Synthesis of the southern furan segment of furanocembranoids

Abstract A convergent synthesis of the southern furan segment of novel furanocembranoids from Croton oblongifolius has been accomplished involving silver-catalyzed cyclization of alkynyl diol as the key step towards 2, 5-disubstituted furan ring formation. Graphical Abstract


Introduction
Khanitha and coworkers identified numerous cytotoxic diterpenoids from Croton oblongifolius, which was used as a folk medicine to treat gastric cancers and ulcers. [1] In 2007, they had isolated novel 14-membered macrocycles called furanocembranoids 1-3 (Figure 1a-c) from the hexane extract of the stem bark of Croton oblongifolius. [2] Eccentrically, the macrocylic frame of these natural products is linked to C2 and C4 positions of furan ring without five-membered lactone, whereas all the natural furanocembranoids has C2 and C5 linkage to furan with a five-membered lactone. [3] Furanocembranoid 1 (1a) and 3 (1c) exhibited cytotoxicity against human tumor cell lines such as BT474 (breast ductal carcinoma), CHAGO (undifferentiated lung carcinoma), Hep-G2 (liver hepatoblastoma), KATO-3 (gastric carcinoma), and SW-620 (colon adrenocarcinoma). [2] The unusual structural feature of novel furanocembranoids 1-3 combined with their biological activity motivated us to explore the synthesis of this molecule. Till date, there are no reports on synthetic efforts toward these novel furanocembranoids, except our recent work wherein fully functionalized acyclic carbon framework has been reported. [4] In this strategy, we were unsuccessful in ring-closing metathesis reaction to complete the total synthesis. Herein, we present the successful realization of our endeavors in our alternative strategy through the synthesis of the southern furan fragment of furanocembranoids.

Results and discussions
The retrosynthetic analysis of furanocembranoids is described in Scheme 1. We envisioned our first target furanocembranoid 1 (1a) to be obtained from the coupling of furan fragment 2 with cyclic phosphonamide 3 through phosphonamide-anion olefination [5] and intramolecular Horner-Wadsworth-Emmons cyclization [6] as the key steps. Furan fragment 2 could be accessed from the coupling of keto-fragment 4 and the alkyne subunit 5 followed by the cyclization of alkynyl-diol. Ketone 4 could be generated from readily accessible b-keto-phosphonate 6 and commercially available diethyl 2isopropylmalonate 7.
As planned, the synthesis of ketone fragment 4 started with the diethyl 2-isopropylmalonate 7, which was subjected to LiAlH 4 -mediated reduction followed by selective silylation using TBDPSCl to give the mono-silylated alcohol 8 in 85% over two steps (Scheme 2). Oxidation of the primary alcohol 8 using DMP in CH 2 Cl 2 provided the corresponding aldehyde, which was subjected to Horner-Wittig olefination with b-keto phosphonate 6 [7] in the presence of Ba(OH) 2 .8H 2 O in wet THF to give the enone 9 in 73% yield over two steps. Next, the reduction of an olefin of the enone 9 in the presence of Pd/C under H 2 atmosphere in EtOAc delivered the saturated ketone 4 in 98% yield (Scheme 2). The synthesis of the protected alkyne 5 has been accomplished following the reported three-step protocol involving opening of methyloxirane with lithiatedtrimethylsilyl acetylene, p-methoxybenzyl (PMB) protection followed by desilylation. [8] Having both the intermediates 4 and 5 in hand, we performed the addition of alkyne on to the ketone to make the alkynyl-diol, key precursor for furan ring formation (Scheme 3). Thus, treatment of ketone subunit 4 with lithiated-alkyne, generated from 5 using nBuLi, at À78 C afforded the propargyl alcohol 10 in 86% yield. Selective deprotection of tert-butyldimethyl silyl (TBS) ether in the presence of PPTS produced the diol 11 in 90% yield. Pleasingly, AgNO 3 -catalyzed cycloaddition [9] of the alkynyl diol 11 in CH 2 Cl 2 at room temperature, provided the desired 2,4-disubstituted furan 12 in 90% yield. The deprotection of tert-butyldiphenyl silyl (TBDPS) ether with TBAF at room temperature in THF furnished the furan 2, exemplifying the entire southern part of furanocembranoid, in 88% yield.

Conclusion
In summary, we have achieved the convergent synthesis of the furan subunit (southern fragment) of structurally novel furanocembranoids. This work demonstrates the utility silver-catalyzed cyclization of alkynyl diol, which facilitated the rapid construction of 2,4-disubstituted furan framework. We believe that the present approach is scalable to complete the total synthesis of furanocembranoids.

Experimental
All the reagents and solvents were purified by usual methods. Reactions were executed in oven-dried round bottom flasks. Crude products were purified by column chromatography on silica gel. Reactions were monitored by thin-layer chromatography. Organic solutions were distilled on a rotary evaporator. 1 H and 13 C NMR spectra were recorded in CDCl 3 solvent on 400 and 500 MHz NMR spectrometers, respectively, at ambient temperature and calibrated against the residual solvent peak. Chemical shifts are reported in parts per million (ppm). Coupling constants (J) are quoted in hertz (Hz). FTIR spectra were recorded on KBr thin films (for liquids). Mass spectra recorded on micro mass VG 70-70 H or LC/MSD trap SL spectrometer operating at 70 eV using direct inlet system. HRMS were recorded on quadrupole time-of-flight (Q-TOF) mass spectrometer equipped with an ESI source.