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A transition metal free coupling reaction of benzylboronic esters and alkyl halides has been developed. Both alkyl bromides and alkyl iodides were found to be competent substrates with the nucleophilic boronate intermediate generated from the combination of benzylboronic ester and an alkyllithium. Good chemoselectivity was observed in substrates with a second electrophile. Both secondary and tertiary benzylboronic esters were effective nucleophiles in the reaction with primary alkyl halides. Mechanistic observations are consistent with a radical mechanism.

A reaction between epoxides and benzylboronic acid pinacol esters is described. CuI was found to be an effective catalyst of this transformation upon activation of the benzylboronic ester with an alkyllithium reagent. The reaction was very efficient and a variety of substituted epoxides were found to be good substrates with good regioselectivity for substitution at the less substituted side of the epoxide. A reaction using an enantioenriched secondary benzylboronic ester was found to not be stereospecific.

Benzylation reactions of N-tosyl imines and N-tert-butanesulfinyl imines using benzylboronic acid pinacol ester are reported. s-Butyllithium was used to activate the boronic ester, rendering it nucleophilic. The reaction was compatible with electronically diverse substituents on the imine in both substrate classes. Good diastereoselectivity was observed in additions to N-tert-butylsulfinylaldimines. The diastereoselectivity observed in these reactions is consistent with an open transition state for the addition. Examples of a secondary alkylboronic ester nucleophile and an N-tert-butanesulfinyl trifluoromethylketimine electrophile are also included.

A method has been developed for the addition of benzylboronic acid pinacol ester to activated ketones including trifluoromethyl ketones in good yields. The use of DABCO as an additive was found to enhance the rate and efficiency of this reaction. In reactions of ketones with a second carbonyl group present such as an ester or amide, good chemoselectivity for the ketone was observed. Competition experiments suggest an electrophile relative reactivity order of CF(2)H ketone > CF(3) ketone > aldehyde under these reaction conditions.

A benzylation of aldehydes using primary and secondary benzylboronic acid pinacol esters is reported. Activation of the boronic ester with s-butyllithium rendered it nucleophilic toward aldehydes. The activated nucleophile chemoselectively transfers the benzyl group over the sec-butyl group, providing excellent yields of the benzylated products. 11B NMR experiments were performed to study the mechanism of this transformation.

The total synthesis and evaluation of a key systematic series of vinblastines that incorporate the first deep-seated changes to the substituent at C4 are detailed. The synthetic approach features an expanded and redefined scope of a 1,3,4-oxadiazole [4 + 2]/[3 + 2] cycloaddition cascade in which electronically mismatched electron-deficient trisubstituted alkenes and unactivated trisubstituted alkenes were found to productively initiate the cycloaddition cascade with tethered electron-deficient 1,3,4-oxadiazoles. Such cycloaddition cascades were used to directly introduce altered C4 substituents, providing the basis for concise total syntheses of a series of C4 modified vindolines and their subsequent single-step incorporation into the corresponding synthetic vinblastines in routes as short as 8–12 steps. Evaluation of the synthetic vinblastines revealed a surprisingly large impact and role of the C4 substituent on activity even though it was previously not thought to intimately interact with the biological target tubulin. Only the introduction of a C4 methyl ester, a constitutional isomer of vinblastine in which the carbonyl carbon and ester oxygen of the C4 acetate are transposed, provided a synthetic vinblastine that matched the potency of the natural product. In contrast, even introduction of a C4 acetamide or N-methyl carboxamide, which incorporate single heavy atom exchanges (amide NH for ester oxygen) in vinblastine or the C4 methyl ester, provided compounds that were ≥10-fold less active than vinblastine. Other C4 acetate replacements, including a C4 amine, carboxylic acid, hydroxymethyl or acetoxymethyl group, led to even greater reductions in potency. Even replacement of the C4 acetoxy group or its equally active C4 methyl ester with an ethyl or isopropyl ester led to 10-fold or more reductions in activity. These remarkable trends in activity, which correlate with relative tubulin binding affinities, retrospectively may be ascribed to the role the substituent serves as a H-bond acceptor for α-tubulin Lys336 and Asn329 side chains at a site less tolerant of a H-bond donor, placing the methyl group of the C4 acetate or C4 methyl ester in a spatially restricted and well-defined hydrophobic half pocket created by a surrounding well-ordered loop. This remarkable impact of the C4 substituent, its stringency, and even the magnitude of its effect are extraordinary, and indicate that its presence was selected in Nature to enhance the effects of vinblastine and related natural products.

In this manuscript the impact of three organic molecules (in the presence and absence of zinc ions) in a more realistic solution medium is presented. The impact of the synthetic urinary medium on the morphology of the calcium oxalate monohydrate formed is similar to that seen in the presence of citric acid, the dominant component. The particles formed are relatively flat, rounded particles. In the presence of zinc ions, the particles are little changed with the main change being more rounded particles. The presence of the different organic acids show different impacts for different organics. Ethylenediamintetraacetic acid complexes calcium ions and lowers the supersaturation as a chelator would be expected to. It also impacts the growing crystal changing the morphology. In the case of tartaric acid, adsorption onto critical nuclei and/or growth features leads to incorporation. Finally, the most complex impact was found for maleic acid. Maleic acid interacts with citric acid, inhibiting the citric acid effect. This can be seen in the morphology of particles being similar to those in pure water. The presence of zinc ions generally led to zeta potential values that were closer to zero and therefore would increase the propensity for these particles to coagulate.

Cystallization of calcium oxalate monohydrate was investigated in the presence of various organic molecules in combination with zinc ions. This work looked at the impacts at physiological pHs (6–8) and temperature (37 °C). It was found that the number of carboxylate and hydroxyl groups was critical in determining the degree of inhibition. This inhibition was found to be mainly due to the ability of the organics to chelate with calcium ions when zinc ions are not present. Zinc ions were found to chelate with oxalate ions leading to lower nucleation rates, but this is not strictly inhibition but a lowering of the supersaturation due to lowering of the activity of the oxalate. Organics have variable impact depending on whether the zinc ions or calcium ions preferentially chelate with the organic.

It is reported that an allene dienophile can initiate a tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles, that the intermediate cross-conjugated 1,3-dipole (a carbonyl ylide) can participate in an ensuing [3 + 2] dipolar cycloaddition in a remarkably effective manner, and that the reaction can be implemented to provide the core pentacyclic ring system of vindoline. Its discovery improves a previous total synthesis of (-)-vindoline and was used in a total synthesis of (+)-4-epi-vindoline and (+)-4-epi-vinblastine that additionally enlists an alternative series of late-stage transformations.

A palladium-catalyzed coupling of allylic carbonates with trimethylsilylisocyanate to provide allylic isocyanates is reported. Amines are added in a second step to yield allylic ureas in this one-pot procedure. Use of a bidentate phosphine ligand with a large bite angle was found to be important in this transformation. The scope of allylic carbonates has been examined, as well as amines compatible with these reaction conditions.

A series of disubstituted C20′-urea derivatives of vinblastine were prepared from 20′-aminovinblastine that was made accessible through a unique Fe(III)/NaBH4-mediated alkene functionalization reaction of anhydrovinblastine. Three analogues were examined across a panel of 15 human tumor cell lines, displaying remarkably potent cell growth inhibition activity (avg. IC50 = 200–300 pM), being 10–200-fold more potent than vinblastine (avg. IC50 = 6.1 nM). Significantly, the analogues also display further improved activity against the vinblastine-resistant HCT116/VM46 cell line that bears the clinically relevant overexpression of Pgp, exhibiting IC50 values on par with that of vinblastine against the sensitive HCT116 cell line, 100–200-fold greater than the activity of vinblastine against the resistant HCT116/VM46 cell line, and display a reduced 10–20-fold activity differential between the matched sensitive and resistant cell lines (vs 100-fold for vinblastine).

B(C6F5)3 was found to catalyze the reaction between trimethylsilyl azide and benzylic acetates. Secondary and tertiary benzylic acetates were competent substrates in this reaction providing the azide products in moderate to high yields. Mechanistic experiments are consistent with the possible formation of a Lewis acid-base pair between the B(C6F5)3 and trimethylsilyl azide.

A palladium-catalyzed coupling of allylic carbonates with trimethylsilylisocyanate to provide allylic isocyanates is reported. Amines are added in a second step to yield allylic ureas in this one-pot procedure. Use of a bidentate phosphine ligand with a large bite angle was found to be important in this transformation. The scope of allylic carbonates has been examined, as well as amines compatible with these reaction conditions.

A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH(4)-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an X-ray cocrystal structure, remarkably large C20' urea derivatives are accommodated.

An Fe(III)/NaBH(4)-mediated reaction for the functionalization of unactivated alkenes is described defining the alkene substrate scope, establishing the exclusive Markovnikov addition, exploring a range of free radical traps, examining the Fe(III) salt and initiating hydride source, introducing H(2)O-cosolvent mixtures, and exploring catalytic variants. Its use led to the preparation of a novel, potent, and previously inaccessible C20'-vinblastine analogue.

The synthesis of a broad spectrum of aniline derivatives including drug analogues provides a mild and convenient complementary method to SNAr reactions.

An iridium-catalyzed allylation reactions of ketones using dienes as ligands has been developed. A variety of ketones underwent allylation and methallylation reactions at room temperature in good yields under these conditions. Competition experiments demonstrate that the reaction is selective for electron-deficient ketones.

A new ternary aluminide, La2NiAl7, has been synthesized from the elements in sealed silica tubes. The crystal structure of La2NiAl7 was determined by single-crystal X-ray diffraction and crystalliz...

The transformation is achieved under exceptionally mild conditions to yield the corresponding Markovnikov addition products.

A powerful Fe(III)/NaBH(4)-mediated free radical hydrofluorination of unactivated alkenes is disclosed using Selectfluor reagent as a source of fluorine and resulting in exclusive Markovnikov addition. In contrast to the traditional and unmanageable free radical hydrofluorination of alkenes, the Fe(III)/NaBH(4)-mediated reaction is conducted under exceptionally mild reaction conditions (0 °C, 5 min, CH(3)CN/H(2)O). The reaction can be conducted open to the air and with water as a cosolvent and demonstrates an outstanding substrate scope and functional group tolerance.

The synthesis of a broad spectrum of aniline derivatives including drug analogues provides a mild and convenient complementary method to SNAr reactions.

N,N-dialkyl-N-chloroamines are an effective source of electrophilic nitrogen for nickel-catalyzed coupling with diarylzinc reagents. A variety of N-chloroamines as well as organozinc reagents react smoothly under the reaction conditions. A one-pot procedure that circumvents the need to isolate the N-chloroamines is described.

N,N-dialkyl-N-chloroamines are an effective source of electrophilic nitrogen for nickel-catalyzed coupling with diarylzinc reagents. A variety of N-chloroamines as well as organozinc reagents react smoothly under the reaction conditions. A one-pot procedure that circumvents the need to isolate the N-chloroamines is described.

[Ir(cod)Cl]2 is a highly reactive catalyst for allylation reactions of ketones using allylboronic ester. Mechanistic experiments are consistent with formation of a nucleophilic allyliridium(I) complex that is activated by the diene ligand toward attack of a ketone. Aryl and alkyl ketones react smoothly at room temperature. Aldimines also undergo allylation under these reaction conditions, requiring increased reaction times relative to the corresponding ketones.

[Ir(cod)Cl](2) is a highly reactive catalyst for allylation reactions of ketones using allylboronic ester. Mechanistic experiments are consistent with formation of a nucleophilic allyliridium(I) complex that is activated by the diene ligand toward attack of a ketone. Aryl and alkyl ketones react smoothly at room temperature. Aldimines also undergo allylation under these reaction conditions, requiring increased reaction times relative to the corresponding ketones.

A new ternary aluminide, La2NiAl7, has been synthesized from the elements in sealed silica tubes. The crystal structure of La2NiAl7 was determined by single-crystal X-ray diffraction and crystalliz...