A Concise Total Synthesis of (+)‐Pancratistatin from <scp>D</scp>‐Glucose Featuring the Henry Reaction

Abstract

Sugar, oh Henry, Henry: A concise and stereoselective synthesis of (+)-pancratistatin is described. The key nitrocyclitol compound was prepared from a D-glucofuranose derivative with a C-aryl group by using an intramolecular Henry reaction. The diastereoselective introduction of a C-aryl moiety was achieved by a Michael addition of an arylcuprate to a key sugar nitroolefin. Pancratistatin (PST, Scheme 1) is a natural compound that was first isolated1 from Spider Lily, a plant native to Hawaii that belongs to the Amaryllidaceae family. As well as antiviral and antiparasitic activities, PST has very strong antitumor activity.2 Furthermore, PST can act as an antitumor secondary metabolite that can induce apoptosis in tumor cells by targeting their mitochondria while leaving normal cells unaffected.3 Therefore, as well as being a challenging compound to synthetic chemists, a facile large-scale synthesis of PST and its analogs would be of great importance in pharmaceutical sciences.4, 5 However, despite many attempts to synthesize PST and its analogs (various epimers and/or deoxy derivatives, Scheme 1),4g,4h,4j a practical and scalable synthesis of from readily available starting compounds has remained elusive. Pancratistatin (PST) and its related compounds. We have been engaged in the total syntheses of naturally occurring branched-chain cyclitol compounds, such as cyclophellitol, mytillitol, laminitol, and (−)-tetrodotoxin (TTX),6 by using D-glucose as the starting material. Herein, we describe the concise stereoselective total synthesis of (+)-PST from D-glucose, which features both inter- and intramolecular Henry reactions7 (nitroaldol reactions) as key transformations. As shown in the retrosynthetic plan (Scheme 2), the key intermediate C-aryl nitrocyclitol B can be prepared from D by the intramolecular Henry reaction of C. As a note, we have previously used a similar step in the synthesis of (−)-TTX by using nitrocyclitol X in an intramolecular Henry reaction (Scheme 3).7 Retrosynthetic analysis of (+)-PST from D-glucose featuring an intramolecular Henry reaction. Our intramolecular nitro aldol approach for the construction of nitrocyclitol X within the total synthesis of (−)-TTX. Based on our experience, the most promising route for synthesizing (+)-PST involves the construction of optically active B from key intermediate D, which in turn can be prepared by a diastereoselective Michael addition of an arylcuprate8 derived from aryl bromide G4b,4c to sugar nitroolefin E. It is important to note that the high stereoselectivity of the Michael addition to the nitroolefin can be attributed to the bulkiness of the C3 protecting group and the organometallic reagent (Scheme 3).6a Paulsen and Stubbe used the same Henry reaction and a similar Michael addition for the synthesis of the 7-deoxy-PST in 1983; however, both reactions did not proceed stereoselectively.9 Coincidentally, during the course of our investigations, Otero et al. also described a similar Michael addition of naphthoquinones to sugar nitroolefin E′, thus achieving the synthesis of 2-(benzyloxy)-1,3,4-trihydroxy-1,2,4,4a,5-hexahydro-11bH-benzo[b]carbazole-6,11-dione (D′, Scheme 4).10 Although, the study by Otero et al. does not consider the bulkiness of the C3 protecting group important,10 we consider it essential from prior experience.6a Nitroolefin E can be synthesized by the condensation of nitromethane with aldehyde F (intermolecular Henry reaction) that is derived from D-glucose. The arylcuprate of aryl bromide G can be synthesized from o-vanillin in three steps.4b,4c The study of Otero et al. on the Michael addition of naphthoquinones to sugar nitroolefin E′ resulted in the synthesis of polyhydroxylated hexahydro-11 H-benzo[b]carbazole-6,11-dione (D′).10 In accordance with our synthetic scheme, (+)-PST was effectively prepared from D-glucose and o-vanillin as shown in Scheme 5. First, 3-O-tert-butyldimethylsilyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (2)11 was prepared from commercially available 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (1). Selective hydrolysis of 2 by using aqueous 70 % acetic acid at room temperature gave 5,6-diol 311 in 85 % yield, which underwent oxidative degradation in the presence of sodium metaperiodate in aqueous methanol to afford the corresponding unstable aldehyde 4 (F, Scheme 5).11a Synthesis of nitrocyclitol 13 featuring an intramolecular Henry reaction. m-CPBA=meta-chloroperbenzoic acid; DMSO=dimethyl sulfoxide; MsCl=methanesulfonyl chloride; TBDMSCl=tert-butyldimethylsilyl chloride; TMSCl=trimethylsilyl chloride. Subsequently, 4 was immediately treated with nitromethane in methanol in the presence of sodium methoxide to give nitroalcohol 5 as a single isomer in 93 % yield over two steps from 3. The R configuration at the C5 position of 5 was confirmed by an alternate preparation via 6-azido-3-O-tert-butyldimethylsilyl-6-deoxy-1,2-O-isopropylidene-α-D-glucofuranose (6). Subsequently, 5 was treated with methanesulfonyl chloride in the presence of triethylamine to give the corresponding single nitroolefin 7 (E) in 81 % yield. The structure of 7 was confirmed by 1H NMR spectroscopy (J5,6=13.1 Hz and NOE correlations, Figure 1). NOE correlations of nitroolefin 7 (E). The Michael addition of the arylcuprate to the nitroolefin was carried out as follows: first, 6-bromo-4-methoxybenzo[1,3-d]dioxole (10, aryl bromide G) was prepared from o-vanillin in three steps by following a procedure described in the literature.4b,4c Next, the corresponding arylcuprate was generated from 10 by using magnesium, trimethylsilyl chloride, and copper(I) iodide. The arylcuprate was then treated with 7 to give the C-aryl glucofuranose derivative 11 in 86 % yield as a single stereoisomer. In contrast, the use of a methyl ether group as the C3 protecting group gave the corresponding Michael adduct in 58 % yield and 10:1 diastereomeric ratio. This result indicates that the bulkiness of the C3 protecting group may be partly important. The configuration at the C5 position of 11 was determined by conversion into C-aryl cyclitol 13, as shown in Scheme 5. After hydrolyzing the 1,2-O-isopropylidene moiety of 11 by heating it to reflux in aqueous 70 % acetic acid, the resulting nitroaldose C was treated with sodium bicarbonate in aqueous methanol to give D-muco-inositol derivative 12 (B) in 62 % yield in two steps from 11. Compound 11 was acetylated with acetic anhydride in pyridine to give tri-O-acetate 13. The configuration and conformation at the C1 position of 13, which corresponds to the C5 position for 11, was determined by 1H NMR coupling constants (J1,2, J4,5, J1,6 and J5,6), and confirmed by X-ray crystal structure analysis (Figure 2).12 ORTEP drawing derived from the single-crystal X-ray analysis of 13. Thermal ellipsoids are drawn at a 30 % probability level. Hydrogen atoms are shown as shapes of arbitrary radius. Although the above intramolecular Henry reaction could have resulted in the formation of 12 and its three isomers, only the desired stereoisomer was obtained. In similar studies on the syntheses of various cyclitol derivatives in Henry reactions, such as those reported by Otero et al.10 and Chakraborty et al.,13 the selectivity was attributed to the stable six-membered transition state TS-1 (Scheme 6).10, 14 TS-1 was stabilized by an intramolecular hydrogen bond, the equatorial orientation of the bulky aryl and nitro groups, and the parallel π-orbital overlapping of the CO bond of the aldehyde and the CN bond of the nitronate. In our case, therefore, compound C also undergoes the intramolecular Henry reaction similarly via the favorable TS-1. Intramolecular Henry reaction via the six-membered cyclic transition states. Reduction of the nitro group of 12 with zinc powder and hydrochloric acid in ethanol afforded the corresponding free amine, which was subsequently treated with methyl chloroformate and sodium hydroxide, then acetylated to afford the fully protected 14 in 82 % yield (Scheme 7). Upon removal of the TBDMS group by using TBAF, deprotected 14 was acetylated with acetic anhydride in pyridine to give tetra-O-acetate 15 in 90 % yield in two steps from 14. The subsequent formation of the lactam B-ring and global deprotection were achieved by using the conditions reported by Magnus and Sebhat.4b,4c The Bischler-Napieralski reaction of 15 under modified Banwell conditions15 afforded the lactam as an inseparable mixture (7:1) of regioisomers 16 and 16 a in a combined yield of 64 %. Synthesis of (+)-PST from nitrocyclitol 12. DMAP=4-dimethylaminopyridine, Tf2O=trifluoromethanesulfonic anhydride, TBAF=tetra-n-butylammonium fluoride. Separation was subsequently achieved because only the desired regioisomer 16 underwent BBr3-mediated demethylation. Finally, the acetyl groups of 17 were removed under Zemplén conditions16 to afford crystalline (+)-PST. The spectral data (1H and 13C NMR spectra and HRMS data) and specific rotation values ([α]=+36.8 (c=1.00 in DMSO)) of our synthetic PST are in good agreement with those of natural compound.1a, 4a,4c,4d,4f In summary, we have achieved the stereoselective total synthesis of optically active (+)-PST from D-glucose in 20 steps featuring Henry reactions as key steps in 5.8 % overall yield from D-glucose and o-vanillin. We believe that our synthetic method can be applied not only for the synthesis of PTS and its analogs, but also towards highly functionalized optically active cyclohexane-based natural products. As a service to our authors and readers, this journal provides supporting information supplied by the authors. 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