Enantioselective synthesis of C2-functionalized, N-protected morpholines and orthogonally N,N′-protected piperazines via organocatalysis

Abstract

In this Letter, we describe a novel three-step, one-pot procedure for the enantioselective synthesis of N-benzyl protected morpholines and orthogonally N,N′-protected piperazines with chiral alkyl groups installed at the C2 position of each heterocyclic core via organocatalysis. This methodology allows for the rapid preparation of functionalized morpholines and piperazines that are not readily accessible through any other chemistry in good to excellent % ee (55–98% ee).

Organocatalysis in Synthesis: L-Proline as an Enantioselective Catalyst in the Synthesis of Pyrans and Thiopyrans

“…The addition of active methylene reagents to arylidenemalononitrile in the presence of homogeneous basic catalysts has been extensively used in the past for the synthesis of these compounds [7,8,9,10,11,12]. Interest in these reactions has recently been revived [13,14] with the aim of developing green laboratory reaction conditions [15,16], such as replacing homogeneous catalysis with heterogeneous ones [17,18,19,20], to synthesize enantiomerically pure pyrans for which diverse biological applications were noticed [21,22,23] and patented [24,25,26]. Many of these new approaches use multicomponent reactions and either an organocatalyst [27,28] or sometimes metal or nanoparticulated catalysts [29,30,31].…”

A general, enantioselective synthesis of β- and γ-fluoroamines

“…1); however, the configurational instability of the incipient α-fluoroaldehyde required its immediate conversion to the β-fluoroamine. 7,8 Later efforts utilized a similar strategy, but employed the analogous α-chloroaldehydes, to access chiral N -terminal aziridines 15 and chiral morpholines and piperazines; 16 however, the configurational instability of the α-chloroaldehyde also necessitated immediate, one-pot use. To provide additional flexibility, we developed an approach (Fig.…”

“…2) that improved yields and % ee for the synthesis of chiral morpholines and piperazines by reducing the α-chloroaldehyde to an alcohol, converting the hydroxyl to a leaving group, displacing the leaving group with an amino alcohol or diamine followed by base-induced cyclization. 16,17 …”

A General, Enantioselective Synthesis of Protected Morpholines and Piperazines

“…A subsequent reductive amination step with an amine containing an embedded ‘O’ or ‘N’ nucleophile ( 3 or 4 ), such that after based-induced cyclization of either 5 or 6 , N -benzyl protected morpholines 7 and orthogonally N , N ′-protected piperazines 8 , respectively, were prepared with C2-functionalization. 12 While this result was gratifying, the methodology suffered from two key limitations: 1) the 3-step overall yield was low (13–50%) and 2) the % ee was variable (55–98% ee) due to the epimerization prone α-chloroaldehyde 2 . In fact, one trial where the α-chloroaldehyde 2 was left on the bench for hours prior to subsequent reductive amination led to an % ee erosion of greater than 30%.…”

“…10–12 Now the challenge was to convert 9a – d into the appropriate bis -electrophile that would allow for a chemoselective displacement of the primary leaving group – something not yet reported in the literature. After surveying a number of potential primary leaving groups (mesylate, tosylate and iodide), the triflate emerged as the optimal moiety to deliver congeners of 5 and 6 .…”