Isolation and Total Syntheses of Cytotoxic Cryptolactones A₁, A₂, B₁, and B₂: α,β-Unsaturated δ-Lactones from a Cryptomyzus sp. Aphid

Abstract

The cryptolactones A1, A2, B1, and B2, which are α,β-unsaturated δ-lactones, were isolated from a Cryptomyzus sp. aphid. The structures were established by 1-D and 2-D NMR spectra and CI-HRMS. Their absolute configurations were determined with the Kusumi-Mosher method, combined with asymmetric total syntheses. The syntheses were accomplished with the Mukaiyama aldol reaction and olefin metathesis, which utilized the second-generation Grubbs catalyst for the key steps. These compounds exhibited cytotoxic activity against human promyelocytic leukemia HL-60 cells with IC50 values of 0.97-5.3 μM.

Total Syntheses and Cytotoxic Evaluations of Cryptolactones A₁, A₂, B₁, B₂, and Their Derivatives

“…The construction of α,β-unsaturated δ-lactone could be carried out by ring-closing metathesis reaction of 7 at the late stage of the synthesis as described in our previous paper. 10) Since elongating the side chains with various lengths could be suitable for Mukaiyama aldol reaction with silyl enol ether, 12,13) aldehyde 8 could serve as a common intermediate. The aldehyde 8 would be synthesized from known optically active epoxide 9 by the addition of a vinyl unit and subsequent acylation.…”

“…[14][15][16] Our synthesis commenced with preparation of common intermediate (S)-8 from (R)-9 as previously reported. 10) With the common intermediate (S)-8 in hand, we next examined the construction of the α,β-unsaturated δ-lactone moiety. Mukaiyama aldol reaction of silyl enol ether 10a-c with (S)-8 using BF 3 •OEt 2 gave 7a-c in 59% (n = 7), 52% (n = 9) and 40% (n = 4) yield, respectively, with around 1 : 1 mixture of the diastereomers in all case.…”

“…We found that 1, 2, 3, and 4 exhibited cytotoxic activities with IC 50 values of 1.2, 5.3, 0.97, and 4.9 µM, respectively. 10) The IC 50 value of doxorubicin, a positive control compound, was 0.14 µM. These results may indicate that the length of the side chain at the 5-position influences the activity.…”

“…6,7) We also accomplished total syntheses of two pigments, furanaphin 8) and xanthouroleuconaphin. 9) Recently, we also focused on bioactive organic compounds in the colorless aphid, Cryptomyzus sp., which was observed feeding on Ribes fasciculatum (family; Saxifragaceae, Japanese common name: yabusanzashi), and we obtained four colorless polyketides, cryptolactones A 1 (1), A 2 (2), B 1 (3), and B 2 (4) 10) ( Fig. 1).…”

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…264) [685]; (5) six-membered ring α,β-unsaturated lactones, including total syntheses of cryptolactones A1, A2, B1, and B2 (e.g. 265) [686], synrotolide (e.g. 266) [687,688], coibacins A and B [689], boronolide, anamarine and epi-spicegerolide [690], noviose (and an alternative route based on sixmembered ring allylic ether-forming RCM followed by allylic oxidation) [691], an intermediate for brevipolide…”