Reactions of Benzylboronate Nucleophiles.

This short review summarizes our laboratory's development of benzylboronic esters as nucleophiles. Activation of the benzylboronic ester is achieved by irreversible coordination of an alkyllithium Lewis base to form a nucleophilic benzylboronate. This boronate was found to react with aldehydes, imines, ketones and alkyl bromides. A copper catalyst was employed in reactions of the boronate with epoxides and aziridines.

Cu-Catalyzed Cross-Coupling of Benzylboronic Esters and Epoxides.

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.

Transition Metal Free sp3-sp3 carbon-carbon coupling between Benzylboronic Esters and Alkyl Bromides.

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.

Nucleophilic Addition of Benzylboronates to Activated Ketones.

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 CF2H ketone > CF3 ketone > aldehyde under these reaction conditions.

Benzylation of Imines with Activated Boronate Nucleophiles.

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.

Chemoselective Benzylation of Aldehydes Using Lewis Base Activated Boronate Nucleophiles.

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 s-butyl group, providing excellent yields of the benzylated products. 11B NMR experiments were performed to study the mechnism of this transformation.

Total synthesis of a key series of vinblastines modified at C4 that define the importance and surprising trends in activity.

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.

Total Synthesis of (-)-Vindoline and (+)-4-epi-Vindoline Based on a 1,3,4-Oxadiazole Tandem Intramolecular [4 + 2]/[3 + 2] Cycloaddition Cascade Initiated by an Allene Dienophile.

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.

The molecular structure of methylfluoroisocyanato silane: a combined microwave spectral and theoretical study.

The structure of methylfluoroisocyanato silane (Me-SiHF-NCO) has been deduced by a combination of microwave (MW) spectra including data from (12,13)C, (14,15)N, and (28,29,30)Si isotopomers, and ab initio calculations. The rotational constants (RC) for the most abundant isotopes are A = 6301.415(45), B = 1535.078(39), and C = 1310.485(39) MHz. The symmetric quartic centrifugal distortion constants have been identified, using the I(r) representation for C1 symmetry, which includes the 3-fold rotor. The spectra of the isotopomer combinations gave a partial substitution structure where the C2Si3, Si3N4, and N4C9 bond lengths are 1.8427(70), 1.7086(77), and 1.2120(90)Å; although the C2Si3N4 angle is close to tetrahedral (109.71° (52)), the Si3N4C9 angle is wide (157.69° (18)). The rotational constants are only consistent with a trans-orientation for each of the dihedral angles (HC2Si3N4, C2Si3N4C9, and Si3N4C9O10). The structural analysis was completed by calculations of the equilibrium structure, using MP3 in conjunction with an aug-cc-pVTZ basis set (434 Cartesian basis functions). This gave A = 6240.324, B = 1518.489, and C = 1297.819 MHz. The equilibrium structure bond lengths for C2Si3, Si3N4, and N4C9 were 1.8485, 1.7147, and 1.1947 Å, with the C2Si3N4 and Si3N4C9 angles 109.55 and 156.67°, respectively. Although the SiNC polynomial bending surface is complex, the data points can be fit to the simple form V(x) = 50.36(91)x(4) - 7.53(44)x(5), with comparatively little loss of accuracy. The A-rotational constant is strongly influenced by the Si3N4C9 angle, and smaller bases lead to this angle being nearly linear. The theoretical results suggest a very heavily polarized molecule, which is supported by the positions of the local electron density minima within the bonds and electron density calculations.

Potent Vinblastine C20' Ureas Displaying Additionally Improved Activity Against a Vinblastine-Resistant Cancer Cell Line.

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 analogs 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 analogs 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).

A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives.

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.

Fe(III)/NaBH4-mediated free radical hydrofluorination of unactivated alkenes.

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.

Iron(III)/NaBH4-mediated additions to unactivated alkenes: synthesis of novel 20'-vinblastine analogues.

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.

Umpolung amination: nickel-catalyzed coupling reactions of N,N-dialkyl-N-chloroamines with diorganozinc reagents.

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.

Diene-ligated iridium catalyst for allylation reactions of ketones and imines.

[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.