyclized product 24 in 90% yield. Acetate was removed under mild conditions17 and the resultant primary alcohol was oxidized to aldehyde 25. Saegusa–Ito oxidation18 of 25 introduced unsaturation into ring B. After the aldehyde was protected by acetal as 26, reduction of lactone to hemiacetal with DIBAL at −78 °C followed by methylenation furnished a butenyl moiety in 27. Benzenesulfonyl protection was removed reductively and a secondary amine in the piperidine ring was acylated to give diene 28, which is a precursor for the formation of a 13-membered ring by a second RCM. The second RCM was catalyzed by Grubbs’ first generation catalyst to give the desired Z-olefin selectively (29). RCM using Grubbs’ second generation catalyst gave a mixture of dimers as a major product. Hydrolysis of acetal in 29 gave aldehyde 30. All three carbonyl groups in 30 were reduced to give ircinol A (31), which was oxidized to ircinal A (3). As the conversion of ircinal A to manzamine A (2) has been reported previously, the present findings represent a formal total synthesis of manzamine A.19
A highlight of this synthesis is the use of a highly efficient FIC for the formation of a 6-membered ring with stereoselective construction of a tetra-substituted carbon center. The furan ring in 20 was completely incorporated into the structure of ircinal A.
Retrosynthetic analysis of ircinal A. A full color version of this figure is available at The Journal of Antibiotics journal online.
Furan-iminium cation cyclization (FIC) for synthesis of core skeleton.
Total synthesis of ircinal A.
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This work was supported by Suzuken Memorial Foundation (to SA) and KAKENHI (2139002) to AN.
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Tokumaru, K., Ohfusa, T., Arai, S. et al. Furan-iminium cation cyclization (FIC) in a total synthesis of manzamine alkaloids. J Antibiot 69, 340–343 (2016). https://doi.org/10.1038/ja.2016.24
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DOI: https://doi.org/10.1038/ja.2016.24
