Kalkitoxin (1) was isolated from cyanobacterium Lyngbya majuscule in the Caribbean Sea. It is reported that 1 posssesses some intersting biological activities. For example, 1 shows a strong ichtyotoxic activity toward the common gold fish and brine shrimp. Also, kalkitoxin has a strong neurotoxicity (LC_<50>=3.86nM) in cerebellar granule neouron (CGN) as an inhibitor N-methyl-D-aspartate (NMDA) receptor antagonists and is a highly potent blocker of the voltage-depending sodium channel in mouse neuro-2a cells (EC_<50>=1nM). We have been attracted by the structure-activity relationship of kalkitoxins. In present paper, we describe the synthesis of kalkitoxin and its analogues (epimer and demethylated kalkitoxins (nor form) and their biological activity with brine shrimp. The synthesis was started from 15, which was converted to α,β-unsaturaed imide 14 with phosphonate 17. 1,4-Addition reaction to 14 with methyl curprate gave imide 18 as 10 : 1 mixture of diastereomers. The imide 18 was transformed into second 1,4-addition precursor 11 in 9 steps. The conjugate addition reaction of 11 proceeded smoothly to give imide 26 as a single diastereomer, which was derived to 1 via condensation with amine 10, synthesize without racemization by novel method, and highly efficient thiazoline formation with TiCl_4. Kalkitoxin analogues 2-7 were synthesized in the similar manner by simply changing the chiral auxiliary or chiral building block. Finally, the biological activity with 1-7 was evaluated as LC_<50> toward brine shrimp.
