The kinetic inertness of copper(II) complexes of several carboxymethyl-armed cyclams and cyclens in 5 M HCl have been determined confirming that the complex derived from crossbridged cyclam (Cu-CB-TE2A) is by far the most resistant to acid decomplexation. FT-IR studies in D 2 O solution revealed its unique resistance to full carboxylate protonation and its retention of coordination by both pendant arms even in 1 M DCl. The X-ray structure of its monoprotonated form, + , also established full coordination by both

A cross-bridged cyclam ligand bearing two N-carboxymethyl pendant arms (1) has been found to form a copper(II) complex that exhibits significantly improved biological behavior in recent research towards (64)Cu-based radiopharmaceuticals. Both the kinetic inertness and resistance to reduction of Cu-1 are believed to be relevant to its enhanced performance. To explore the influence of pendant arm length on these properties, new cross-bridged cyclam and cyclen ligands with longer N-carboxyethyl pendant arms, 2 and 4, and their respective copper(II) complexes have been synthesized. Both mono- as well as di-O-protonated forms of Cu-2 have also been isolated and structurally characterized. The spectral and structural properties of Cu-2 and Cu-4, their kinetic inertness in 5 M HCl, and electrochemical behavior have been obtained and compared to those of their N-carboxymethyl-armed homologs, Cu-1 and Cu-3. Only the cyclam-based Cu-1 and Cu-2 showed unusually high kinetic inertness towards acid decomplexation. While both of these complexes also exhibited quasi-reversible Cu(II)/Cu(I) reductions, Cu-2 is easier to reduce by a substantial margin of +400 mV, bringing it within the realm of physiological reductants. Similarly, of the cyclen-based complexes, Cu-4 is also easier to reduce than Cu-3 though both reductions are irreversible. Biodistribution studies of (64)Cu-labeled 2 and 4 were performed in Sprague Dawley rats. Despite comparable acid inertness to their shorter-armed congeners, both longer-armed ligand complexes have poorer bio-clearance properties. This inferior in vivo behavior may be a consequence of their higher reduction potentials.

Copper-64, a positron emitter suitable for positron emission tomography (PET), demonstrates improved in vivo clearance when chelated by the cross-bridged tetraazamacrocycle CB-TE2A compared to TETA. Good in vivo clearance was also observed for 64Cu-CB-TE2A conjugated to a peptide, which converts one coordinating carboxylate pendant arm to an amide. To better understand the in vivo stability of peptide- conjugated CB-TE2A, cross-bridged monoamides were synthesized. Crystal structures of natCu(II)-CB-TEAMA and natCu(II)-CB-PhTEAMA revealed hexadentate, distorted octahedral coordination geometry. In vivo biodistribution showed clearance of all 64Cu-radiolabeled cross-bridged monoamides from liver and bone marrow such that uptake at 24 h was <10% of uptake at 30 min. In contrast, >60% of 30 min uptake from 64Cu-TETA was retained in these tissues at 24 h. Clearance of 64Cu-cross-bridged monoamides from nontarget organs suggests good in vivo stability, thus supporting the use of CB-TE2A as a bifunctional chelator without modifications to the macrocycle backbone.

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Nickel-catalyzed reductive coupling reactions of 1,3-enynes and aromatic aldehydes efficiently afford conjugated dienols in excellent regioselectivity and modest enantioselectivity when conducted in the presence of catalytic amounts of a monodentate, P-chiral ferrocenyl phosphine ligand. 1-(Trimethylsilyl)-substituted enynes are shown to be effective coupling partners in these reactions, and the dienol products thus formed readily undergo protiodesilylation under mild conditions. Keywords: allylic alcohols; asymmetric catalysis; C À C bond formation; nickel; reductive coupling 1,3-Dienes are important and versatile intermediates in organic synthesis. They are able participants in an array of cycloaddition reactions, most notably the Diels-Alder reaction, [1 -3] and there are a variety of efficient methods for preparing them.[4] Many of these, such as olefination reactions, [5,6] cross-couplings, [7,8] alkene/ enyne metathesis, [9] and other transformations, [10] facilitate convergent synthesis because they simultaneously construct a new carbon-carbon bond. Recently, our laboratory [11] and others [12] reported a new strategy for the synthesis of 1,3-dienes via transition metal-catalyzed reductive coupling reactions of 1,3-enynes and aldehydes. In addition to forming a new carbon-carbon bond, these methods also generate a stereogenic center, [13] allowing for efficient construction of chiral 1,3-dienes that have been widely employed in diastereoselective Diels-Alder reactions. [14,15] We now report the first enantioselective examples of catalytic reductive coupling reactions of 1,3-enynes, promoted by sub-stoichiometric amounts of a monodentate, P-chiral ferrocenyl phosphine ligand.Previous work from our laboratory has shown that nickel-catalyzed reductive couplings of aryl-substituted alkynes (Ar À C C À R) and aldehydes are highly enantioselective when ( þ )-neomenthyldiphenylphosphine (NMDPP) is employed as a chiral ligand (Scheme 1).[16]We have also described a class of P-chiral, monodentate ferrocenyl phosphines (e.g., 1a, 1b; Figure 1) that are efficient promoters of related couplings of aliphatic internal alkynes (Alkyl À C C À Alkyl') and aldehydes, [17] and of multi-component coupling reactions of alkynes, imines, and organoboron reagents. [18] Reductive coupling reactions of 2-methyl-1-hexen-3-yne and benzaldehyde in the presence of catalytic amounts of Ni(cod) 2 and ( þ )-NMDPP, and a stoichiometric quantity of triethylborane (Et 3 B), afforded dienol 2a in low yield and low enantioselectivity, but with high regioselectivity (Table 1, entry 1). Ferrocenylphosphine 1a maintained this high regioselectivity but enhanced both the efficacy and enantioselectivity of the transformation (entry 2). ortho-Isopropylphenyl-substiScheme 1. Asymmetric, nickel-catalyzed reductive coupling of arylalkynes and aldehydes. tuted-ferrocenylphosphine 1b provided even higher levels of both reactivity and enantioselectivity (entry 3). A variety of aromatic aldehydes undergo reductive coupling with 2-methyl-1-hexen-3...

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Pumiliotoxins 209F and 251D were synthesized using highly selective nickel-catalyzed epoxidealkyne reductive cyclizations as the final step. The exocyclic (Z)-alkene found in the majority of the pumiliotoxins was formed stereospecifically and regioselectively, without the use of a directing group on the alkyne, and the epoxide underwent ring opening exclusively at the less hindered carbon to provide the requisite tertiary alcohol. The epoxides were prepared using diastereoselective addition of a sulfoxonium anion to a proline-derived methyl ketone.The pumiliotoxins were first isolated in 1967 from the Dendrobates pumilio frogs in South America. i,ii The structure and stereochemistry of these alkaloids were initially established via X-ray crytallographic analysis of the hydrochloride salt of pumiliotoxin 251D (1) iii and confirmed by total syntheses of several members of this family of natural products. iv,v,vi,vii Thirty pumiliotoxins have a (Z)-6-alkylideneindolizidine ring system and a tertiary alcohol at C8. Several different strategies have been developed for the synthesis of the ubiquitous (Z)-alkene. Overman used an iminium ion-vinylsilane cyclization to this end in the first total synthesis of pumiliotoxin 251D 6a and later employed a related iodide-promoted, iminium ion-alkyne cyclization to synthesize more complex pumiliotoxins. 4,viii Gallagher used a stereospecific elimination of a β-hydroxylactam to install the (Z)-alkene in the synthesis of pumiliotoxin 251D. 6b In the synthesis described herein, we have reduced the construction of the pumiliotoxins to simultaneous and stereospecific installation of the exocyclic Z-alkene and tertiary alcohol present in the final step of the synthesis.Our strategy is based on the notion that both of these challenges could be addressed by nickel-catalyzed reductive cyclizations ix of epoxy-alkynes previously developed in our laboratory (Figure 1). x However, all of the epoxides in our earlier investigations were monosubstituted (terminal). Thus a major question in the context of the pumiliotoxins was whether or not 1,1-disubstituted epoxides (e.g., 3a and 3b), which we had previously found to be recalcitrant substrates, would undergo reductive cyclization. xi Furthermore, in order to tfj@mit.edu. Supporting Information Available: Experimental procedures and full spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. be used as the final step, the regioselectivity of both alkyne addition and epoxide ringopening could not depend upon the use of a directing group on the alkyne. Nevertheless, proline-derived ketones 4a and 4b and propargyl bromides 5a and 5b were attractive precursors and readily available. Accordingly, we began our investigations by preparing these intermediates via chiral ketones 4a and 4b. NIH Public AccessTreatment of carbamate-protected proline methyl esters 6a and 6b xii with N,Odimethylhydroxylamine hydrochloride and trimethylaluminium afforded Weinreb amides 7a and 7b...

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