Organocatalytic Enantioselective Intramolecular Oxa-Michael Reaction of Enols: Synthesis of Chiral Isochromenes

Abstract

An unprecedented enantioselective intramolecular oxa-Michael reaction of enols has been described. A squaramide-containing tertiary amine based bifunctional organocatalyst efficiently activates the o-homoformyl chalcones to provide the chiral isochromenes in moderate yields and good to excellent enantioselectivities. Further, late-stage functionalizations of the vinyl ether moiety of the chiral isochromene products have also been exemplified.

Racemic hemiacetals as oxygen-centered pronucleophiles triggering cascade 1,4-addition/Michael reaction through dynamic kinetic resolution under iminium catalysis. Development and mechanistic insights

“…6 In fact, this type of reactions still represent one of the most challenging cases of conjugate addition of heteroatom-centered nucleophiles under organocatalytic activation because, in addition to reversibility issues, the typical oxygen-centered pronucleophiles, such as alcohols or carboxylic acids, typically show very poor reactivity towards Michael acceptors and normally undergo competitive 1,2-addition. Consequently, the reported examples of organocatalytic and enantioselective conjugate addition of oxygen pronucleophiles are limited to the use of oximes, 7 phenols, 8 enols, 9 alkoxyboronates, 10 hydroxylamines, 11 or peroxides 12 under iminium or H-bonding activation. 13 Organocatalytic cascade processes initiated by conjugate addition of O -nucleophiles have been mainly focused on the epoxidation of α,β-unsaturated carbonyls with peroxides 14 and some limited examples of conjugate addition followed by aldol, 15 Mannich, 16 Henry, 17 α-amination 18 and α-fluorination 19 have also been published.…”

Organocatalytic, Enantioselective Synthesis of Cyclohexadienone Containing Hindered Spirocyclic Ethers through an Oxidative Dearomatization/Oxa‐Michael Addition Sequence

“…[15] Ab ifunctional mechanism similar to those previously proposed for the squaramide/thiourea-based amino catalysts in the oxa-Michael reaction of enone [2,3] may be cited to explain the observed absolute stereochemistry. Ak etone functionality of the cyclohexadienone moiety of 3b was selectively reduced over benzyl ketone with DIBAL-H to provide 11 b with 2.9:1 d.r.…”

“…[1] Nevertheless,s uch moieties are ubiquitous in natural products and pharmaceuticals.A lthough, enantioselective intramolecular oxa-Michael addition is one of the most straightforward routes to chiral oxa-cycles, [2,3] the enantioselective synthesis of sterically hindered tetrahydrofurans/-pyrans through the oxa-Michael addition of a-tertiary alcohols constitutes adaunting, yet unsolved, challenge owing to their a-crowding and thereby reduced nucleophilicity. [1] Nevertheless,s uch moieties are ubiquitous in natural products and pharmaceuticals.A lthough, enantioselective intramolecular oxa-Michael addition is one of the most straightforward routes to chiral oxa-cycles, [2,3] the enantioselective synthesis of sterically hindered tetrahydrofurans/-pyrans through the oxa-Michael addition of a-tertiary alcohols constitutes adaunting, yet unsolved, challenge owing to their a-crowding and thereby reduced nucleophilicity.…”

“…Enantioselective synthesis of sterically hindered ethers such as tetrahydrofurans/-pyrans is al ong-standing challenge in organic chemistry. [1] Nevertheless,s uch moieties are ubiquitous in natural products and pharmaceuticals.A lthough, enantioselective intramolecular oxa-Michael addition is one of the most straightforward routes to chiral oxa-cycles, [2,3] the enantioselective synthesis of sterically hindered tetrahydrofurans/-pyrans through the oxa-Michael addition of a-tertiary alcohols constitutes adaunting, yet unsolved, challenge owing to their a-crowding and thereby reduced nucleophilicity. [4] Cyclohexadienone connected to atetrahydrofuran moiety in aspiro-fashion (CHD-spiro-THF) is afascinating skeleton found in natural products aculeatins A-D and an aculeatin analogue A, which are active antimalarial agents against the P. falciparum 3D7 strain (Figure 1a).…”

“…[11] In recent years,a symmetric oxa-Michael reactions using bifunctional organocatalysts bearing an H-bond donor moiety and at ertiary amino group on ac hiral scaffold, [12] has gained considerable momentum in catalytic endeavors. [2,3] As ap art of our effort to extend the power of these transformations, [3] we decided to utilize as imilar mode of action for the present reaction. First, an OD of substituted phenol 1b was performed using PhI(OAc) 2 as an oxidant to prepare the desired 4-hydroxy cyclohexadienone Ib,which was used for the asymmetric oxa-Michael addition in the presence of various organocatalysts as shown in Table 1( for details,s ee the Supporting Information).…”