Total Synthesis of (−)‐Amphidinolide K

Abstract

À)-Amphidinolide K (1; see Scheme 1) is a member of the cytotoxic macrolides that were isolated by Kobayashi and coworkers from the laboratory-cultured dinoflagellates Amphidinium sp., which are symbionts of the marine flatworms Amphiscolops sp. found in Okinawan. [1] Amphidinolide K (l) is known to possess cytotoxic activity against L1210 (IC 50 = 1.65 mg mL À1 ) and KB (IC 50 = 2.9 mg mL À1 ) cancer cells in vitro. The total synthesis of (+)-amphidinolide K reported by Williams and Meyer [2] has clarified the problems concerning configurational ambiguities at C2, C4, and C18, and as a result (À)-amphidinolide K (1) was found to be the natural product. The unique structural features and potent bioactivity of 1 elicited considerable interest in the synthetic community, [3] and herein we wish to report the results of our recent efforts on the synthesis of this intriguing molecule.In the retrosynthetic analysis, epoxidation of the allylic alcohol intermediate A (R = H) was envisaged as the final step (Scheme 1). The macrolide intermediate A would be obtained by lactonization of the seco acid B, which would in turn be synthesized through the Julia-Kocienski reaction [4] of aldehyde C and sulfone D. Fragment C would be obtained from fragment E (Y = B(pinacol)) by a Suzuki coupling reaction. Fragment E would be the product of the enyne cross-metathesis reaction [5] of alkynyl boronate F and alkene G. In another key step, a radical cyclization reaction [6] of the homopropargylic b-alkoxyacrylate I would provide the methylidene-substituted oxolane intermediate H en route to fragment D.In practice, b-alkoxyacrylate 4 was prepared from the known homopropargylic alcohol 3 [7] (Scheme 2). Next, the radical cyclization reaction [6] of 4 in the presence of tributylstannane and triethylborane proceeded efficiently and gave mainly (16:1) the cis-2,5-disubstituted oxolane intermediate 5 after acidic destannylation. The corresponding aldehyde was converted into the homologous aldehyde 6, which was then treated with alcohol 7 [8] to produce the homoallylic alcohol 8. After protection of the alcohol as the benzoate derivative, 1phenyl-1H-tetrazolyl sulfone 9 was prepared by using the standard procedures as outlined.Olefin 12 was prepared from the known alcohol 11 [9] through mesylation and subsequent reduction (Scheme 3). Alkyne 14 was prepared from (R)-glycidol (13) through protection of the alcohol with THP, then treatment with lithium TMS-acetylide, protection with a TBS group, and hydrolytic cleavage of the alkynyl TMS group. Then alkynyl boronate 15 was prepared from alkyne 14 under standard reaction conditions. Subsequently, the enyne cross-metathesis reaction [5,10] of 15 with olefin 12 proceeded effectively in the presence of the second-generation Grubbs catalyst to yield a mixture (7.5:1) that favored the desired E isomer 16. The use of alkynyl boronate 15 in the enyne cross-metathesis reaction was important; the use of methyl-substituted alkynes did not yield useful amount of the cross-metathesis products. For the syn...

Recent Progress on Enyne Metathesis: Its Application to Syntheses of Natural Products and Related Compounds

“…Recently, same group succeeded in the total synthesis of amphidinolide K using intramolecular cross enyne metathesis in the key step [ 115 ].…”