Diasteroselective Preparation of Cyclopropanols Using Methylene Bis(iodozinc)

A diastereoselective synthesis of trans-2-substituted cyclopropanols is outlined. Bimetallic CH2(ZnI)2 was found to react with α-chloroaldehydes to give cyclopropanols in yields of 64−89% and dr’s ≥ 10:1. The high trans-selectivity resulted from equilibration of the cyclopropoxide intermediates

Stereoselective Synthesis of β-Hydroxy Enamines, Aminocyclopropanes, and 1,3-Amino Alcohols via Asymmetric Catalysis

Tandem methods for the catalytic asymmetric preparation of enantioenriched β-hydroxy (E)-enamines and aminocyclopropanes are presented. The diastereoselective hydrogenation of enantioenriched (E)-trisubstituted hydroxy enamines to generate 1,2-disubstituted-1,3-amino alcohols is also outlined. These methods are initiated by highly regioselective hydroboration of N-tosyl-substituted ynamides with diethylborane to generate β-amino alkenyl boranes. In situ boron-to-zinc transmetalation generates β-amino alkenylzinc reagents. These functionalized vinylzinc intermediates are subsequently added to aldehydes in the presence of a catalyst derived from an enantioenriched amino alcohol (morpholino isoborneol, MIB). The catalyst promotes highly enantioselective C−C bond formation to provide β-hydroxy enamines in good isolated yields (68−86%) with 54−98% enantioselectivity. The intermediate zinc β-alkoxy enamines can be subjected to a tandem cyclopropanation to afford aminocyclopropyl carbinols with three continuous stereocenters in a one-pot procedure with good yields (72−82%), enantioselectivities of 76−94%, and >20:1 diastereomeric ratios. Diastereoselective hydrogenation of isolated enantioenriched β-hydroxy enamines over Pd/C furnished syn-1,2-disubstituted-1,3-amino alcohols in high yields (82−90%) with moderate to excellent diastereoselectivities. These methods were used in an efficient preparation of the enantioenriched precursor to PRC200-SS derivatives, which are potent serotonin−norepinephrine−dopamine reuptake inhibitors

Generation and Tandem Reactions of 1-Alkenyl-1,1-Heterobimetallics: Practical and Versatile Reagents for Organic Synthesis

A practical and straightforward method for generation of versatile 1-alkenyl-1,1-heterobimetallic intermediates and their application to construction of functionalized building blocks are disclosed. Beginning with readily available air-stable 1-alkynyl-1-boronate esters, hydroboration with dicyclohexylborane generates 1-alkenyl-1,1-diboro species. In situ transmetallation with dialkylzinc reagents furnishes 1-alkenyl-1,1-heterobimetallic intermediates. Direct treatment with aldehydes followed by workup allows isolation of B(pin)-substituted allylic alcohols in 70−95% yield. The B(pin)-substituted allylic alcohols react with NBS to afford (E)-α,β-unsaturated aldehydes in 51−77% yield via a semipinacol-type rearrangement. In situ treatment of 1-alkenyl-1,1-heterobimetallic intermediates with aldehydes followed by TBHP oxidation enables the preparation of α-hydroxy ketones. Under optimized conditions, addition of 1-alkenyl-1,1-heterobimetallic intermediates to a variety of protected α- and β-hydroxy aldehydes proceeds with good to excellent control over diastereoselectivity to furnish differentially protected dihydroxy ketones. The 1-alkenyl-1,1-heterobimetallic intermediates have also been employed in tandem aldehyde addition/Suzuki cross-coupling reactions to provide densely functionalized allylic alcohols in good to excellent yields

Generation and Tandem Reactions of 1-Alkenyl-1,1-Heterobimetallics: Practical and Versatile Reagents for Organic Synthesis

A practical and straightforward method for generation of versatile 1-alkenyl-1,1-heterobimetallic intermediates and their application to construction of functionalized building blocks are disclosed. Beginning with readily available air-stable 1-alkynyl-1-boronate esters, hydroboration with dicyclohexylborane generates 1-alkenyl-1,1-diboro species. In situ transmetallation with dialkylzinc reagents furnishes 1-alkenyl-1,1-heterobimetallic intermediates. Direct treatment with aldehydes followed by workup allows isolation of B(pin)-substituted allylic alcohols in 70−95% yield. The B(pin)-substituted allylic alcohols react with NBS to afford (E)-α,β-unsaturated aldehydes in 51−77% yield via a semipinacol-type rearrangement. In situ treatment of 1-alkenyl-1,1-heterobimetallic intermediates with aldehydes followed by TBHP oxidation enables the preparation of α-hydroxy ketones. Under optimized conditions, addition of 1-alkenyl-1,1-heterobimetallic intermediates to a variety of protected α- and β-hydroxy aldehydes proceeds with good to excellent control over diastereoselectivity to furnish differentially protected dihydroxy ketones. The 1-alkenyl-1,1-heterobimetallic intermediates have also been employed in tandem aldehyde addition/Suzuki cross-coupling reactions to provide densely functionalized allylic alcohols in good to excellent yields

Stereoselective Synthesis of β-Hydroxy Enamines, Aminocyclopropanes, and 1,3-Amino Alcohols via Asymmetric Catalysis

Tandem methods for the catalytic asymmetric preparation of enantioenriched β-hydroxy (E)-enamines and aminocyclopropanes are presented. The diastereoselective hydrogenation of enantioenriched (E)-trisubstituted hydroxy enamines to generate 1,2-disubstituted-1,3-amino alcohols is also outlined. These methods are initiated by highly regioselective hydroboration of N-tosyl-substituted ynamides with diethylborane to generate β-amino alkenyl boranes. In situ boron-to-zinc transmetalation generates β-amino alkenylzinc reagents. These functionalized vinylzinc intermediates are subsequently added to aldehydes in the presence of a catalyst derived from an enantioenriched amino alcohol (morpholino isoborneol, MIB). The catalyst promotes highly enantioselective C−C bond formation to provide β-hydroxy enamines in good isolated yields (68−86%) with 54−98% enantioselectivity. The intermediate zinc β-alkoxy enamines can be subjected to a tandem cyclopropanation to afford aminocyclopropyl carbinols with three continuous stereocenters in a one-pot procedure with good yields (72−82%), enantioselectivities of 76−94%, and >20:1 diastereomeric ratios. Diastereoselective hydrogenation of isolated enantioenriched β-hydroxy enamines over Pd/C furnished syn-1,2-disubstituted-1,3-amino alcohols in high yields (82−90%) with moderate to excellent diastereoselectivities. These methods were used in an efficient preparation of the enantioenriched precursor to PRC200-SS derivatives, which are potent serotonin−norepinephrine−dopamine reuptake inhibitors

Diasteroselective Preparation of Cyclopropanols Using Methylene Bis(iodozinc)

A diastereoselective synthesis of trans-2-substituted cyclopropanols is outlined. Bimetallic CH2(ZnI)2 was found to react with α-chloroaldehydes to give cyclopropanols in yields of 64−89% and dr’s ≥ 10:1. The high trans-selectivity resulted from equilibration of the cyclopropoxide intermediates

Insight into Substrate Binding in Shibasaki’s Li₃(THF)_<i>n</i>(BINOLate)₃Ln Complexes and Implications in Catalysis

Heterobimetallic Lewis acids M3(THF)n(BINOLate)3Ln [M = Li, Na, K; Ln = lanthanide(III)] are exceptionally useful asymmetric catalysts that exhibit high levels of enantioselectivity across a wide range of reactions. Despite their prominence, important questions remain regarding the nature of the catalyst−substrate interactions and, therefore, the mechanism of catalyst operation. Reported herein are the isolation and structural characterization of 7- and 8-coordinate heterobimetallic complexes Li3(THF)4(BINOLate)3Ln(THF) [Ln = La, Pr, and Eu], Li3(py)5(BINOLate)3Ln(py) [Ln = Eu and Yb], and Li3(py)5(BINOLate)3La(py)2 [py = pyridine]. Solution binding studies of cyclohexenone, DMF, and pyridine with Li3(THF)n(BINOLate)3Ln [Ln = Eu, Pr, and Yb] and Li3(DMEDA)3(BINOLate)3Ln [Ln = La and Eu; DMEDA = N,N′-dimethylethylene diamine] demonstrate binding of these Lewis basic substrate analogues to the lanthanide center. The paramagnetic europium, ytterbium, and praseodymium complexes Li3(THF)n(BINOLate)3Ln induce relatively large lanthanide-induced shifts on substrate analogues that ranged from 0.5 to 4.3 ppm in the 1H NMR spectrum. X-ray structure analysis and NMR studies of Li3(DMEDA)3(BINOLate)3Ln [Ln = Lu, Eu, La, and the transition metal analogue Y] reveal selective binding of DMEDA to the lithium centers. Upon coordination of DMEDA, six new stereogenic nitrogen centers are formed with perfect diastereoselectivity in the solid state, and only a single diastereomer is observed in solution. The lithium-bound DMEDA ligands are not displaced by cyclohexenone, DMF, or THF on the NMR time scale. Use of the DMEDA adduct Li3(DMEDA)3(BINOLate)3La in three catalytic asymmetric reactions led to enantioselectivities similar to those obtained with Shibasaki’s Li3(THF)n(BINOLate)3La complex. Also reported is a unique dimeric [Li6(en)7(BINOLate)6Eu2][μ-η1,η1-en] structure [en = ethylenediamine]. On the basis of these studies, it is hypothesized that the lanthanide in Shibasaki’s Li3(THF)n(BINOLate)3Ln complexes cannot bind bidentate substrates in a chelating fashion. A hypothesis is also presented to explain why the lanthanide catalyst, Li3(THF)n(BINOLate)3La, is often the most enantioselective of the Li3(THF)n(BINOLate)3Ln derivatives

Insight into Substrate Binding in Shibasaki’s Li₃(THF)_<i>n</i>(BINOLate)₃Ln Complexes and Implications in Catalysis

Heterobimetallic Lewis acids M3(THF)n(BINOLate)3Ln [M = Li, Na, K; Ln = lanthanide(III)] are exceptionally useful asymmetric catalysts that exhibit high levels of enantioselectivity across a wide range of reactions. Despite their prominence, important questions remain regarding the nature of the catalyst−substrate interactions and, therefore, the mechanism of catalyst operation. Reported herein are the isolation and structural characterization of 7- and 8-coordinate heterobimetallic complexes Li3(THF)4(BINOLate)3Ln(THF) [Ln = La, Pr, and Eu], Li3(py)5(BINOLate)3Ln(py) [Ln = Eu and Yb], and Li3(py)5(BINOLate)3La(py)2 [py = pyridine]. Solution binding studies of cyclohexenone, DMF, and pyridine with Li3(THF)n(BINOLate)3Ln [Ln = Eu, Pr, and Yb] and Li3(DMEDA)3(BINOLate)3Ln [Ln = La and Eu; DMEDA = N,N′-dimethylethylene diamine] demonstrate binding of these Lewis basic substrate analogues to the lanthanide center. The paramagnetic europium, ytterbium, and praseodymium complexes Li3(THF)n(BINOLate)3Ln induce relatively large lanthanide-induced shifts on substrate analogues that ranged from 0.5 to 4.3 ppm in the 1H NMR spectrum. X-ray structure analysis and NMR studies of Li3(DMEDA)3(BINOLate)3Ln [Ln = Lu, Eu, La, and the transition metal analogue Y] reveal selective binding of DMEDA to the lithium centers. Upon coordination of DMEDA, six new stereogenic nitrogen centers are formed with perfect diastereoselectivity in the solid state, and only a single diastereomer is observed in solution. The lithium-bound DMEDA ligands are not displaced by cyclohexenone, DMF, or THF on the NMR time scale. Use of the DMEDA adduct Li3(DMEDA)3(BINOLate)3La in three catalytic asymmetric reactions led to enantioselectivities similar to those obtained with Shibasaki’s Li3(THF)n(BINOLate)3La complex. Also reported is a unique dimeric [Li6(en)7(BINOLate)6Eu2][μ-η1,η1-en] structure [en = ethylenediamine]. On the basis of these studies, it is hypothesized that the lanthanide in Shibasaki’s Li3(THF)n(BINOLate)3Ln complexes cannot bind bidentate substrates in a chelating fashion. A hypothesis is also presented to explain why the lanthanide catalyst, Li3(THF)n(BINOLate)3La, is often the most enantioselective of the Li3(THF)n(BINOLate)3Ln derivatives

Impact of Na− and K−C π-Interactions on the Structure and Binding of M₃(sol)<i>_n</i>(BINOLate)₃Ln Catalysts

Shibasaki's heterobimetallic complexes M3(THF)n(BINOLate)3Ln [M = Li, Na, K; Ln = lanthanide(III)] are among the most successful asymmetric Lewis acid catalysts. Why does M3(THF)n(BINOLate)3Ln readily bind substrates when M = Li but not when M = Na or K? Structural studies herein indicate Na− and K−C cation−π interactions and alkali metal radius may be more important than even lanthanide radius. Also reported is a novel polymeric [K3(THF)2(BINOLate)3Yb]n structure that provides the first evidence of interactions between M3(THF)n(BINOLate)3Ln complexes

Insight into Substrate Binding in Shibasaki’s Li₃(THF)_<i>n</i>(BINOLate)₃Ln Complexes and Implications in Catalysis

Heterobimetallic Lewis acids M3(THF)n(BINOLate)3Ln [M = Li, Na, K; Ln = lanthanide(III)] are exceptionally useful asymmetric catalysts that exhibit high levels of enantioselectivity across a wide range of reactions. Despite their prominence, important questions remain regarding the nature of the catalyst−substrate interactions and, therefore, the mechanism of catalyst operation. Reported herein are the isolation and structural characterization of 7- and 8-coordinate heterobimetallic complexes Li3(THF)4(BINOLate)3Ln(THF) [Ln = La, Pr, and Eu], Li3(py)5(BINOLate)3Ln(py) [Ln = Eu and Yb], and Li3(py)5(BINOLate)3La(py)2 [py = pyridine]. Solution binding studies of cyclohexenone, DMF, and pyridine with Li3(THF)n(BINOLate)3Ln [Ln = Eu, Pr, and Yb] and Li3(DMEDA)3(BINOLate)3Ln [Ln = La and Eu; DMEDA = N,N′-dimethylethylene diamine] demonstrate binding of these Lewis basic substrate analogues to the lanthanide center. The paramagnetic europium, ytterbium, and praseodymium complexes Li3(THF)n(BINOLate)3Ln induce relatively large lanthanide-induced shifts on substrate analogues that ranged from 0.5 to 4.3 ppm in the 1H NMR spectrum. X-ray structure analysis and NMR studies of Li3(DMEDA)3(BINOLate)3Ln [Ln = Lu, Eu, La, and the transition metal analogue Y] reveal selective binding of DMEDA to the lithium centers. Upon coordination of DMEDA, six new stereogenic nitrogen centers are formed with perfect diastereoselectivity in the solid state, and only a single diastereomer is observed in solution. The lithium-bound DMEDA ligands are not displaced by cyclohexenone, DMF, or THF on the NMR time scale. Use of the DMEDA adduct Li3(DMEDA)3(BINOLate)3La in three catalytic asymmetric reactions led to enantioselectivities similar to those obtained with Shibasaki’s Li3(THF)n(BINOLate)3La complex. Also reported is a unique dimeric [Li6(en)7(BINOLate)6Eu2][μ-η1,η1-en] structure [en = ethylenediamine]. On the basis of these studies, it is hypothesized that the lanthanide in Shibasaki’s Li3(THF)n(BINOLate)3Ln complexes cannot bind bidentate substrates in a chelating fashion. A hypothesis is also presented to explain why the lanthanide catalyst, Li3(THF)n(BINOLate)3La, is often the most enantioselective of the Li3(THF)n(BINOLate)3Ln derivatives