Synthesis of a Nonracemic C2-Symmetric Tetrahydro-1,4-azaborine and Evaluation of Hydroboration Enantioselectivity.

Tetrahydro-1,4-azaborines were accessed by hydroboration of N,N-diprenyltoluenesulfonamide 4. Conversion to the methylborinates 11 and 12 followed by heating with l-alanine and crystallization afforded (R,R,S)-13 (27%). Reduction of borinic acid (R,R)-18 with Soderquist's KH* gave (R,R)-19, and hydride abstraction by TMSCl in the presence of alkenes resulted in hydroboration, 84-86% ee for (Z)-alkenes, but (E)-alkenes or 1,1-disubstituted alkenes gave <5% ee.

Development of a Chiral DMAP Catalyst for the Dynamic Kinetic Resolution of Azole Hemiaminals.

A new catalyst for the dynamic kinetic resolution of azole hemiaminals has been developed using late-stage structural modifications of the tert-leucinol-derived chiral subunit of DMAP species.

Stereoselective synthesis of the diazonamide a macrocyclic core.

Stereoselective synthesis of the right-hand heteroaromatic macrocycle of diazonamide A features C16-C18 bond formation in the Suzuki-Miyaura cross-coupling and atropodiastereoselective Dieckmann-type macrocyclization as key steps. The Suzuki-Miyaura cross-coupling gave the best yields when it was catalyzed by a palladium-dioxygen complex.

Enantiocontrolled synthesis of a tetracyclic aminal corresponding to the core subunit of diazonamide A.

A chiral benzylic ether serves as an auxiliary for oxindole carboxylation (dr 5.2:1.0) that sets C10 configuration in a potential diazonamide precursor. The chiral substituent allows diastereomer separation and departs during a subsequent acid-catalyzed ring closure to form a tetracyclic aminal. With suitable N-protection, crystallization affords the aminal with 98-99% ee.

Electrophilic C-H Borylation and Related Reactions of B-H Boron Cations.

Catalytic procedures are described for aminedirected borylation of aliphatic and aromatic tertiary amine boranes. Sequential double borylation is observed in cases where two or more C-H bonds are available that allow 5-center or 6-center intramolecular borylation. The HNTf2 catalyzed borylation of benzylamine boranes provides a practical means for the synthesis of ortho-substituted arylboronic acid derivatives, suitable for Suzuki-Miyaura cross-coupling applications.

Weakly stabilized primary borenium cations and their dicationic dimers.

Hydride abstraction from monocationic hydride bridged salts [H(H2B-L)2](+) [B(C6F5)4]¯ (L = Lewis base) generates an observable primary borenium cation for L = iPr2NEt, but with L = Me3N, Me2NPr, or several N-heterocyclic carbenes, highly reactive dicationic dimers are formed.

Stille coupling of an aziridinyl stannatrane.

An aziridinyl stannatrane 8 couples with aryl or alkenyl halides RX under modified Stille conditions to afford substituted aziridines. Efficient coupling at room temperature is possible in the best examples in the presence of ((t)Bu3P)2Pd and CuOP(O)Ph2 (CuDPP).

P-directed borylation of phenols.

Internal borylation occurs upon activation of aryl di-isopropylphosphinite boranes with HNTf(2) to give heterocyclic intermediates that can be reductively quenched to afford 6 or treated with KHF(2) to give the phenolic potassium aryl trifluoroborate salts 10. The latter salts are useful for Pd-catalyzed coupling with aryl iodides under Molander conditions, provided that precautions are taken to remove the KNTf(2) byproduct from the preceding KHF(2) step.

Borenium ion catalyzed hydroboration of alkenes with N-heterocyclic carbene-boranes.

Treatment of alkenes such as 3-hexene, 3-octene, and 1-cyclohexyl-1-butene with the N-heterocyclic carbene (NHC)-derived borane 2 and catalytic HNTf(2) (Tf = trifluoromethanesulfonyl (CF(3)SO(2))) effects hydroboration at room temperature. With 3-hexene, surprisingly facile migration of the boron atom from C(3) of the hexyl group to C(2) was observed over a time scale of minutes to hours. Oxidative workup gave a mixture of alcohols containing 2-hexanol as the major product. A similar preference for the C(2) alcohol was observed after oxidative workup of the 3-octene and 1-cyclohexyl-1-butene hydroborations. NHC-borenium cations (or functional equivalents) are postulated as the species that accomplish the hydroborations, and the C(2) selective migrations are attributed to the four-center interconversion of borenium cations with cationic NHC-borane-olefin π-complexes.

Mechanistic variations in ionic hydrogenation of unsaturated phosphine and amine boranes.

Internal hydride transfer occurs when tethered carbocations are generated from unsaturated phosphine or phosphinite boranes. 3-Methylenecyclohexyl-derived boranes 12 or 18 react with MsOH to give ionic hydrogenation products with high syn-selectivity. With unsaturated amine boranes, initial hydrogen evolution gives BH(2)(OMs) complexes, but IH occurs using excess MsOH in a slower second stage. A diastereoselective reaction occurs from 26b using camphorsulfonic acid (first stage) and MsOH (second stage), affording 33 (68% ee) after hydrolysis.

Reactivity of aziridinomitosene derivatives related to FK317 in the presence of protic nucleophiles.

The syntheses and reactivity of N-TBDPS and N-trityl protected derivatives of an aziridinomitosene corresponding to FK317 are described. New reactivity patterns were observed for these highly sensitive and functionally dense heterocycles under mild nucleophilic conditions approaching the threshold for degradation. Thus, the silyl or trityl protected aziridinomitosene reacted with Cs(2)CO(3)/CD(3)OD to give isomeric products where substitution occurred at C(10) and C(9a) (mitomycin numbering) providing a CD(3) ether and a CD(3) hemiaminal, respectively. These findings show that heterolysis at C(10) is faster than at aziridine C(1), in contrast to the behavior of typical aziridinomitosenes in the mitomycin series. The labile N-TBDPS hemiaminal and the more stable N-trityl hemiaminal resemble the mitomycin K substitution pattern. A reagent consisting of CsF in CF(3)CH(2)OH/CH(3)CN desilylated a simple N-TBDPS aziridine but caused nucleophilic cleavage at C(1) as well as C(10) without cleavage of the N-TBPDS group in the fully functionalized penultimate aziridinomitosene. The high reactivity of the C(10) carbamate with nucleophiles precludes the use of deprotection methodology that requires N-protonation for fully functionalized aziridinomitosenes in the FK317 series.

N-Directed aliphatic C-H borylation using borenium cation equivalents.

Highly electrophilic boron cations derived from hindered amine borane complexes have been shown to undergo intramolecular aliphatic C-H borylation.

Metalated aziridines for cross-coupling with aryl and alkenyl halides via palladium catalysis.

The palladium-catalyzed coupling of an aziridinylzinc chloride intermediate with alkenyl and aryl halides has been demonstrated. The method provides products with retention of aziridine stereochemistry. The utility of the coupling procedure is illustrated in the synthesis of structures related to l-furanomycin.

Aziridinomitosanes via lactam cyclization.

Aziridinomitosane ketones 4 and 24 are accessed by internal acyl anion equivalent-lactam cyclization of 29 in a convergent route. The key aziridinolactam 6 is prepared by tin-lithium exchange via the lithiated aziridine 11.

Catalytic parallel kinetic resolution under homogeneous conditions.

Two complementary chiral catalysts, the phosphine 8d and the DMAP-derived ent-23b, are used simultaneously to selectively activate a mixture of two different achiral anhydrides as acyl donors under homogeneous conditions. The resulting activated intermediates 25 and 26 react with the racemic benzylic alcohol 5 to form enantioenriched esters (R)-24 and (S)-17 by fully catalytic parallel kinetic resolution (PKR). The aroyl ester (R)-24 is obtained with near-ideal enantioselectivity for the PKR process, but (S)-17 is contaminated by ca. 8% of the minor enantiomer (R)-17 resulting from a second pathway via formation of mixed anhydride 27 and its activation by 8d.

Superelectrophilic intermediates in nitrogen-directed aromatic borylation.

The first examples of borylation under conditions of borenium ion generation from hydrogen-bridged boron cations are described. The observable H-bridged cations are generated by hydride abstraction from N,N-dimethylamine boranes Ar(CH(2))(n)NMe(2)BH(3) using Ph(3)C(+) (C(6)F(5))(4)B(-) (TrTPFPB) as the hydride acceptor. In the presence of excess TrTPFPB, the hydrogen-bridged cations undergo internal borylation to afford cyclic amine borane derivatives with n = 1-3. The products are formed as the corresponding cyclic borenium ions according to reductive quenching experiments and (11)B and (1)H NMR spectroscopy in the case with Ar = C(6)H(5) and n = 1. The same cyclic borenium cation is also formed from the substrate with Ar = o-C(6)H(4)SiMe(3) via desilylation, but the analogous system with Ar = o-C(6)H(4)CMe(3) affords a unique cyclization product that retains the tert-butyl substituent. An ortho-deuterated substrate undergoes cyclization with a product-determining isotope effect of k(H)/k(D) 2.8. Potential cationic intermediates have been evaluated using B3LYP/6-31G* methods. The computations indicate that internal borylation from 14a occurs via a C-H insertion transition state that is accessible from either the borenium pi complex or from a Wheland intermediate having nearly identical energy. The Ar = o-C(6)H(4)SiMe(3) example strongly favors formation of the Wheland intermediate, and desilylation occurs via internal SiMe(3) migration from carbon to one of the hydrides attached to boron.

Stereocontrol in N-directed hydroboration: synthesis of amino alcohols related to the piperidine alkaloids.

Treatment of 2-(2'-alkenyl)-piperidine boranes with iodine or triflic acid induces internal hydroboration with high regiocontrol, even with a terminal alkene (R = H). Good stereocontrol is possible for the N-benzyl substrates. Comparisons with acyclic model structures show that the source of regiocontrol with the terminal alkene is due to a steric effect of the axial piperidine C(3,5) hydrogens that destabilize the competing bridged bicyclic transition state.

AcOLeDMAP and BnOLeDMAP: conformationally restricted nucleophilic catalysts for enantioselective rearrangement of indolyl acetates and carbonates.

The rate of indolyl O- to C-acetyl or carboxyl rearrangement is accelerated by the electron-withdrawing N-diphenylacetyl group (DPA) using the conformationally restricted chiral catalysts AcOLeDMAP (12b) and BnOLeDMAP (13b). Highly enantioselective conversion to quaternary C-acetylated and C-carboxylated oxindoles is observed, even for substrates containing branched substituents. The rearrangement of the carboxylate substrates 19 occurs with complementary enantiofacial selectivity using catalyst 13b compared to the acetyl migrations of 16 catalyzed by 12b. Access to N-unsubstituted oxindoles is demonstrated by DPA cleavage with Et(2)NH.