Total Synthesis and Cytotoxic Activity of 7-O-Methylnigrosporolide and Pestalotioprolide D

Abstract

A convergent total synthesis of 7-O-methylnigrosporolide and pestalotioprolide D has been accomplished in 17 longest linear steps starting with 1.7% and 2.6% overall yields, respectively, starting from (S)-propylene oxide and known (S)-benzyl glycidyl ether. Our synthesis exploited acetylide addition and Shiina macrolactonization to assemble the macrocycle, Lindlar reduction, Wittig and Still–Gennari olefination to construct the three olefins as well as a Jacobsen hydrolytic kinetic resolution to install the stereogenic center. The selection of silyl protecting group of C-4 alcohol was crucial for final deprotection step. Our synthesis also led to a hypothesis that pestalotioprolide D could be an artifact of 7-O-methylnigrosporolide. Cytotoxic activity of both synthetic compounds against six human cancer cell lines was evaluated. Synthetic pestalotioprolide D showed more potent cytotoxic activity against all cancer cell lines tested than 7-O-methylnigrosporolide, and the SiHa cervical cancer cell line was the most sensitive cell to both synthetic compounds.

Total Synthesis and Biological Evaluation of Seiricuprolide and Pestalotioprolide B

“…[13,15] Synthesis of macrolides 4 and 5 started with preparation of chiral epoxy aldehyde 14. The first method was the use of our previously reported Z-allylic alcohol intermediate 15, which was obtained from epichlorohydrin in 8 steps via the key Jacobsen hydrolytic kinetic resolution and Still-Gennari olefination, [16] as epoxidation substrate according to Baltas's protocol. [13] Z-Allylic alcohol 15 was therefore subjected to m-CPBA in the presence of NaHCO absolute configuration of newly formed epoxides could not be determined by comparison of J 3/4 vicinal coupling constants due to unclear multiplicity of H3 and H4 signals of the major product 19 b.…”

“…Wittig olefination would be employed to generate the C2−C3 ( E )‐α,β‐unsaturated ester moiety of both 10 and 11 . The Z ‐ or E ‐double bond at C8−C9 (of 10 or 11 , respectively) would be derived from selective reduction of chiral propargylic alcohol 12 , which would in turn be elaborated from acetylide addition of known chiral alkyne 13 [9,16] prepared from ( S )‐propylene oxide to chiral epoxy aldehyde 14 . It was anticipated that the adjacent chiral epoxide of aldehyde 14 would direct the stereoselectivity of this acetylide addition step [12] .…”

“…Synthesis of macrolides 4 and 5 started with preparation of chiral epoxy aldehyde 14 . The first method was the use of our previously reported Z ‐allylic alcohol intermediate 15 , which was obtained from epichlorohydrin in 8 steps via the key Jacobsen hydrolytic kinetic resolution and Still‐Gennari olefination, [16] as epoxidation substrate according to Baltas's protocol [13] . Z ‐Allylic alcohol 15 was therefore subjected to m ‐CPBA in the presence of NaHCO 3 at 0 °C to provide the separable epoxy alcohol diastereomers 19 a (18 %, R f =0.57 in 2 % EtOAc/CH 2 Cl 2 ) and 19 b (50 %, R f =0.38 in 2 % EtOAc/CH 2 Cl 2 ) in 68 % combined yield (dr=1 : 2.7) (Method I, Scheme 2B).…”

“…Since m ‐CPBA epoxidation of 15 provided the modest diastereomeric ratio, allylic alcohol substrate 15 may not be suitable for gram‐scale synthesis. In addition, although our reported preparation of 15 is efficient, it is somewhat lengthy and requires the use of some relatively expensive reagents, [16] leading us to screen another method to efficiently access the requisite β‐epoxide.…”