Divergent Syntheses of (-)-Chicanine, (+)-Fragransin A2, (+)-Galbelgin, (+)-Talaumidin, and (+)-Galbacin via One-Pot Homologative γ-Butyrolactonization

In this study, the divergent syntheses of (-)-chicanine, (+)-fragransin A2, (+)-galbelgin, (+)-talaumidin, and (+)-galbacin are detailed. In this approach, an early-stage modified Kowalski one-carbon homologation reaction is utilized to construct the central γ-butyrolactone framework with the two necessary β,γ-vicinal stereogenic centers. The two common chiral γ-butyrolactone intermediates were designed to be capable for assembling five different optically active tetrahydrofuran lignans from commercially available materials in a concise and effective divergent manner in five to eight steps. These five syntheses are among the shortest and highest-yielding syntheses reported to date.


Introduction
Lignans and neolignans have been discovered in a number of pharmacologically important and structurally complex natural products [1][2][3].It is generally understood that lignans have significant biological roles in plants, including protection against herbivores and microbes.It is remarkable how much structural flexibility lignans display with just two phenylpropane (C6-C3) subunits in their molecular framework.Lignans have a broad spectrum of medicinal effects, including anticancer, anti-inflammatory, neuroprotective, antioxidant, and antiviral activities [4][5][6].These units and their synthetic derivatives are becoming increasingly popular owing to their use in cancer therapy and a variety of other pharmacological effects [7].
Among those lignans, 2,5-diaryl-3,4-dimethyltetrahydrofurans have fueled considerable synthetic efforts owing to their molecular diversity and pharmacological profile [3,[8][9][10].Despite these impressive advances, effective approaches have so far been largely limited in terms of stereoselectivity and the availability of starting materials for lignan synthesis.Importantly, these structures are commonly embedded in larger and more complex structures, resulting in design complications for step-efficient synthesis.
In our previous report, we detailed the stereoselective aldol protocols and the Kowalski ester homologation [23][24][25][26][27] reaction, which we modified for our proposed transformation.This process involved one-carbon homologative γ-butyrolactonization and yielded a variety of γ-butyrolactones with β,γ-cis-vicinal stereogenic centers [28].According to the results of our previous study, including the investigation of a range of chiral auxiliaries, the acylthiazolidinethione [29,30] group was determined to be substantially more productive than oxazolidinones or oxazolinethiones, implying that it plays a significant role in the generation of dibromoketone enolate III in Scheme 1.Additionally, we demonstrated the synthesis of the challenging trans-γ-butyrolactone, which can be generated through a sterically hindered anti-aldol product [31].
yielded a variety of γ-butyrolactones with β,γ-cis-vicinal stereogenic centers [28].According to the results of our previous study, including the investigation of a range of chiral auxiliaries, the acylthiazolidinethione [29,30] group was determined to be substantially more productive than oxazolidinones or oxazolinethiones, implying that it plays a significant role in the generation of dibromoketone enolate III in Scheme 1.Additionally, we demonstrated the synthesis of the challenging trans-γ-butyrolactone, which can be generated through a sterically hindered anti-aldol product [31].

Results
Although this approach enables the rapid and reliable synthesis of a range of chiral γ-butyrolactone frameworks, it also has certain restrictions, resulting in modest to poor chemical yields in some cases.A number of bases and quenching protocols have recently been re-evaluated with the model substrate in an attempt to identify more comprehensive procedures for one-pot one-carbon homologative lactonizations [32].yielded a variety of γ-butyrolactones with β,γ-cis-vicinal stereogenic centers [28].According to the results of our previous study, including the investigation of a range of chiral auxiliaries, the acylthiazolidinethione [29,30] group was determined to be substantially more productive than oxazolidinones or oxazolinethiones, implying that it plays a significant role in the generation of dibromoketone enolate III in Scheme 1.Additionally, we demonstrated the synthesis of the challenging trans-γ-butyrolactone, which can be generated through a sterically hindered anti-aldol product [31].

Results
Although this approach enables the rapid and reliable synthesis of a range of chiral γ-butyrolactone frameworks, it also has certain restrictions, resulting in modest to poor chemical yields in some cases.A number of bases and quenching protocols have recently been re-evaluated with the model substrate in an attempt to identify more comprehensive procedures for one-pot one-carbon homologative lactonizations [32].

Results
Although this approach enables the rapid and reliable synthesis of a range of chiral γ-butyrolactone frameworks, it also has certain restrictions, resulting in modest to poor chemical yields in some cases.A number of bases and quenching protocols have recently been re-evaluated with the model substrate in an attempt to identify more comprehensive procedures for one-pot one-carbon homologative lactonizations [32].
The optimized conditions involved the replacement of lithium tetramethylpiperidide (LiTMP) with the less hindered and less selective lithium diisopropylamide (LDA) and the substitution of acidic methanol with HCl (3 equiv.) in THF for the quenching process (Scheme 1).These modifications successfully yielded a single diastereomer of γ-butyrolactone without the formation of acyclic products, which was a primary issue with the original reaction conditions.
The following is a simplified representation of the transformation mechanism for the preparation of the key γ-butyrolactone skeleton.Our process is initiated by the preparation of dibromomethyllithium from methylene bromide and lithium diisopropylamide (LDA), followed by the addition of 6 and 7 to the dibromomethyllithium solution, resulting in the tetrahedral intermediate, II.The subsequent treatment of the intermediate, II, with LiHMDS is expected to result in the di-and monobromoketone enolates, III.This is followed by the generation of the ynolate anion, V, via the metal-halogen exchange rearrangement of IV.The chiral γ-butyrolactones could then be formed by quenching the ynolate anion, V, in THF with HCl (3 equiv.),presumably via the successive intramolecular cyclization of the ketene intermediate, VI.It should be noted that one of the key factors in this process for the formation of intermediates II-V is the addition of reagents at −78 • C, followed by stirring at −20 • C for 90 s, which enables high yields of 8 and 9. Notably, the stereochemical outcome of the two vicinal stereogenic centers in γ-butyrolactones is conserved under these reaction conditions (see the Supplementary Materials for details).It should also be highlighted that by taking advantage of the great stereofacial selectivity of auxiliary-mediated asymmetric aldol processes, all the stereoisomers are accessible.
As outlined in Scheme 2, our synthesis of (-)-chicanine (1) began with a highly diastereoselective Evans syn-aldol addition reaction, as described by Crimmins [33][34][35].Commercially available 4-benzyloxy-3-methoxybenzaldehyde was reacted with thiazolidinethione propionate (10) in the presence of TiCl 4 and NMP to provide the desired syn-aldol adduct, 6, in a 97% yield as a single diastereomer.Compound 6 was then subjected to our modified one-pot homologative γ-butyrolactonization conditions to afford 8 at an excellent conversion (91%).It is of note that the developed reaction proceeds with the complete retention of the stereochemistry in 8. Having successfully secured the γ-butyrolactone, 8, we continued our investigation of the biaryl skeleton and completion of the synthesis of (-)-chicanine.To this end, the treatment of 8 with Eschenmoser's salt (LiHMDS, THF, −78 • C, 1 h) and its subsequent in situ elimination (m-CPBA, CH 2 Cl 2 , 25 • C, 5 min) afforded the α-exomethylene lactone, 11, in a 76% yield.The subsequent diastereoselective hydrogenation was most effectively carried out using Wilkinson's catalyst (RhCl(PPh 3 ) 3 , H 2 , 25 • C, 1 h) in toluene.At this juncture, the C-4 methyl group determines the facial selectivity, resulting in the formation of 12 as a single diastereomer with the optimal conversion (90%, dr > 20:1).
An additional benefit of the current approach is that the same intermediate, 8, can also be used to access the straightforward synthesis of naturally occurring (+)-fragransin A2 (2) and (+)-galbelgin (3) (Scheme 3).The biological profiles of these compounds, which includes antioxidant and antiviral activities, as well as the all trans 2,5-diaryl-3,4-dimethyltetrahydrofuran structural feature, have drawn the attention of organic chemists to pursue a stereoselective synthesis of target molecules.
An additional benefit of the current approach is that the same intermediate, 8, can also be used to access the straightforward synthesis of naturally occurring (+)-fragransin A 2 (2) and (+)-galbelgin (3) (Scheme 3).The biological profiles of these compounds, which includes antioxidant and antiviral activities, as well as the all trans 2,5-diaryl-3,4dimethyltetrahydrofuran structural feature, have drawn the attention of organic chemists to pursue a stereoselective synthesis of target molecules.

General Information
All the reactions were conducted in oven-dried glassware under nitrogen.Unless otherwise stated, all the reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA); Acros; or Fisher (Hampton, NH, USA) and were used without further purification.All the solvents were ACS grade or higher and purified before use.Dichloromethane (CH2Cl2) and dimethylformamide (DMF) were distilled from CaH2.Tetrahydrofuran (THF) was distilled from sodium benzophenone.Methanol (MeOH) was distilled from Mg/I2.Analytical thin-layer chromatography (TLC) was performed with glass-backed silica gel (60 Å) plates and a fluorescent indicator (Whatman, St. Louis, MO, USA).Visualization was accomplished by UV irradiation at 254 nm and/or by staining with ceric ammonium molybdate, phosphomolybdic acid in EtOH, or p-anisaldehyde solution.Flash column chromatography was performed using silica gel (particle size: 70-230 mesh, ASTM).All the 1 H-NMR and 13 C-NMR spectra were recorded at 298 K on a Bruker Avance III HD 500 MHz (Bruker Corporation, Billerica, MA, USA) spectrometer in CDCl3 using the signal of the residual CHCl3 as an internal standard.All the NMR δ values are given in ppm, and all the J values are in Hz.Optical rotation values were measured with a Rudolph Research Analytical (AUTOPOL II, Hackettstown, NJ, USA) polarimeter.6): To a cooled (0 °C) solution of (S)-1-(4-benzyl-2-thioxothiazolidin-3-yl)propan-1-one, 10, (670 mg, 2.52 mmol) in CH2Cl2 (13 mL, 0.2 M), titanium(IV) chloride (2.8 mL, 1.0 M in CH2Cl2, 2.8 mmol, 1.1 equiv.) was added.After being stirred for 15 min at the same temperature, i-Pr2NEt (0.53 mL, 3.0 mmol, 1.2 equiv.) was added dropwise, and the reaction mixture was stirred for 40 min at 0 °C.NMP (0.49 mL, 5.1 mmol, 2 equiv.)was added, and the reaction mixture was stirred for an additional