Total Synthesis of Lycoricidine and Narciclasine by Chemical Dearomatization of Bromobenzene

Abstract

The total synthesis of lycoricidine and narciclasine is enabled by an arenophile-mediated dearomative dihydroxylation of bromobenzene. Subsequent transpositive Suzuki coupling and cycloreversion deliver a key biaryl dihydrodiol intermediate, which is rapidly converted into lycoricidine through site-selective syn-1,4-hydroxyamination and deprotection. The total synthesis of narciclasine is accomplished by the late-stage, amide-directed C–H hydroxylation of a lycoricidine intermediate. Moreover, the general applicability of this strategy to access dihydroxylated biphenyls is demonstrated with several examples.

The isocarbostyril alkaloids from the Amaryllidaceae family of plants are an important class of natural products with impressive biological activities. Specifically, lycoricidine, narciclasine, 7-deoxypancratistatin, and pancratistatin (1–4, Scheme 1) are well-known anticancer agents,^[1] exhibiting submicromolar inhibitory activity against multiple cancer cell lines.^[2] Structurally, these alkaloids possess a highly functionalized aminocyclitol core, with four contiguous stereocenters in the case of lycoricidine (1) and narciclasine (2) and six in the case of 7-deoxypancratistatin (3) and pancratistatin (4). Owing to their potential oncological relevance as well as their low natural abundance, these metabolites have attracted significant interest in the synthetic community, resulting in numerous synthetic studies and several dozen total syntheses reported to date.^[3–5] Nevertheless, the strategic application of dearomative processes^[6] to access the polyfunctionalized cyclohexenyl or cyclohexyl motifs of these natural products has been very limited, with only microbial arene oxidation used successfully by the Hudlickly^[4g,5c] and Banwell groups.^[4n,5f] Herein, we report the total synthesis of lycoricidine (1) and narciclasine (2) based on a chemical-based dearomatization of bromobenzene, as well as a general method for the preparation of 4-aryl-substituted cis-dihydrodiols.

Scheme 1.

Structures of lycoricidine (1), narciclasine (2), 7-deoxypancratistatin (3), and pancratistatin (4).

We have recently reported an arenophile-mediated dearomative dihydroxylation that provides access to dihydrodiol derivatives that are complementary to those obtained through biotechnological processes (i.e., 6 vs. 7, Scheme 2a).^[7] Specifically, the chemical dihydroxylation of bromobenzene (5) delivers bromo-3,4-dihydrodiol (6), a constitutional isomer that is well-suited for the synthesis of lycoricidine (1) and narciclasine (2) as the vinyl bromide in 6 is properly situated for appending on the aryl portion of these molecules. Therefore, we envisioned that these natural products could be traced back to bromobenzene (5) and aryl boronic acid 8 through a Suzuki coupling and two olefin transformations to install the required cis-1,2-diol and 1,4-syn-aminodiol, as shown retrosynthetically in Scheme 2b. Additionally, we anticipated that the phenol moiety that distinguishes 2 from 1 could be introduced at a late stage in the synthesis, allowing for common intermediates to be used in the construction of both molecules.

Scheme 2.

a) Chemical and biological dearomative dihydroxylation of bromobenzene (5). b) Key retrosynthetic disconnections for lycoricidine (1) and narciclasine (2). c) Preparation of 4-aryl-substituted cis-dihydrodiols 11.

Moreover, to increase the atom economy and overall yield of this dearomative approach, we reasoned that the application of arenophile MTAD (9) with bromobenzene (5) under Narasaka–Sharpless dihydroxylation conditions^[8] would permit expedited preparation of the required dihydroxylated biphenyl intermediate 11 (Scheme 2c). In this protocol, the aryl boronic acid serves as a turnover reagent for osmium and becomes embedded within the dearomatized product as a cyclic boronate ester (5→10). A subsequent transpositive Suzuki coupling and cycloreversion of the arenophile moiety would incorporate the aryl ring into the carbon framework of the molecule and deliver 4-aryl-substituted cis-dihydrodiol 11. Importantly, the preparation of biaryl dihydrodiols of type 11 has not been widely explored,^[9] and the application of microbial oxidation to biphenyl substrates generally gives alternative constitutional isomers to the desired oxidation product 11.^[10] Only engineered enzymes can produce such compounds; however, their synthetic application has not been explored.^[11]

We commenced our studies by investigating the arenophile-assisted dihydroxylation of bromobenzene (Scheme 3). Based on our previous work, we chose to employ Narasaka–Sharpless dihydroxylation conditions as this modification gave superior results with halogenated aromatic substrates. Accordingly, visible-light irradiation of bromobenzene (5) and arenophile MTAD (9) with subsequent addition of osmium tetroxide, boronic acid 8, and NMO delivered bicycle 10a in 63% yield. Importantly, this reaction was routinely run on multigram scale, and more than 100 g of 10a have been prepared to date in our laboratories. With intermediate 10a in hand, which features both a vinyl bromide and an aryl boronic ester, we turned our attention to the development of the transpositive Suzuki coupling to install the benzodioxole ring into the carbon framework of these alkaloids. Initial screening of reaction conditions using standard conditions with Pd(PPh₃)₄ as the catalyst gave suboptimal results, with protodeborylation as a major process. Extensive screening identified Pd(dppf)Cl₂ as an optimal catalyst in combination with triethylamine as a base in THF, furnishing coupling product 12 in 54% yield. Small amounts of water proved crucial for high yields, likely for pre-hydrolysis of the boronate ester to facilitate the pre-transmetalation event.^[12] Next, acid-catalyzed acetonide protection of the free diol with 2,2-dimethoxypropane and subsequent cycloreversion (KOH, heat then CuCl₂) cleanly afforded intermediate dihydrodiol 11a′.

Scheme 3.

Total synthesis of (±)-lycoricidine (1) and (±)-narciclasine (2). Reagents and conditions: a) PhBr (5), MTAD (9), white LEDs, CH₂Cl₂, −78 °C; then 8, OsO₄ (10 mol%), NMO, CH₂Cl₂, −78 to 0 °C, 63 %; b) Pd(dppf)Cl₂ (5 mol%), NEt₃, THF/H₂O = 9:1, 70 °C, 54 %; c) PPTS (cat.), CH₂Cl₂/2,2-DMP = 1:1, 50 °C, 86%; d) KOH, iPrOH, 100°C; then CuCl₂, pH 7, RT, 93%; e) 14, THF, 0 °C to RT; then Zn, AcOH, RT, 60%; f) TBAF, THF, 0°C, 98 %; g) PIFA, MeCN/H₂O = 9:1, 0 °C; then TFA, 0°C, 95 %; h) TIPSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C to RT, 77%; i) (TMP)₂Cu(CN)Li₂, THF, 0°C; then tBuOOH, THF, −78 °C; then Ac₂O, NEt₃, DMAP, 0 °C to RT, 50 % and 10% of the free phenol derivative; j) TBAF, THF, 0°C, 82%; k) PIFA, MeCN/H₂O = 9:1, 0 °C; then TFA, 0°C, 92%; l) K₂CO₃, MeOH, 0 °C to RT, 68%. NMO =N-methylmorpholine-N-oxide, THF =tetrahydrofuran, dppf =1,1′-bis(diphenylphosphino)ferrocene, PPTS =pyridinium p-toluenesulfonate, 2,2-DMP =2,2-dimethoxypropane, TBAF =tetrabutyl-ammonium fluoride, TIPSOTf =triisopropylsilyl trifluoromethanesulfonate, TMP =2,2,6,6-tetramethylpiperidine, PIFA =bis(trifluoroacetoxy)iodobenzene, TFA =trifluoroacetic acid.

With the carbon skeleton completed and the cis-1,2-diol installed, we turned towards the introduction of the required 1,4-syn-amino alcohol moiety. To this end, we anticipated that a nitroso-Diels–Alder reaction with subsequent reduction of the N–O bond could deliver the desired motif, though we anticipated that electronic tuning of the nitroso cycloaddend might be required to obtain the desired constitutional isomer.^[13] Indeed, we observed that cycloaddition with electron-rich arylnitroso species 14 proceeded exclusively with the desired selectivity, while acyl- and alkylnitroso species gave the opposite isomer. To facilitate deprotection of the amide nitrogen atom, a TIPS-protected phenolnitroso compound was employed during the cycloaddition step; after zinc-mediated N–O cleavage, lactam 15 was produced as a single diastereo- and constitutional isomer. Deprotection of the phenol with TBAF (15→16) followed by one-pot oxidative cleavage and acetonide deprotection afforded lycoricidine (1), whose physical properties (¹H and ¹³C NMR, MS data) matched those reported for the natural material.

Although more than a dozen chemical syntheses of lycoricidine (1) exist, its conversion into narciclasine (2) through late-stage arene C–H hydroxylation has never been established. We undertook this task and found that the amide 15 could also serve as a viable intermediate to narciclasine (2). Inspired by the recent work from Uchiyama and co-workers,^[14] we reasoned that a benzamide group could serve as a viable directing group for deprotonative cupration and subsequent oxidation of the resulting aryl cuprate with tert-butyl hydroperoxide. Gratifyingly, silylation of alcohol 15 and hydroxylation of 17 under Uchiyama’s conditions, with in situ acetylation, afforded intermediate 18. Protection of the phenol moiety after hydroxylation proved to be crucial for the subsequent oxidative deprotection of the tertiary amide. Thus global deprotection (1) TBAF, 2) PIFA, 3) TFA, 4) K₂CO₃) afforded narciclasine (2).

Considering that dearomative dihydroxylation with arenophiles provides a new entry into the synthesis of biaryl cis-dihydrodiol derivatives from readily available bromobenzene and aryl boronic acids, we evaluated the generality of this synthetic strategy (Table 1). Thus a three-step procedure involving 1) dearomative Narasaka–Sharpless dihydroxylation of bromobenzene in the presence of a variety of aryl boronic acids, 2) transpositive Suzuki coupling, and 3) cycloreversion furnished the desired biaryl dihydrodiol derivatives 11. Different electronic and steric properties were tolerated during the course of this reaction; electron-rich (e.g., 11c, 11d) and electron-deficient (11h, 11i, and 11j) boronic acids could be employed as well as arenes with substituents in the ortho, meta, and para position relative to the boron atom. Finally, 2-naphthylboronic acid was used to afford polynuclear dihydrodiol 11k.

Table 1.

Synthesis of biaryl 3,4-dihydodiols.^[a]

^[a]Reaction conditions: Step 1: MTAD (9, 2.0 equiv), PhBr (5, 20 equiv), visible light, CH₂Cl₂, −78 °C; then ArB(OH)₂ (1.0 equiv), OsO₄ (10 mol%), NMO (2.4 equiv), −78 °C to RT. Step 2: Pd(dppf)Cl₂ (5.0 mol%), Et₃N (5.0 equiv), THF/H₂O (9:1), 70 °C. Step 3: N₂H₄ (30 equiv), 100°C, 12 h; then CuCl₂ (1.0 equiv) pH 7, RT, 5 min. Yields of isolated products are given.

In conclusion, (±)-lycoricidine (1) and (±)-narciclasine (2) have been synthesized in seven and ten steps, respectively, with chemical dearomatization of bromobenzene as a key step. The Narasaka–Sharpless dihydroxylation and a subsequent transpositive Suzuki coupling enabled the incorporation of the aryl ring of a boronic ester into the carbon skeleton, providing rapid access to these molecules. Moreover, a unique deprotonative cupration/oxidation hydroxylation sequence allowed for the conversion of a late-stage lycoricidine intermediate into a precursor for narciclasine. Finally, this approach provides a concise entry into the synthesis of a variety of biaryl 3,4-dihydrodiols, which could greatly advance the synthesis of analogues of these important alkaloids.