Ortho‐TMS Benzaldehyde: An Effective Linchpin for Type II Anion Relay Chemistry (ARC)

Abstract

Ortho-TMS benzaldehyde, an effective bifunctional linchpin for Type II Anion Relay Chemistry (ARC), permits efficient multi-component union of a variety of nucleophiles and electrophiles, including the first example of a Pd-mediated ARC Type II process. To demonstrate the utility of the Type II ARC protocol, a "proof of concept" synthetic sequence was designed and implemented for construction of a focused library of "natural product-like" compounds. Nature, with beautiful elegance, constructs natural products often in iterative fashion with both superb efficiency and exquisite stereochemical control.[1] For more than 100 years chemists have atempted to mimic the elegance of Nature with laboratory syntheses. The shortcomings of many synthetic ventures however lie in the multi-step sequences, often leading to minimum structure augmentation, in conjunction with isolation and purification at each stage, leading to inefficient material advancement. Fortunately, multi-component reactions[2] hold considerable promise of alleviating this inefficiency by orchestrating the conversion of simple starting materials, in a single (one-pot) operation, to advanced intermediates of high structural complexity without the need for multiple isolations and purifications.[3] Towards this end, we recently turned to the development of multi-component reaction sequences exploiting Anion Relay Chemistry (ARC).[4] At the highest level, the ARC tactic can be divided into two processes involving anion migration either through bonds or though space, the latter requiring the availability of a carrier to transport the negative charge. A simple example of "through-bond" anion relay is the well-known conjugate addition, through the π-system, with subsequent capture of the intermediate enolate. For "through-space" anion relay two possibilities exist involving σ-bonds (Type I and II), the difference residing in the resulting locus of the transposed anion. Type I ARC is defined as a multi-component coupling protocol (Scheme 1), wherein a linchpin nucleophile reacts with an electrophile to generate an oxyanion that subsequently transfers (i.e., relays) the negative charge "back" to the initiating site, followed by reaction with a suitable electrophile. The Type II process, entails reaction of a nucleophile with a bifunctional electrophilic linchpin to generate an anionic species that relays the negative charge to a new (i.e., different) locus, which then reacts with a second electrophile. An important feature of the Type II ARC process is the potential for iteration with a sequential series of bifunctional linchpins, a process not disimilar to living polymerization. [5] In 1997, based on the early work of Matsuda,[6] Tietze,[7] and Oshima,[8] we introduced an example of the Type I ARC process involving mono-silyl dithianes,[9] which through aegis of a solvent-controlled Brook rearrangement[10] led to the development of an effective three-component union protocol employing a wide variety of different second electrophiles. The utility of this process w...

Uniting Anion Relay Chemistry with Pd-Mediated Cross Coupling: Design, Synthesis and Evaluation of Bifunctional Aryl and Vinyl Silane Linchpins

“…Recently, we recorded a single example employing ortho -TMS benzaldehyde 10 as linchpin that demonstrated the feasibility of uniting Anion Relay Chemistry with Pd-mediated cross coupling (Scheme 2). 3 The reaction sequence involved treatment of 10 with n -BuLi followed in turn by addition of CuI and HMPA to induce 1,4-silyl C(sp 2 )→O migration, vinyl bromide with a catalytic amount of Pd(PPh 3 ) 4 for the CCR, and TBAF to remove the TMS group; tricomponent adduct 10a was produced in 56% yield.…”

Evolution of multi-component anion relay chemistry (ARC): construction of architecturally complex natural and unnatural products

“…With this scenario in mind, treatment of linchpin 86 in THF at -78 °C with a nucleophile (Table 6), followed by cannula-addition of a solution of CuI (1.2 equiv) in a mixture of THF and HMPA (1:1) followed by introduction of a series of electrophiles, including allyl halides, tri- n -butylstanyl chloride or diphenyl disulfide in THF, and work-up involving removal of the TMS group with TBAF, furnished multi-component adducts 87-93 in good to excellent yield. Of particular significance, a multi-component palladium-mediated cross coupling reaction sequence was achieved employing n -BuLi, linchpin 86 and vinyl bromide, in the presence of 3 mol % Pd(PPh 3 ) 4 (Table 6; Entry 7) 32. To our knowledge this comprises the first example of a Pd-mediated Type II multi-component ARC process.…”

Diversity-Oriented Synthesis of 2,4,6-Trisubstituted Piperidines via Type II Anion Relay Chemistry

“…1 In an attempt to mimic Nature’s iterative biosynthesis of complex molecules, we developed and validated Type I and Type II A nion R elay C hemistry (ARC) (Scheme 1), 2 two closely related synthetic methods comprising multicomponent union protocols. In addition to providing access to specific architectures, the ARC tactic also holds considerable potential for D iversity- O riented S ynthesis (DOS).…”