First Total Synthesis and Structural Reassignment of (−)-Aplysiallene

Abstract

The first total synthesis of (-)-aplysiallene has been completed in 16 steps, and features a key sequential Mukaiyama aerobic oxidative cyclization to prepare the fused bis-THF core. The original stereochemical assignment has been revised as shown.Aplysiallene 1 was first isolated in 1985 from the red alga Laurencia okamurai Yamada by Suzuki and Kurosawa. 1 Its intriguing structural features include 1) a unique cis-fused 2,6-dioxabicyclo[3,3,0]octane skeleton consisting of two trans-tetrahydrofuran rings, 2) an unusual (E,E)-bromodiene side chain, and 3) an Rbromoallene 2 appendage. The absolute stereochemistry of 1 was assigned according to its strong negative optical rotation (due to the allene 3 ) and the relative stereochemistry was assigned by NOE correlations and comparison with kumausallene. 4 In 2001, Okamoto also reported the isolation of 1 from the sea hare aplysia kurodai and found it functions as a Na + /K + ATPase inhibitor with IC50 = 0.7 μM. 5 In this communication, we(1) Suzuki, M.; Kurosawa, E. Phytochemistry 1985, 24, 1999-2002 (2) For review on bromoallene natural products, see: HoffmannRöder, A.; Krause, N. Angew. Chem. Int. Ed. 2004, 43, 1196-1216 (3) Lowe, G. report the first asymmetric total synthesis of aplysiallene and provide evidence for its structural revision. 6 It was envisaged that the R-bromoallene substituent could be prepared from the corresponding R-propargyl alcohol 2a, which in turn should be accessible by an antiselective alkynylation between aldehyde 3 and trimethylsilylacetylene. 7 Although we are unaware of precedence for the direct introduction of the bromodiene subunit, a plausible derivation could be from alcohol 4, which would be stereoselectively prepared by sequential oxidative cyclization 8 of the known (R,R)-diol 5.The synthesis began with reaction of (S,S)-diepoxybutane 6 with vinyl magnesium bromide in the presence of CuBr to give the (S,S)-diol ent-5 in 72% yield. Note the stereochemistry of ent-5 is opposite to that required for the reported natural product, so this should in principle lead to a synthesis of ent-1. While the isolated yield of 13b was only 35%, the dienes 13a and 13b were separable by flash chromatography on gram scale, and unwanted 13a can be recycled by ozonolysis followed by a NaBH4 work up to give alcohol ent-4 in 53% yield. In contrast, attempted conversion of 13a directly into 9 by ozonolysis with a PPh3 work up resulted in complete decomposition of 13a.With the bromodiene side chain at hand, deprotection of the silyl ether 13b by treatment with TBAF followed by Swern oxidation afforded the highly labile aldehyde ent-3 (81%, 2 steps), which was used immediately in the following addition step. As expected, alkynylation of ent-3 with the titanium acetylide of trimethylsilylacetylene (generated in situ with nBuLi and ClTi(OiPr)3) gave ent-2 (13) Initial efforts were undertaken to furnish the bromodiene side chain on a model system by a one-step olefination strategy, but such reactions under various conditions consistently gave ...

Survey of marine natural product structure revisions: A synergy of spectroscopy and chemical synthesis

“…Structural motifs misassigned on the basis of NOEs include epoxides (calafianin, 96–98 symbiodinolide 99, 100 ), cyclopropyl rings (clavosolide A, 101, 102 laurentristich-4-ol 103, 104 ), bridges (vannusals A and B 105–107 ), fused ring junctions (itomanallene A, 108, 109 asperdimin, 110, 111 aplysiallene 112, 113 ), polyethers (aplysiol B, 114, 115 azaspiracids 116–119 ), vicinal polyols (amphidinolide H2, 120, 121 hyrtiosterol, 122, 123 pericosine A 124, 125 ), sugars (callipeltoside C; 126, 127 fusapyrone and deoxyfusapyrone, 128, 129 Table 6) and macrolides (palmerolide A, 130–132 neopeltolide 133, 134 ).…”

Stereoselective Halogenation in Natural Product Synthesis

“…Whereas Pagenkopf and co-workers could prepare the undesired anti-diastereomer of propargylic alcohol 34 by the substrate-controlled addition of an alkynyltitanium reagent to the aldehyde,attempts to produce the desired syn-diastereomer was unsuccessful even under reagent-controlled, asymmetric alkynylation conditions. [18] Eventually,t he syn-configuration was generated via the Mitsunobu reaction of 34.T hrough these synthetic studies, the structure of (À)-aplysiallene was revised as 36.A lternatively and more efficiently,adirect installation of sulfonate with inversion of configuration was demonstrated by Kim and Scheme 2. Allylic halogen displacement during attempted syn-dichlorination.…”

The direct oxidative diene cyclization and related reactions in natural product synthesis

“…[125] and the bis-THF acetogenin bullatacin by Pagenkopf and co-workers [126]. The latter group also employed this methodology in the total synthesis of aplysiallene [127], and more recently to bovidic acid [128] and cyclocapitelline [129]. …”