Total synthesis of malyngamides K, L, and 5''-epi-C and absolute configuration of malyngamide L.

An accelerated, enantioselective, and general synthetic route to a class of malyngamides, K (1), L (3), and 5''-epi-C (4), bearing a cyclohexenone ring or a heavily oxygenated six-membered ring and a vinyl chloride structural motif was developed. The key step was the Suzuki cross-coupling reaction of boronic acids 6-8 with unsaturated carboxylic amides 5a,b possessing the chlorovinyl iodide functionality for the construction of the skeletons of 1-4. The key intermediates 10a,b were prepared using Ogilvie's method for the construction of the chlorovinyl iodide functionality. The NMR data of the synthetic compound 2 were in full agreement with those of the reported product, and the discrepancy in the specific rotation data suggested that the correct structure of malyngamide L should be 3, in which the absolute configuration of the amine part was enantiomeric to that in compound 2. Then the absolute configuration of the stereogenic center at C(3'') and C(4'') in malyngamide L was confirmed by synthesis of compound 3.

Total synthesis and absolute configuration of malyngamide W.

A concise enantioselective synthesis of malyngamide W (1) and its 2'-epimer was described. The strategy was based on three key steps: (1) ozonolysis of compound 11 which was derived from (R)-(-)-carvone 8, followed by copper-iron-catalyzed rearrangement to give the key cyclohex-2-enone intermediate 5, (2) Nozaki-Hiyama-Kishi coupling reaction between aldehyde 4 and iodide 14 to afford alcohol 3, and (3) asymmetric (R)-CBS reduction of the ketone functionality in compound 21 to establish the C-2' chiral center in the target compound 1. The absolute configuration of malyngamide W (1) was thus confirmed via the synthesis of 1 and 2'-epi-1.

A convergent route for the total synthesis of malyngamides O, P, Q, and R.

A convergent, enantioselective and general synthetic route to a class of marine natural products-malyngamides O (1), P (2), Q (3), R (4), 5''-epi-3 and 5''-epi-4-bearing a novel vinyl chloride structural motif was developed. The key steps involved construction of the vinyl chloride functionality by Wittig reaction, a DCC/HOBt-promoted amidation, an aldol reaction in the construction of the basic backbone of 1, 2, 3, 4, 5''-epi-3, and 5''-epi-4, and methylation of an enol moiety via either base/acid conditions or a Mitsunobu reaction. Moreover, the absolute configuration of the stereogenic center at C-5'' in 3 was further confirmed by synthesis of the natural product and its C-5'' epimer.

An improved asymmetric synthesis of malyngamide U and its 2'-epimer.

An accelerated and improved asymmetric synthesis of malyngamide U (1) and its 2'-epimer (2'-epi-1) was accomplished from readily available n-hexanal, ethanolamine and (R)-(-)-carvone. The key steps involved a Johnson-Claisen rearrangement in the synthesis of an unsaturated carboxylic acid 4 and an aldol reaction in the construction of the skeleton of 1 and 2'-epi-1. There are 13 steps in the synthesis, with a 2.7% overall yield for 1 and a 0.4% yield for 2'-epi-1.