Total Synthesis and Configurational Assignment of the Marine Natural Product Haliclamide

Abstract

The marine natural product haliclamide has been synthesized based on macrocyclization by ring-closing olefin metathesis. Using either enantiomer of two of the four building blocks that were employed to assemble the diene precursor for the metathesis reaction, three non-natural isomers of haliclamide were also prepared. On the basis of the comparison of the (1)H and (13)C NMR spectra of the individual stereoisomers with literature data for the natural product, the configuration of the previously unassigned stereocenters at C9 and C20 of haliclamide could be determined to be S for both carbons. The absolute configuration of haliclamide thus is 2S, 9S, 14R, 20S. The antiproliferative activity of synthetic haliclamide against several human cancer cell lines was found to be in the high μM range. The compound showed no antifungal or antibiotic activity.

Marine natural products

“…651 have been achieved, with the latter study determining the absolute conguration 631 of the NP. 652,653 Two separate collections of Pachastrissa nux (Koh Tao, Surat Thani Province, and Chumphon Is. National Park, Thailand) yielded the antimalarial trioxazole macrolide kabiramide L 632.…”

Recent Advances in Total Synthesis via Metathesis Reactions

“…As a first series of examples in this category, it is worth mentioning the polyketide-type compounds ripostatin B (28) 35 and A (29), 36 FD-895 (30), 37 cruentaren A (31), 38 pikromycin (32), 39 zampanolide (33), 40 amphidinolide G (34), 41 palmerolide A (35), 42 ecklonialactone B (36), 43 gambieric acid A (37), 44 nominal gobienine A (38), 45 trienomycin A (39) and F (40), 46 13-demethyllyngbyasolide B (41), 47 incednam (42), 48 sekothrixide (43), 49 aspicillin (44), 50 macrolide fragment of FD-891 (45), 51 carolacton (46) 52 ( Figure 2), cytospolide P (47), 53 pectenotoxin (48), 54 Sch725674 (49), 55 aspergillide B (revised structure, 50), 56 iriometolide 3a (51), 57 paecilomycin B (52), 58 fidaxomicin (53), 59 exiguolide (54), 60 neopeltolide (55), 61 methynolide (56), 62 and iriomoteolide-2a (57) 63 (Figure 3). In addition, the group of alkaloids and cyclodepsipeptides are illustrated with the examples of manzamine A (58), 64 isoschizogamine (59), 65 vertine (60), 66 haliclamide (61), 67 5-epi-torrubiellutin (62), 68 petrosin (63), 69 the YM-254890 analogue 64, 70 nannocystin A (65) and A0 (66), 71 nakadomarin A (67), 72 marineosin A (68), 73 kanamienamide (69),…”

Total synthesis of haliclamide

“…The absolute configuration of the two chiral centers at C2 and C14 was resolved by Randazzo and co-workers with the help of 2D NMR analysis and the Yamaguchi method, 3 however the remaining two centers C9 and C20 were assigned by Altmann and co-workers by chemical synthesis and NMR studies. 4 To the best of our knowledge, until now only one synthesis of haliclamide 1 has been reported by Altmann and co-workers since the time of its isolation, employing ring closing metathesis (RCM), Brown's asymmetric allylboration and asymmetric allylation of oxazolidinone as the key steps. Haliclamide 1 has been a synthetic target of considerable interest due to its potent antitumor activity and with an array of functionalities.…”