Synthesis and Diversification of Macrocyclic Alkynediyl Sulfide Peptides

Abstract

The synthesis of rare macrocyclic alkynediyl sulfides by aC u-catalyzedC sp ÀSc ross-coupling is presented. The catalytic protocol (Cu(MeCN) 4 PF 6 /dtbbpy) promotes macrocyclization of peptides, dipeptides and tripeptides at ambient temperature (14 examples, 23!73 %y ields) via thiols and bromoalkynes, and is chemoselective with regardst ot erminal alkynes.I mportantly,t he underexplored alkynediyl sulfide functionality incorporates arigidifying structurale lement ando pens new opportunities for diversification of macrocyclic frameworks throughSo xidation, halide addition and azide-alkyne cycloaddition chemistries to integrate sulfones,h alideso rv aluablef luorophores (7 examples, 37!92 %y ields). Macrocycles offer au nique topology within chemical space. [1] Despite their large ring structures they can retain remarkable conformational bias with appropriate functionality present. Currentb ioactive macrocyclic drugs are almost exclusively derived from natural products, [2] yet synthetic macrocycles represent ag rowingc lass of drug candidates. Retrosynthetically,a macrocyclic precursor typically containsac ore from which extend appendages with functionality for cyclization. Upon formation of the macrocycle, the newly formed functionality is often referred to as the "linker". [3] Through the linker and macrocyclization,aconformation that is preferentialf or biological activity can be locked in, or alternatively,c onformers exhibiting unwanted side-effects can be locked out. [4] Consequently, the "linker" plays ac riticalr ole and is often modified systematically to examine its effects on activity.T he most common linkers exploit well-known functional group manipulations (Figure 1). Macrolactonization [5] via stoichiometrica ctivationo faseco-acid can be used to form ester-based linkers. Macrocyclic olefin metathesis, [6] now ac ommons trategy to form large rings was investigated by Ts uji in 1980 [7] andt he reactionw as first ap

The Synthetic Potential of Thiophenium Ylide Cycloadducts**

“…Alkynyl sulfides also benefit from being generally easy to synthesize, the traditional approach being the addition of metal acetylides onto electrophilic sulfide species (disulfides or thiosulfonates). A multitude of complementary methods have been more recently developed for the synthesis of alkynyl sulfides with much milder conditions, [23] such as cross coupling reactions, which has widened the diversity of structures onto which they can be installed, even to macrocyclic peptides [24, 25] . While the alkynyl portion of alkynyl sulfides has been well documented to participate as a two‐atom component in cyclization processes, [22] its full use as a three‐atom component is sparse.…”

The Synthetic Potential of Thiophenium Ylide Cycloadducts

“…A multitude of complementary methods have been more recently developed for the synthesis of alkynyl sulfides with much milder conditions, 23 such as cross coupling reactions, which has widened the diversity of structures onto which they can be installed, even to macrocyclic peptides. 24,25 To date, the (3+2) cycloaddition between alkynyl sulfides 8 and alkynes 1 has not been addressed. Other than the recent work on ynamides, 20,21 the literature on heteroatomsubstituted alkynes as TACs is limited to the pyrolysis of neat compounds 17 or the use of highly reactive benzynes as 2-atom cycloaddition partners, 18,19 which both impose great limits on functional group tolerance and structural diversity.…”

Computational Insight into Cu-Catalyzed Csp–S Coupling to Form a Macrocyclic Alkynyl Sulfide

“…The substrate scope includes the functionalization of cysteine in dipeptides as well the synthesis of rare bis-heteroatom-substituted alkynes. The method was particularly adept at forming rare macrocyclic alkynyl sulfides and demonstrated the versatile diversification permitted by the functional groups . Interestingly, the Cu-catalyzed chemistry formed the macrocycle 1 in higher yields than the corresponding metallaphotoredox route (73 vs 21% yield) at even higher concentrations (5 vs 2 mM).…”