Total synthesis of diplodialides C and D

A highly convergent, stereoselective total synthesis of diplodialides C and D is described. The protocol involves the use of regioselective ring opening of a chiral epoxide, sequential double alkylation of 1,3-dithiane with a bromide and a chiral epoxide, hydroboration and Yamaguchi macrolactonisation as key steps


Introduction
2][3] Diplodialides (C(1), and D(1a)) are the first 10-membered lactone pentaketides (Figure 1), which were isolated from the plant pathogenic fungus Diplodia pinea (IFO 6472) by Wada and Ishida. 4,5Diplodialides possess unique biological activity, i.e., inhibitory activity against progesterone 11α-hydroxylase in vegetable cell cultures of Rhizopus stolonifer at 125 ppm.The absolute stereochemistry of diplodialides C and D is (3R, 9R), as determined by Wada ][9][10][11][12] The first total synthesis of (±)-diplodialide C was reported by Wakamatsu et al. 7 in 1977, using their own methodology, from enediol-bis(trimethylsilyl) ether which is prepared by acyloin condensation of diethyl adipate in the presence of trimethyl chlorosilane and methyl lithium.Later, Sharma et al. 11 reported the stereoselective synthesis of diplodialides-B,C using a combination of Jacobsen's hydrolytic kinetic resolution and Sharpless epoxidation, further ring-closing metathesis strategy was used for the construction of the lactone ring.Recently, Pratapareddy et al. 12 reported the asymmetric total synthesis of diplodialide C using Grubb's cross-metathesis reaction as a crucial step.In this context, most of the research groups only focused on the total synthesis of diplodialide A, B and C and to the best of our knowledge, no reports were found in the literature regarding the total synthesis of diplodialide D. Intriguing by this, in this communication, we report our successful total synthesis of diplodialides C 1 and D 1a using sequential double alkylation of 1,3-dithiane with a bromide and a chiral epoxide and Yamaguchi macrolactonisation as the key steps in a simple and highly convergent approach.

Results and Discussion
Our retrosynthetic approach to the synthesis of 1 and 1a is outlined in Scheme 1.The target molecules 1 and 1a could be made from a common intermediate, hydroxyacid 2, by intramolecular Yamaguchi macrolactonization, whereas 2 could be synthesized from the coupling reaction of two key fragments: the bromo compound 4 and the chiral epoxide 5, with 1,3 dithiane, while both bromo compound 4 and chiral epoxide 5 could be obtained from the known chiral epoxide 6.

Scheme 1. Retrosynthesis of diplodialides C and D.
As shown in the retrosynthesis (Scheme 1), our approach to the total synthesis of the title molecule was initiated by regioselective opening of the known chiral epoxide 13 6 with vinylmagnesium bromide in the presence of CuI in THF, at −10 °C to room temperature, furnishing the tosylate 7 in 84% yield, which on nucleophilic cyclization in the presence of K 2 CO 3 in MeOH afforded epoxide 5 in 86% yield.On the other hand, tosylate 7 on treatment with LiAlH 4 in THF at 0 o C for 12 h under a nitrogen atmosphere gave 8 in 92% yield, which on subsequent silyl ether formation of the alcohol using TBSCl in the presence of imidazole in CH 2 Cl 2 at 0 o C to rt for 6 h, provided the silyl ether 9 in 87% yield.Next, silyl ether 9 was subjected to hydroboration with BH 3 -DMS followed by treatment with sodium hydroxide and H 2 O 2 to give alcohol 10 in 77% yield.Treatment of alcohol 10 with CBr 4 and PPh 3 in CH 2 Cl 2 at 0 o C to rt for 4 h gave the bromide 4 in 81% yield.The detailed synthetic scheme is depicted in Scheme 2. Reagents and conditions: (a) vinylmagnesium bromide, copper(I) iodide, dry THF, - Having both the bromo compound 4 and the epoxide 5 in hand, construction of the macrocyclic framework was achieved as shown in Scheme 3.
Sequential double alkylation of 1,3-dithiane 14 with the bromide 4 and chiral epoxide 5 led to the alcohol 11 in 74% yield, which on subsequent treatment with PMBBr and NaH in tetrahydrofuran solvent at 0 o C to rt for 8 h afforded 12 in 87% yield.Next, ozonolysis of 12 followed by oxidation of resulting aldehyde with NaClO 2 and NaH 2 PO 4 , 2-methyl-2-butene in aqueous t-butanol afforded the acid 13 in 77% yield.In the next step, the silyl protecting group (TBS) was removed from acid 13 using TBAF to afford the desired hydroxy-acid segment 2 in 91% yield.
After successful synthesis of the intermediate 2, the next aim was macrolactonization and further transformation to complete the synthesis of diplodialides C (1) and D (1a).Accordingly, the hydroxy-acid 2 was subjected to macrolactonisation under Yamaguchi high-dilution conditions 15 using 2,4,6-trichlorobenzoyl chloride and Et 3 N in dry THF to afford the lactone 14 in 71% yield.Removal of the PMB group from lactone 14 was achieved using DDQ in aq.CH 2 Cl 2 to give the compound 15 in 91% yield.
Finally, removal of the dithiane moiety from 15 under reductive conditions 16 furnished diplodialide C (1) in 65% yield.On the other hand, deprotection of the 1,3-dithiane group in compound 15 with CaCO 3 and I 2 in THF:H 2 O 17 for 5 h afforded the diplodialide D (1a) in 68% yield.The analytical data of our synthetic compounds are in good agreement with the reported data. 4,5hus, we have accomplished the total synthesis of diplodialides C (1) and D (1a) in an enantioselective way.

Scheme 3. Synthesis of diplodialides C (1) and D (1a).
In summary: we have developed a concise and highly convergent approach to the total synthesis of diplodialides C (1) and D (1a).The present strategy involves regioselective ring opening of a chiral epoxide, sequential double alkylation of 1,3-dithiane with a bromide and a chiral epoxide and Yamaguchi macrolactonisation as the key steps.The syntheses of other related compounds are underway in our laboratory.

Experimental Section
General

(S)-2-Allyloxirane (5).
Copper iodide (0.75 g, 2.61 mmol) was gently heated under vacuum and slowly cooled under nitrogen atmosphere, then THF (10 mL) was added, the resulting suspension was cooled to −10 o C and vinylmagnesium bromide (43.4 mL, 43.41 mmol, 1.0 M in THF, 1.1 eq) was added at the same temperature while stirring.A solution of epoxide 6 (9.0 g, 39.47 mmol) in dry THF (20 mL) was added to the above reagent and the mixture was stirred at -10 o C for 2 h.After completion of the reaction, the reaction was quenched with saturated aqueous NH 4 Cl, extracted into EtOAc (3 × 30 mL), the combined organic layers was washed with brine, dried over Na 2 SO 4 and concentrated to give the tosylate 7 (8.47 g, 84%) which was used for the next step without purification.
To a stirred solution of tosylate 7 (4.5 g, 17.57 mmol) in MeOH (20 mL) at 0 o C was added K 2 CO 3 (4.85g, 35.15 mmol) and the resultant mixture was allowed to stir for 1 h at rt.After completion of reaction as indicated by TLC, the reaction was quenched by the addition of pieces of ice and the MeOH was evaporated.The concentrated reaction mixture was then extracted with EtOAc (3 x 30 mL), the combined organic layers was washed with brine, dried (Na 2 SO 4 ), and concentrated.The crude product was purified by column chromatography (60-120 silica gel, 5% EtOAc in pet.ether) to afford 5 (1.26 g, 86%) as a colorless liquid. 1  (R)-4-(tert-Butyldimethylsilyloxy)pentan-1-ol (10).To a stirred solution of 9 (2.1 g, 10.5 mmol) in dry THF (30 mL) at 0 o C, a solution of borane-dimethylsulfide (2.0 N solution in THF) (6.3 mL, 12.63 mmol) was added dropwise and allowed to stir for 4 h at rt.After that, the reaction mixture was cooled to 0 o C and treated with 2N NaOH solution (15.7 mL) and H 2 O 2 (2.8 mL) dropwise and stirred for 3 h at rt.After the completion of the reaction, it was washed with water and extracted with EtOAc (2 × 50 mL).The organic layers were combined, dried (Na 2 SO 4 ) and evaporated under reduced pressure.The crude product was purified by column chromatography (60-120 silica gel, 25% EtOAc in pet.ether) to afford the silyloxy-pentanol 10 (1.76 g, 77%) as a colorless liquid.
13All chemicals and reagents were obtained from Aldrich (Sigma-Aldrich, St. Louis, MO, USA), Lancaster (Alfa Aesar, Johnson Matthey Company, Ward Hill, MA, USA) and were used without further purification.Reactions were monitored by TLC, performed on silica gel glass plates containing 60 F-254, and visualization on TLC was achieved by UV light or iodine indicator.1Hand13CNMR spectra were recorded on 300 and 75 MHz instruments.Chemical shifts (δ) are reported in ppm downfield from internal TMS standard.ESI spectra were recorded on Micromass, Quattro LC using ESI+ software with capillary voltage 3.98 kV and ESI mode positive ion trap detector.Melting points were determined with an electrothermal melting point apparatus.FT-IR spectra were taken on IR spectrophotometer by using NaCl optics.Optical rotation values are recorded on digital polarimeter at 25 o C.