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.

Kinetics of N-oxyl Radicals’ Decay

“…The study of various N -hydroxy compounds facilitates the development of new methods and strategies for the functionalization of organic molecules and opens up new possibilities for new and well-known structures of NHPI-type catalysts. For example, recently, the groups of Brown and Liu demonstrated that Cl 4 -NHPI and 4-CH 3 O-NHPI can be used as components of catalytic systems for enantioselective synthesis.…”

“…12c The study of various N-hydroxy compounds facilitates the development of new methods and strategies for the functionalization of organic molecules and opens up new possibilities for new and well-known structures of NHPI-type catalysts. For example, recently, the groups of Brown 30 and Liu 31 demonstrated that Cl 4 -NHPI and 4-CH 3 O-NHPI can be used as components of catalytic systems for enantioselective synthesis. The effect of the structure of N-hydroxy compounds in the oxidation of n-butylbenzene was studied by Boaz et al 32 The authors used a catalyst system consisting of ammonium iodate with an NHPI-type catalyst and showed that the yield of the main product 1-phenylbutyl acetate slightly decreased in the presence of 4-CH 3 -NHPI (76%), F 4 -NHPI (76%), Br 4 -NHPI (73%), NDHPI (81%), or NHNI (67%) compared with unsubstituted NHPI (86%).…”

Potential for Ladderane (Bio)synthesis from Oligo-Cyclopropane Precursors

“…It is difficult to answer this question, but what is clear is that if a ladderane radical cation is produced, conversion to chair-like structures must be prevented, that is, initial ring-opening can occur because that process is likely to be reversible given the reduction potential of species such as 38 , but further ring-opening must be prevented. Note, however, that ladderane lipids containing cyclohexane rings are also known, − and species such as 44 could, in principle, serve as precursors to them.…”

“…Ladderanespolycyclic molecules with two or more fused cyclobutane ringshave attracted the attention of biologists, biochemists, computational chemists, and synthetic chemists because of their unusual, highly strained, molecular skeletons. − Reported methods for the laboratory synthesis of ladderanes include templated photodimerizations , and several innovative target-oriented multistep syntheses. ,− While various aspects of ladderane biosynthesis have been revealed, − energetically viable, biologically relevant reactions that form ladderanes have not been characterized either experimentally or theoretically. Rattray et al described a variety of gene candidates that might be involved in ladderane biosynthesis, and suggested that the cyclization of polyunsaturated fatty acids was unlikely to generate ladderane lipids as previously hypothesized .…”

Modular Synthesis of Stereodefined Benzocyclobutene Derivatives via Sequential Cu- and Pd-Catalysis

“…With an efficient protocol for the Cu-catalyzed step in hand, we investigated suitable conditions for the Pd-mediated cyclization, for which we identified the following challenges: First, no catalytic Suzuki-Miyaura protocols have been reported for 4-membered carbocyclic ring formation. , Second, under Pd-catalysis, the presence of a nucleophilic nitrogen-center within 3 could promote the formation of indoline derivatives 5 , through a Buchwald-Hartwig-type coupling (Table ). With these considerations in mind, we sought to identify chemoselective conditions for the formation of BCB 4a .…”