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