Organocatalytic Enantiospecific Total Synthesis of Butenolides

Biologically important, chiral natural products of butenolides, (−)-blastmycinolactol, (+)-blastmycinone, (−)-NFX-2, (+)-antimycinone, lipid metabolites, (+)-ancepsenolide, (+)-homoancepsenolide, mosquito larvicidal butenolide and their analogues were synthesized in very good yields in a sequential one-pot manner by using an organocatalytic reductive coupling and palladium-mediated reductive deoxygenation or organocatalytic reductive coupling and silica-mediated reductive deamination as the key steps.


Introduction
Developing a simple, sustainable, one-pot protocol by utilizing readily available starting materials for synthesizing a library of natural products, drugs and their analogues is a challenging task for the synthetic chemistry community [1][2][3]. The common drawbacks in the total synthesis of natural products and drugs are associated with multiple steps involving each step in column purification, leading to increases in solvent consumption, harmful wastes and decreases in yield. Furthermore, for the total synthesis of biologically important molecules to be industrially viable, use of toxic metal catalysts has to be avoided. Keeping these facts in mind, more attention has been devoted towards organocatalytic double domino, triple domino and quadruple domino sequential multi-step one-pot reactions. These sequential one-pot reactions can address the above cited problems by reducing the number of steps and thus minimizing the problems associated with them. That is why organocatalysis has been considered the green alternative route to the classical synthetic methods [4][5][6][7][8][9][10][11][12][13][14][15][16]. Even though there exist a considerable number of organo-catalytic asymmetric methods, only a few among them have made their way into the total synthesis of natural products and their analogs [17][18][19]. Among the known organocatalytic reactions, Michael [20][21][22], aldol [23,24], Diels-Alder [25] and Friedel-Crafts [26] reactions are the ones which have been repeatedly used in asymmetric total synthesis of natural products, drugs and drug intermediates.
Recently, our laboratory discovered the three-component organocatalytic reductive coupling (OrgRC) reaction for the selective C-alkylation of cyclic/acyclic CH-acids with different carbonyls in the presence of Hantzsch ester and this reaction has been utilized by many other synthetic chemistry groups in the total synthesis of natural products and drugs [27][28][29][30][31][32][33][34][35]. In our quest to develop organocatalytic methods and apply those methods in the total synthesis of natural products/drugs, we chose a medicinally important small library of natural products containing a butenolide (3-alkyl-5-methyl-2[5H] furanone) core as our synthetic target to synthesize through an organocatalytic sequential one-pot manner.
We established the structure of the intermediates (+)-3 and the natural products (+)-2 by IR/NMR/mass analysis and the absolute configuration was confirmed by correlation with the published literature data including optical rotation (see SI). The above results encouraged us to apply the OrgRC reaction for the synthesis of the butenolide S, an important natural product showing significant mosquito larvicidal properties (LC 50 = 0.41 ppm), along with its partially reduced counterpart T (LC 50 = 0.47 ppm) [40]. The required aldehyde 5f was prepared from 1,10-decanediol in five simple steps. The chiral tetronic acid (+)-4 and the aldehyde 5f were subjected to Or-gRC reaction conditions under proline catalysis in DCM to furnish the expected alkylated product (+)-3f {[α] D 25 = +8.1 • (c = 0.57, CHCl 3 )} in 90% yield. In our efforts to obtain the required deoxygenated product (+)-2f and S, we followed Pashkovsky's approach. The desired OrgRC product (+)-3f was converted into the corresponding enaminone derivative 7f followed by reducing the conjugated double bond and the elimination of the amine moiety . This three-step method is shown to be better compared to the previous synthetic methods [51,59] with respect to the yields, reaction times and chemicals used (see Table S5, SI for correlation). Another important mosquito larvicide natural product T is the partially reduced counterpart of (+)-2f/S and can be obtained by simple functional group transformation as shown by Yao et al. [51].
We established the structure of the intermediates (+)-3 and the natural products (+)-2 by IR/NMR/mass analysis and the absolute configuration was confirmed by correlation with the published literature data including optical rotation (see SI).

General Information
The 1 H NMR and 13 C NMR spectra were recorded at 400 or 500 MHz and 100 or 125 MHz, respectively. The chemical shifts are reported in ppm downfield to TMS (δ = 0) for 1 H NMR and relative to the central CDCl3 resonance (δ = 77.0) for 13 C NMR. In the 13 C NMR spectra, the nature of the carbons (C, CH, CH2 or CH3) was determined by recording the DEPT-135 experiment and is given in parentheses. The coupling constants J are given in Hz. Column chromatography was performed using Acme's silica gel (particle size 0.063-0.200 mm). High-resolution mass spectra were recorded on micromass ESI-TOF MS. IR spectra were recorded on JASCO FT/IR-5300 (JASCO Corporation, Tokyo, Japan) and Thermo Nicolet FT/IR-5700 (Thermo Electron Corporation, Waltham, Madison, USA). For thin-layer chromatography (TLC), silica gel plates Merck 60 F254 (Merck KGaA, Darmstadt, Germany) were used and compounds were visualized by irradiation with UV light and/or by treatment with a solution of p-anisaldehyde (23 mL), conc. H2SO4 (35 mL), acetic acid (10 mL) and ethanol (900 mL) followed by heating.
Experimental procedures and characterization data ( 1 H NMR, 13 C NMR and HRMS) can be found in Supplementary Materials.

Materials
All solvents and commercially available chemicals were used as received without further purification unless otherwise stated. Optically pure (S)-(+)-γ-methyltetronic acid 4 was prepared according to the literature procedure from (S)-(-)-ethyl lactate [61].

General Procedure for the Synthesis of OrgRC Products 3
A vial equipped with a magnetic stirbar containing proline (0.05 equiv.), (S)-(+)-γ-methyltetronic acid 4 (1.0 equiv) and Hantzsch ester 6 (1.0 equiv.) was charged with DCM (0.2 M), followed by addition of aldehyde 5a-f (1.0 equiv.), and the resulting mixture was stirred at room temperature until the completion of the reaction as monitored by TLC. After completion of the OrgRC reaction, the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product 3a-f was used for the next step without purification.

General Information
The 1 H NMR and 13 C NMR spectra were recorded at 400 or 500 MHz and 100 or 125 MHz, respectively. The chemical shifts are reported in ppm downfield to TMS (δ = 0) for 1 H NMR and relative to the central CDCl 3 resonance (δ = 77.0) for 13 C NMR. In the 13 C NMR spectra, the nature of the carbons (C, CH, CH 2 or CH 3 ) was determined by recording the DEPT-135 experiment and is given in parentheses. The coupling constants J are given in Hz. Column chromatography was performed using Acme's silica gel (particle size 0.063-0.200 mm). High-resolution mass spectra were recorded on micromass ESI-TOF MS. IR spectra were recorded on JASCO FT/IR-5300 (JASCO Corporation, Tokyo, Japan) and Thermo Nicolet FT/IR-5700 (Thermo Electron Corporation, Waltham, Madison, USA). For thin-layer chromatography (TLC), silica gel plates Merck 60 F254 (Merck KGaA, Darmstadt, Germany) were used and compounds were visualized by irradiation with UV light and/or by treatment with a solution of p-anisaldehyde (23 mL), conc. H 2 SO 4 (35 mL), acetic acid (10 mL) and ethanol (900 mL) followed by heating.
Experimental procedures and characterization data ( 1 H NMR, 13 C NMR and HRMS) can be found in Supplementary Materials.

Materials
All solvents and commercially available chemicals were used as received without further purification unless otherwise stated. Optically pure (S)-(+)-γ-methyltetronic acid 4 was prepared according to the literature procedure from (S)-(−)-ethyl lactate [61].

General Procedure for the Synthesis of OrgRC Products 3
A vial equipped with a magnetic stirbar containing proline (0.05 equiv.), (S)-(+)-γmethyltetronic acid 4 (1.0 equiv) and Hantzsch ester 6 (1.0 equiv.) was charged with DCM (0.2 M), followed by addition of aldehyde 5a-f (1.0 equiv.), and the resulting mixture was stirred at room temperature until the completion of the reaction as monitored by TLC. After completion of the OrgRC reaction, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The crude product 3a-f was used for the next step without purification.

General Procedure for the Synthesis of Products 2 through OrgRC and Palladium-Mediated Reductive Deoxygenation
Step 1: A vial equipped with a magnetic stirbar containing proline (0.05 equiv), (S)-(+)-γ-methyltetronic acid 4 (1 equiv) and Hantzsch ester 6 (1 equiv) was charged with DCM (0.2 M), followed by addition of aldehyde 5 (1 equiv), and the resulting mixture was stirred at room temperature until the completion of the reaction as monitored by TLC. After completion of the OrgRC reaction, DIPEA (2 equiv) was added to it. The reaction mixture was cooled to −78 • C and Tf 2 O (1.5 equiv, freshly distilled over P 2 O 5 ) was added to it drop wise. After 30 min. (or completion of the reaction), the reaction mixture was quenched with saturated NH 4 Cl solution and partitioned between DCM (15 mL × 3) and water. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The crude enol-triflate product was used for the next step without purification.

General Procedure for the Synthesis of Products 2 through Silica-Mediated Reductive Deamination
Step 1: Compound 3 (1 equiv) was taken in a dry round bottom flask equipped with a Dean-Stark apparatus and reflux condenser in dry toluene (20 mL). Pyrrolidine (1.5 equiv) was added to it followed by catalytic p-TSA. The mixture was refluxed at 130 • C. After completion of the reaction, the mixture was concentrated and purified by column chromatography (neutral alumina) to get 7.
Step 2: Procedure for the reduction of enaminone derivative: Compound 7 (1 equiv) was taken in MeOH and catalytic methyl orange was added to it. The mixture was acidified with a few drops of 2N HCl in MeOH so as to retain the deep red color of the indicator. NaBH 3 CN (2.5 equiv) was added in portions with simultaneous addition of acid to maintain the pH. After completion of the reaction, MeOH was removed under reduced pressure. The residue was diluted with water, neutralized with 1N NaOH and extracted with EtOAc (10 mL × 3). The combined organic layer was evaporated and the crude diastereomeric mixture of aminolactones was refluxed in toluene (6 mL) with silica gel for 7 h to get the product 2.

Conclusions
In conclusion, we have developed a common methodology for the high-yield total synthesis of important butenolide natural products, from readily available simple substrates through the combination of organocatalytic reductive coupling and palladium-mediated reductive deoxygenation or organocatalytic reductive coupling and silica-mediated reductive deamination reaction sequences as the key steps. This high-yield sequential reductive protocol is an ideal method to synthesize the entire family of butenolide natural products.
Supplementary Materials: The following are available online. Experimental procedures, and characterization data ( 1 H NMR, 13 C NMR, and HRMS) can be found in Supplementary Materials.