Catalytic Asymmetric Allylboration of Indoles and Dihydroisoquinolines with Allylboronic Acids: Stereodivergent Synthesis of up to Three Contiguous Stereocenters

Abstract

Abstract:The catalytic asymmetric allylboration of cyclic imines with g,g-disubstituted allylboronic acids provides products with adjacent stereocenters in high yield and stereoselectivity.V arious electrophiles,i ncluding 3,4-dihydroisoquinolines and indoles,were prenylated in afully stereodivergent fashion by switching the E/Z geometry of the allylboronate and/or the enantiomer of the BINOL catalyst. 3-Methylindole provided products with three adjacent stereocenters with high stereoselectivity in one synthetic operation.The allylboration reaction has become an indispensable method for the stereoselective synthesis of homoallylic alcohols and amines.[1] Recently,o ur group described the first catalytic asymmetric synthesis of homoallylic alcohols from g,g-disubstituted allylboronic acids and ketones,furnishing products bearing adjacent quaternary stereocenters. [2] Extending this reaction to imines for the synthesis of chiral amines with adjacent stereocenters is important as these motifs are common in drug-like molecules and natural products.[3] In addition, ac omparison of the asymmetric allylboration of ketones and imines using similar catalysts is highly interesting in terms of the stereoinduction.Although great progress has been made towards the allylboration of imines, [4] asymmetric examples have remained sparse.[5] Hoveyda [5f] and co-workers recently reported on the catalytic asymmetric allylboration of phosphinoyl imines,w hich provides access to enantioenriched products containing adjacent stereocenters.While this work is impressive,t he substrate scope is currently limited to monosubstitution at the g-position of the allylboronate,a nd only the anti products could be formed. Ac omplementary approach has been reported by the Aggarwal group [5g] for the enantiospecific allylboration of imines,k etimines,a nd indoles with enantioenriched g,g-disubstituted allylboronates. This method is impressive in its ability to provide amines with adjacent quaternary stereocenters in as tereodivergent manner,y et it proceeds through chirality transfer and requires enantioenriched precursors.M erging the merits of these two methods into am anifold wherein achiral g,gdisubstituted allylboronates undergo allylboration with imines in ac atalytic asymmetric fashion would be highly desirable.I no ur quest to fill this niche,w et hought that the allylboration of indole would be af ertile proving ground. Allylborations at the C2 position of indole have been reported by the groups of Aggarwal,[5g] Batey, [6] Bubnov, [7] and our group.[4c] Af ormidable challenge is to realize these reactions by asymmetric catalysis.In our previous studies, [4c] we found that ah ighly diastereoselective allylboration of indole could be achieved under mild conditions using a g,g-disubstituted geranylboronic acid, thus forming an indoline bearing an exocyclic quaternary stereocenter.C hong [5b] and Wu have reported on the asymmetric allylboration of cyclic imines using BINOL modified allylboronates whereas the Schaus group [8] described t...

Organocatalytic Synthesis of α-Trifluoromethyl Allylboronic Acids by Enantioselective 1,2-Borotropic Migration

“…The racemic background reaction can be avoided by addition of EtOH to the reaction mixture, which forms unreactive alkylboronic esters 2-OEt , which are weaker Lewis acids 37 than the corresponding boroxines 2 . 30 , 31 Because of the dynamic covalent bonding 38 ability of boron, BINOL 4 undergoes transesterification with 2-OEt to form chiral alkenyl boronate A . Exchange of the alkyl group to an aromatic moiety leads to a substantial increase in the Lewis acidity of boron, 37 and therefore, A and 3 form ate complex B in the stereoinduction step of the process (see Figure S3 ).…”

“…As we reported previously, in the presence of molecular sieves (or other drying agents), pure allylboronic acids form very reactive allylboroxines. 2 , 30 , 31 , 37 Purified 1a in the presence of molecular sieves reacted with 6a in just 10 min to afford 7a ( Table 2 , entry 1). Notably, the enantioselectivities with purified and in situ-formed 1a were identical.…”

“…Acyclic aliphatic ketone 6e reacted in high yield (72%) but with only 82% ee, affording densely functionalized tertiary homoallyl alcohol 7i . The synthetic utility of purified chiral allylboronic acids was further demonstrated by allylboration of indoles 11 , 31 , 51 , 52 6f and 6g with 1d to afford 7j and 7k with high selectivities (entries 9 and 10). From skatole 6g , the E -alkenyl-CF 3 product 7k with three adjacent stereocenters was formed with 89% ee.…”

“…From skatole 6g , the E -alkenyl-CF 3 product 7k with three adjacent stereocenters was formed with 89% ee. Isoquinoline derivative 31 , 53 6h reacted with purified 1d to afford 7m with 93% ee in 54% yield. Allylboration of 6i ( 54 , 55 ) with 1a gave α-amino acid derivative 7n with 98% ee in 72% yield.…”

Asymmetric Traceless Petasis Borono‐Mannich Reactions of Enals: Reductive Transposition of Allylic Diazenes

“…The intermediate diazene is formed in situ by fragmentation of the corresponding allylic sulfonylhydrazide, synthesized by a chiral biphenol-catalyzed Petasis borono-Mannich reaction of sulfonylhydrazides, enals, and allylboronates (Scheme 1). [6][7] Subsequent rearrangement of the enantioenriched diazene, with concomitant extrusion of molecular nitrogen, results in the allylic transposition of chirality from the diazene stereocenter to the allylic, sp 2 hybridized carbon center. When a γ-substituted allylboronate (R 3 or R 4 = methyl) is employed, two tertiary stereocenters in a 1,4-relationship are generated in a stereoselective manner.…”