Lessons in Strain and Stability: Enantioselective Synthesis of (+)‐[5]‐Ladderanoic Acid

Abstract

The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)‐[5]‐ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic design that ultimately led to the development of a novel stepwise cyclobutane assembly by an allylboration/Zweifel olefination sequence.

Ladderane Natural Products: From the Ground Up

“…In contrast, Burns and co‐workers utilized a convergent approach through the dimerization of smaller [2]‐ladderene fragments (blue disconnection) [33] . Finally, Brown's strategy hinged on a late‐stage, enantioselective [2+2]‐cycloaddition to assemble the final cyclobutane; however, complications required development of a novel cyclobutane synthesis by Zwiefel olefination (red disconnection) [34] …”

“…The most recent synthesis of [5]‐ladderanoic acid was reported by Brown and co‐workers in 2020 (Scheme 5). [34] The synthesis commenced with a [2+2]‐photocycloaddition of known cyclobutene acetal 61 [36] and cyclopentenone ( 33 ) to yield 62 (1:1 regioisomeric mixture, inconsequential). Diazo‐transfer and irradiation of the corresponding α‐diazoketone prompted a Wolff rearrangement to yield carboxylic acid 63 .…”

Saturated Boronic Acids, Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

“…[258] Further developments included the use of allyl phosphates (CuCl-(R,R)-QuinoxP*-LiOMe, asymmetric version), [259] ICH 2 F (CuCl-IMes-tBuONa in DMA), [260] CO 2 (ICyCuCl-tBuONa in THF, 1 atm of CO 2 ), [261] acyl chlorides (SIMesCuCl-tBuONa in Et 2 O, as well as asymmetric modification employing a chiral N-heterocyclic carbene complex), [262] ArÀ N=C=O (SIMesCuCl-tBuOLi in toluene), [263,264] RÀ C�CÀ Br (SIMesCuCl-tBuOLi in THF), [265] as well as dimethylmalonodinitrile (DMM) as an electrophilic cyanating agent (CuCl-dppf-tBuOLi-CsF in nBu 2 O). [266] An extension of the alkene scope included strained bycyclic alkenes [267,268] and indoles. [269] As in the case of Cu-catalyzed hydroboration (Scheme 51), the regioselectivity of carboboration can be controlled by adjusting the Cu environment.…”

Uncommon Four‐Membered Building Blocks – Cyclobutenes, Azetines and Thietes

“…β‐Eliminations constitute a simple approach to cyclobutenes. It was exploited by the group of Corey [43] and more recently by Brown and co‐workers (Scheme 5) [44] to access ladderane derivative through iterative construction of four‐membered rings. Olefination was performed either by installing a selenoxide on the saturated four‐membered ring followed by a Cope‐type rearrangement, or by direct elimination through intermediate formation of a cyclobutylbromide.…”