Stereoselective total synthesis of antiplasmodial resorcylic acid lactone paecilomycin F

A facile and convergent approach for the total synt hesis of 14-membered resorcylic acid lactone paecilomycin F is described. The synthesis emanates from the readily available inexpensive (+)diethyl L-tartrate. Mitsunobu etherification, Still e coupling and ring-closing metathesis are key steps in the synthesis.


Introduction
The impressive biological properties i.e., antifungal, 1 antibiotic, 2 inhibition of ATPase activity of HSP90, 3 exhibited by the first resorcylic acid lactone (RAL) radicicol (Figure 1), 4 a 14membered benzannulated macrolide, has attracted significant attention to the related RALs 5 (both synthetic and natural RALs) which have emerged over the last two decades.The resorcylic acid lactones with unique structural architecture are also found to exhibit potent biological activities ranging from antimalarial, 6 antiviral, antiparasitic, 7 antifungal, 8 cytotoxic, 9 estrogenic 10 to nematocidal 11 activities.3][14][15] Chen et al. have recently isolated six new resorcylic acid lactones, namely paecilomycin A-F [16][17][18] (Figure 1) along with other known RALs from the mycelial solid culture of Paecilomyces fungus SC0924.Interestingly, when these compounds were subjected to screening for plasmodicidal activity, paecilomycin F was found to display antiplasmodial activity against Plasmodium falciparum line 3D7 with an IC 50 value of 20.0 nM and moderate activity against P. falciparum line Dd2.Eventhough, the structures of these compounds were determined by extensive NMR analysis and chemical correlations, our own investigation for the total synthesis of paecilomycin E and F lead to the structural reassignment 18,19 for these two molecules and was however later reconfirmed by total synthesis from Mohapatra et al 20 and also our group. 21In continuation of our work on the total synthesis of lactonic natural products, [22][23][24][25][26][27] herein we present a facile and convergent strategy for the total synthesis of paecilomycin F. 28

Results and Discussion
Our retrosynthesis is based on a convergent approach and involved two key intermediates, an aliphatic chiral chain 8 comprising a double bond and a secondary alcohol, and an aromatic acid (9).These two compounds can be coupled in an esterification followed by a ring closing metathesis to provide the precursor skeleton for the target molecule.The aromatic acid 9 can be synthesized from 2,4,6-trihydroxybenzoic acid in five known steps, and the aliphatic side chain 8 can be synthesized from the alcohol 11 by a four step sequence, i.e. oxidation, allylation, MOM protection of the resulting allyl alcohol, and deprotection of the TBDPS moiety (Scheme 1).The alcohol 11 can be synthesized from alkyne 12 in a one-pot reaction through hydrogenation, which in turn can be synthesized by a coupling reaction of terminal alkyne 13 with triflate 14.
The synthesis began with isopropylidene protection 29 of the readily available (+)-diethyl Ltartrate to get the corresponding acetonide product 15 followed by the diester reduction with lithium aluminium hydride to deliver 1,4-diol 16.The diol 16 was sequentially protected as the corresponding benzyl ether 17 by treatment with benzyl bromide and NaH and activated as the triflate 14 by triflic anhydride in presence of 2,6-lutidine to set up the stage for coupling with the terminal acetylene 13.The alkyne 13 (obtained from the commercially available (S)-but-3-yne-2ol after protection with TBDPSCl) was metalated with n-BuLi in presence of hexamethylphosphoramide (HMPA) and treated with triflate 14 to furnish the di-substituted alkyne 12. 30 One pot benzyl deprotection and alkyne reduction was achieved smoothly with Pd/C under hydrogen atmosphere to provide the primary alcohol 11 in good yield (Scheme 2).The alcohol 11 was oxidized under Swern conditions 31 to yield the aldehyde and then subjected to allylation with allyl bromide in presence of Zinc 32 and NH 4 Cl and further treated with MOM-Cl to furnish the corresponding MOM ethers.The product obtained after allylation was a mixture of diastereomers, which were inseparable and were directly treated with MOM-Cl to get the corresponding MOM ethers (9:1) which were easily separable by column chromatography.Based on the earlier experience for the allylation reaction, 19,21 we proceeded further with the major diastereomer 18.Thus, treatment of the major diastereomer 18 with TBAF resulted in the formation of 8, the key side chain fragment with the required stereochemistry.
The other key fragment aromatic acid 9 was synthesized starting from 2,4,6trihydroxybenzoic acid 10 (THBA) following known protocols as shown in Scheme 3. Thus, THBA 10 was treated with trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) following Danishefsky's protocol 33 to get the acetonide protected product 19.The regioselective methylation of 19 at para-position to carboxylic functionality was easily achieved with MeOH under Mitsunobu conditions 34 to yield 20 in 85% yield.The free hydroxyl group in 20 ortho-to carboxylic acid functionality was activated by converting it to the corresponding triflate 21 with triflic anhydride and later subjected to Stille coupling 35 with n-tributyl(vinyl tin) to furnish the vinylated aromatic ester 22 (Scheme 3).Ester hydrolysis of 22 with LiOH at room temperature provided the aromatic acid 9 in 86% yield, which can be used for coupling reaction towards the target synthesis.With the two key intermediates 8 and 9 in hand, the stage was set to proceed further for coupling to get the macrocyclic core skeleton.This was performed under Steglich esterification conditions 36 to furnish the ester 23 in 67% yield.Although, our initial attempts at ring-closing metathesis of 23 with Grubbs first generation catalyst did not succeed and ended up with the recovery of starting material, the reaction was successful with Grubbs second generation catalyst 37 in CH 2 Cl 2 at room temperature to provide the desired core structure 24 exclusively in 85% yield (Scheme 4).The geometry of the product was characterized based on the coupling constant value of 14.9 Hz for the olefinic protons.The compound 24 when exposed to 2N HCl for 15 h underwent complete deprotection of MOM and acetonide functionalities furnishing the target molecule paecilomycin F. The spectroscopic data of the synthesized product was in full agreement with the reported data 16,18 of the natural product (See table 1).

Conclusions
We have achieved a total synthesis of paecilomycin F from the readily available (+)-diethyl Ltartrate.Ring closing metathesis and standard DCC, DMAP coupling (Steglich esterification) have been once again pivotal for constructing the macrocycle core.The synthesis involved 12 steps with an overall yield of 14 %.Synthesis of other paecilomycins are currently being investigated in our laboratory.

Table 1 .
13mparative 1 H and13C NMR data of natural and synthetic paecilomycin F Scheme 3. Synthesis of aromatic acid 9. Scheme 4. Conclusion of synthesis of paecilomycin F 7.