Total synthesis of (−)-nakadomarin A

Abstract

A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereoselective synthesis of (-)-nakadomarin A.

Alkyne Metathesis on the Rise

“…Exposure of this compound to mildly acidic conditions at higher temperature prompted the sterically more hindered hydroxy group at C21 to engage in the necessary second cyclization event. The integrity of ketal 139 thus formed was confirmed by X-ray diffraction before this product was elaborated into the target compound spirastrellolide F (140). [164]…”

“…Complex 1 a was also used by Dixon and co-workers in their RCAM-based route to nakadomarin A reported shortly thereafter. [140] The elaborate substrate 102 was cyclized in 69 % yield and the resulting pentacyclic product 103 swiftly elaborated to the target by annulation of the still missing eight-membered E ring. In a slightly different setting, the Dixon research group reported yet another approach involving the use of diyne 104 as the substrate, in which the E ring had already been set.…”

Conjugate addition nitro-Mannich reaction of carbon and heteroatom nucleophiles to nitroalkenes

“…1 The product β-nitroamines have emerged as flexible synthetic building blocks due to the complimentary oxidation states of the two nitrogen atoms. They have been used in the synthesis of many nitrogen containing functional groups including α-amino carbonyls, 2, 3 1,2-diamines, [4][5][6][7] peptidomimetics, 8 natural products [9][10][11][12][13][14][15] and many heterocyclic small molecules. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] To address the paucity of structurally diverse nitroalkanes we have developed conjugate addition nitro-Mannich protocols (Scheme 1).…”

Recent Developments on the Total Synthesis of Nakadomarin A

“…Finally RCM was adapted on the compound to get the desired material 1 in good yield, but with a mixture of Z and E isomer in 63:37 ratio. This problem: in the formation of Z ‐isomer exclusively, was solved by using alkyne during metathesis reaction. Till 2013, their approach attracted the attention of synthetic organic chemists for efficient construction of ABCDE ring in very few steps, highlighting the cascade reaction and enantioselective cojugate adiition reaction.…”