(−)-Complanine, an inflammatory substance of marine fireworm: a synthetic study

Summary The synthesis of (−)-complanine, an inflammatory substance of Eurythoe complanata, was accomplished by a “chiral synthon” approach. The absolute configuration of this molecule was determined to be R.

From a structural perspective, complanine possesses amphipathic properties due to its characteristic unsaturated carbon chain and a γ-aminobutyric acid (GABA)-derived trimethylammonium substructure. Natural complanine shows negative optical rotation ([α] D 25 = −10.0 (c 1.0, H 2 O)), but the configuration of the hydroxy-substituted carbon atom has not been revealed because derivatization to determine the absolute configuration failed due to the lack of availability of the natural product. In this study, the absolute structure of complanine was unambiguously determined by means of synthetic methodology by a "chiral synthon" approach. Related amino alcohols possessing olefins from marine natural resources have been identified [3,4], but synthetic studies of these compounds have not been reported.

Results and Discussion
Our synthesis started from the known compound 3 [5,6] that could be derived from (R)-malic acid, (R)-2, in three steps (1. BH 3 ·SMe 2 ; 2. cat. TsOH, Et 2 CO; 3. TsCl, pyridine) (Scheme 1). The resultant tosylate 3 was treated with lithium acetylide ethylenediamine complex to give the terminal acetylene 4 in 51% yield [7]. The bromomagnesium salt of 4 generated with EtMgBr was successively treated with 1-iodopent-2-yne in the presence of CuI to give the corresponding diyne compound 5 in 43% yield [8]. The partial reduction was achieved by using Lindlar catalyst to give the desired Z olefin, which was then subjected to acidic deprotection to afford the diol 6 in 43% yield (2 steps). The primary alcohol was converted into the azide via the mesylate (79%), which was then successfully converted into the corresponding amino alcohol 7 (78%). From a spectral perspective, the amino alcohol 7 was identical to the degradation product of natural complanine (NMR, MS and R f value of TLC).
The activated ester (hydroxysuccinimide ester) of 4-(trimethylammonio)butanoate was synthesized from the commercially available γ-aminobutyric acid (GABA) in two steps (1. MeI, NaHCO 3 , MeOH, rt, 24 h; 2. HOSu; DCC, CH 3 CN, rt, 24 h) [9]. A reaction occurred between the amino alcohol and the activated ester (2.0 equiv) in MeOH to give the desired (−)complanine in 44% yield. The synthesized product was identical to the natural material in all its spectral data, including optical rotation ([α] D 20 = −9.9 (c 0.12, H 2 O)). The configuration of the hydroxy-substituted carbon atom was determined to be R. The configuration is comparable to that of the related compound, obscuraminol, isolated from an ascidian from Tarifa Island, Spain. Obscuraminol possesses a vic-amino alcohol and an unsaturated carbon chain; its absolute configuration (of the OH adjacent carbon atom) is R [4]. The similarity of the structures suggests a close relationship in their biosynthetic pathways. It can be hypothesized that complanine is biosynthesized from glycine, based on comparison with serine-or alaninederived natural products [3,4,10,11].
The enantiomer of the natural product, (+)-complanine, was also successfully synthesized from the corresponding (S)-malic acid, (S)-2, in 10 steps, including coupling with 4-(trimethylammonio)butanoate. (S)-1 (ent-complanine) showed positive optical rotation ([α] D 23 = 11.1 (c 0.65, H 2 O)); which was in reasonably good agreement with the absolute configuration of the natural product. The biological activities of both enantiomers were examined, but no significant difference between them was observed based on the inflammatory activity on a mouse foot pad. Detailed biological properties (for example, PKC activation) of both enantiomers are under consideration at the present time.
In conclusion, (−)-complanine was successfully synthesized from (R)-malic acid by acetylene coupling and catalytic hydrogenation as key steps. The absolute configuration of the natural product was determined to be R.