Short Enantioselective Total Synthesis of Tatanan A and 3‐epi‐Tatanan A Using Assembly‐Line Synthesis

Abstract

Short and highly stereoselective total syntheses of the sesquilignan natural product tatanan A and its C3 epimer are described. An assembly‐line synthesis approach, using iterative lithiation–borylation reactions, was applied to install the three contiguous stereocenters with high enantio‐ and diastereoselectivity. One of the stereocenters was installed using a configurationally labile lithiated primary benzyl benzoate, resulting in high levels of substrate‐controlled (undesired) diastereoselectivity. However, reversal of selectivity was achieved by using a novel diastereoselective Matteson homologation. Stereospecific alkynylation of a hindered secondary benzylic boronic ester enabled completion of the synthesis in a total of eight steps.

Towards the generalized iterative synthesis of small molecules

“…86 Amination followed by amide formation furnished the core of (+)-kalkitoxin in an overall 52% yield. This same approach has been used to synthesize baulamycin A, 87 tatanan A, 88 fluorohexestrol, 89 and C30 botryococcene 90 and many other targets. 91 More broadly, the versatility of this homologation method, which tolerates a diversity of structural variation in its building blocks, opens the door for divergent synthesis.…”

“…This strategy allowed highly complex building blocks to be efficiently assembled in an iterative manner. 88 Other family members of the halichondrin family could also be accessed by incorporating variant building blocks into a similar synthetic sequence. 100 This efficient and modular synthesis enabled Kishi and coworkers to discover that half of halichondrin B, the portion that contains the macrocycle, is nearly equipotent as an anticancer agent to the exceptionally potent natural product.…”

Stereospecific 1,2‐Migrations of Boronate Complexes Induced by Electrophiles

“…Furthermore,it was used in the total synthesis of tatanan A, where complex boronic ester 36-constructed using iterative reagent-controlled homologation-was employed in an enantiospecific Zweifel-type alkynylation to afford alkyne 37 (Scheme 7b). [24] It should be noted that alkynyl anions cannot be used directly in Zweifel-type alkynylation since they react reversibly with boronic esters.H owever,t hey can used in reactions with boranes or borinic esters. [25] Intramolecular Zweifel olefination has also been achieved, which provides access to methylene cycloalkanes (Scheme 8).…”

Stereoselective Synthesis of Trisubstituted Vinylboronates from Ketone Enolates Triggered by 1,3‐Metalate Rearrangement of Lithium Enolates

“…> 99:1) under the reaction conditions of ZnEt 2 /CH 2 I 2 . [25] Meanwhile,i nt he presence of NaOH/I 2 , 2a was smoothly converted into the stereospecific vinyl iodide 2h-l, [26] which was believed to be useful building block for further transformations (Scheme 7c).…”