HETEROCYCLES, Vol. 95, No. 2, 2017 1245 HETEROCYCLES, Vol. 95, No. 2, 2017, pp. 1245-1253. © 2017 The Japan Institute of Heterocyclic Chemistry Received, 19th September, 2016, Accepted, 13th December, 2016, Published online, 15th February, 2017 DOI: 10.3987/COM-16-S(S)80 A FISCHER INDOLIZATION STRATEGY TOWARD THE TOTAL SYNTHESIS OF (–)-GONIOMITINE Beau P. Pritchett, Jun Kikuchi, Yoshitaka Numajiri, and Brian M. Stoltz* This manuscript is dedicated to Prof. Masakatsu Shibasaki for his 70th birthday. The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Blvd. MC101-20, Pasadena, CA 91125 (USA); Email: [email protected] Abstract – A Fischer indolization strategy toward the core of (–)-goniomitine is reported. Initial investigations into the Pd-catalyzed asymmetric allylic alkylation of dihydropyrido[1,2-a]indolone (DHPI) substrates are also discussed. (–)-Goniomitine (1, Figure 1), isolated from the bark of Gonomia Malagasy, is differentiated from other Aspidosperma alkaloids (e.g., 2–4) by its unique aminal-containing tetracyclic core.1 There are currently seven reported total syntheses of (±)-goniomitine (1),2 along with three asymmetric total syntheses.3 We anticipated that sufficiently rapid assemblage of the highlighted tricyclic subunit, combined with our group’s expertise in the asymmetric synthesis of all-carbon quaternary centers,4 would facilitate an efficient catalytic enantioselective synthesis of (–)-goniomitine (1). OH N N N N Et Et Et H Et N N N HN H H H H CO2Me (–)-goniomitine (1) (+)-aspidospermidine (2) (–)-quebrachamine (3) (+)-vincadifformine (4) Figure 1. Representative Aspidosperma Alkaloids In our initial retrosynthetic analysis of (–)-goniomitine (1), we believed that late-stage redox manipulations and alcohol deprotection could furnish the natural product from lactam 5 (Scheme 1). We expected the quaternary center in lactam 5 could arise from the enantioselective Pd-catalyzed decarboxylative allylic alkylation of racemic β-amidoester 6. Importantly, we believed that 1246 HETEROCYCLES, Vol. 95, No. 2, 2017 enantioconvergent construction of the quaternary center would offer significant improvement over the comparatively poor stereocontrol featured in previous enantioselective syntheses of (–)-goniomitine (1).3 Disconnection of the ethyl and alloc groups revealed key dihydropyrido[1,2-a]indolone (DHPI) 7, which we anticipated could be accessed via the Fischer indolization of 1,3-cyclohexanedione 8. OH hydroamination/ OBn OBn reduction/ Pd-catalyzed deprotection allylic alkylation N N N H Et HN O O Et Et O O (–)-goniomitine (1) 5 6 OBn O C-acylation/ Fischer OBn C-alkylation indolization N O O 7 keto-8 Scheme 1. Initial Retrosynthesis of (–)-Goniomitine The acid-promoted Fischer indolization reaction, first discovered in 1883, is one of the most robust and widely utilized methods for the synthesis of substituted indoles from carbonyl precursors.5 Ketones and aldehydes can be converted to the respective arylhydrazones under either Brønsted or Lewis acidic conditions (Scheme 2A). The arylhydrazone intermediate undergoes tautomerization to the corresponding enehydrazine, followed by a [3,3]-sigmatropic rearrangement and finally elimination of ammonia to deliver an indole product. This venerable transformation has seen widespread use in the realm of total synthesis,6 and has been rendered enantioselective in an elegant desymmetrization reaction of meso cyclic ketones.7 Of particular relevance to our synthetic plan toward (–)-goniomitine (1) was a report from Teuber and co-workers describing a Fischer indolization protocol for the synthesis of DHPI products Scheme 2. A) General Fischer Indolization Reaction. B) DHPI Synthesis via Fischer Indolization of 1,3-Cyclohexanediones HETEROCYCLES, Vol. 95, No. 2, 2017 1247 (Scheme 2B).8 They found that treatment of 2-substituted 1,3-cyclohexanediones (9) with phenylhydrazine and sulfuric acid first gives tricycle 10, which undergoes sequential hydrolysis and N-acylation to furnish DHPI 11. Our studies on the Pd-catalyzed allylic alkylation of the previously unexplored DHPI substrate class commenced with C3-methyl DHPI 13, which is readily available from 2-methyl-1,3-cyclohexanedione (12, Scheme 3).8 DHPI 13 was smoothly acylated using LHMDS and allyl cyanoformate. Subsequent site-selective alkylation with iodomethane delivered racemic β-amidoester 15 in 77% overall yield from 13. We found that subjecting 15 to the catalyst complex derived from Pd2(pmdba)3 (5 mol%) and (S)-(CF3)-t-BuPHOX (L1, 12.5 mol%) in toluene at 60 °C resulted in minimal conversion, despite prolonged reaction times (Table 1, Entry 1). Full consumption of starting material was only achieved after switching from toluene to TBME as solvent, and raising the loading of Pd2(pmdba)3 and ligand to 10 mol% and 25 mol%, respectively (Entry 2). Under these conditions, we were able to isolate α-quaternary DHPI 16 in 60% yield and 90% enantiomeric excess. O H2SO4 LHMDS; PhNHNH allyl cyanoformate MeI, K2CO3 2 N N THF, –78 °C → 0 °C DMF, 50 °C O O (80% yield) O (97% yield) O (79% yield) O 12 13 14 CF3 O Table 1: Pd-Catalyzed Allylic Alkylation of 15 (4-CF3-C6H4)2P N Pd (pmdba) ligand entry 2 3 solvent time [h] yield [%] ee [%] L1 mol% mol% N N Pd2(pmdba)3 1 5 12.5 toluene 72 <10% 90 O solvent, 60 °C O O 2 10 25 TBME 24 60 90 O 15 16 Scheme 3. Synthesis of C3-Methyl α-Quaternary DHPI 16 Regarding the total synthesis of (–)-goniomitine (1), our first challenge was to establish a regioselective C-alkylation of 1,3-cyclohexanedione (17) with (2-benzyloxy)ethyl iodide (18). Although Ma and co-workers have previously reported this transformation, we were unsuccessful in our attempts to reproduce their work.9 We discovered that slightly different conditions afforded the desired C-alkylated product 8 in 70% yield as the enol tautomer (Scheme 4). After investigating several conditions for the Fischer indolization reaction, it was discovered that subjecting enol-8 to 2N HCl in refluxing toluene furnished key DHPI 7, albeit in an unsatisfactory range of 10–33% yield. Nevertheless, we were able to synthesize β-amidoester 6 from DHPI 7 in 55% yield over a two-step sequence analogous to that 1248 HETEROCYCLES, Vol. 95, No. 2, 2017 described above (cf. Schemes 3 and 4), which put us in position to test the allylic alkylation chemistry on the real system. Once again, we observed that TBME as solvent, along with high catalyst loading, was required to deliver α-quaternary allylic alkylation product 5 in a disappointing 59% yield and 87% enantiomeric excess. I OBn OBn O (18 , 1.1 equiv) O 2N HCl 1. LHMDS; allyl cyanoformate KOH (2 equiv) OBn PhNHNH2 THF, –78 → 0 °C EtOH/H2O, 100 °C toluene, 110 °C N 2. EtI, K2CO3, DMF, 50 °C O OH (70% yield) (10–33% yield) O (55% yield, 2 steps) 17 enol-8 7 OBn OBn OH L1 (25 mol%) Pd2(pmdba)3 (10 mol%) N N N TBME, 60 °C H Et O O Et O (59% yield, 87% ee) Et HN O 6 5 (–)-goniomitine (1) Scheme 4. Synthesis of α-Quaternary DHPI 5 Toward (–)-Goniomitine (1) Previous studies by our group have revealed that electron-withdrawing substituents on the lactam nitrogen atom provide the best results in the allylic alkylation chemistry.4b We therefore hypothesized that a C3-alkyl substituent might be too electron-donating, and thus reevaluated our synthetic plan. Gratifyingly, C3-brominated substrate 19 performed exceptionally well in the Pd-catalyzed allylic alkylation, delivering α-quaternary DHPI 20 in 83% yield and 96% ee (Scheme 5). We were then able to advance this compound to (–)-goniomitine (1) in just three steps and 29% overall yield.10 Br Br OH L1 (12.5 mol%) three steps Pd (pmdba) (5 mol%) N N 2 3 N H TBME, 60 °C Et HN O O Et O (83% yield, 96% ee) Et O (–)-goniomitine (1) 19 20 Scheme 5. Strategic Bromination Enables a Total Synthesis of (–)-Goniomitine (1) To summarize, we employed a Fischer indolization protocol to synthesize a key tricyclic DHPI intermediate (7) toward (–)-goniomitine (1) in three steps from commercial materials. While this transformation failed to deliver the product in good yield, sufficient material was made available to study the Pd-catalyzed enantioselective allylic alkylation of the DHPI substrate class. As a result, we discovered a critical electronic effect at the C3 position of the indole moiety that led to the first catalytic enantioselective total synthesis of (–)-goniomitine (1). HETEROCYCLES, Vol. 95, No. 2, 2017 1249 EXPERIMENTAL Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried glassware under an argon atmosphere using dry, deoxygentated solvents (distilled or passed over a column of activated alumina).11 Commercially available reagents were used as received. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 pre-coated plates (250 nm) and visualized by UV fluorescence quenching, potassium permanganate, or p-anisaldehyde staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 40-63 nm) was used 12 for flash chromatography. (S)-(CF3)-t-BuPHOX, and tris(4,4’-methoxydibenzylideneacetone)- 13 dipalladium(0) [Pd2(pmdba)3] were prepared by known methods. Phenyl hydrazine was purified immediately before use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. 1H and 13C NMR spectra were recorded on a Varian Inova 500 (500 MHz and 126 MHz, respectively) and are reported in terms of chemical shift relative to CHCl3 (δ 7.26 and 77.16, respectively). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 Spectrometer and are reported in frequency of absorption (cm-1).