Synthesis of PDE IVb Inhibitors. 3. Synthesis of (+)-, (−)-, and (±)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-pyrrolizin-3-one via Reductive Domino Transformations of 3-β-Carbomethoxyethyl-Substituted Six-Membered Cyclic Nitronates

Abstract

Simple three-step asymmetric and racemic syntheses of GlaxoSmithKline's highly potent PDE IVb inhibitor 1 were developed. The suggested approach is based on reductive domino transformations of 3-β-carbomethoxyethyl-substituted six-membered cyclic nitronates, which are easily accessed by a stereoselective [4 + 2] cycloaddition of an appropriate nitroalkene to vinyl ethers. In vitro studies of PDE IVb inhibition by enantiomeric pyrrolizidinones (+)-1 and (-)-1 were performed.

Catalytic Reductive Amination of Aldehydes and Ketones With Nitro Compounds: New Light on an Old Reaction

“…In most of these reactions, standard hydrogenation catalysts like Pd/C, Raney nickel and Adam's catalyst were used. The stereochemical outcome of the intramolecular reductive amination can be controlled by the nature of hydrogenation catalyst (Sukhorukov et al, 2012), albeit the diastereoselectivity is moderate in many cases (Zhu et al, 2010;Lu et al, 2012). The initial γnitrocarbonyl compounds are readily accessed by the Michael addition of nitroalkanes to α,β-unsaturated carbonyl compounds (Ballini et al, 2005) or by the addition of aldehydes/ketones to conjugated nitroalkenes (Barrett and Graboski, 1986;Berner et al, 2002) (Figure 2e).…”

“…In this process, two sequential reductive amination reactions lead to the formation of a fully unsymmetrically substituted tertiary amine motif. In another example shown in Figure 2e, the synthesis of a potent PDE4 inhibitor was accomplished by a catalytic cascade recyclization of a cyclic nitronate involving hydrogenolysis of NO 2 group, intramolecular reductive amination forming a pyrrolidine ring, and subsequent lactamization (Sukhorukov et al, 2012).…”

Recent Advances in the Synthesis and Chemistry of Nitronates

“…In recent years, several other novel transformations of nitronates have been reported, namely [3,3]-sigmatropic rearrangement in O-allyl nitronates, 66 [3+2]/retro-[n+2] cycloaddition processes, 67 Beckman-type rearrangements of nitronates, 68 ring contraction of six-membered cyclic nitronates to pyrrolidine 69 and pyrroline 70 derivatives. The discussion of these specific transformations falls beyond the scope of this short review.…”

A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds

“…For 25 example, three bi-connective building blocks -the aldehyde 87, the enol ether 88, and the methoxycarbonyl-substituted nitro compound 89 -were exploited in the synthesis of the phosphodiesterase (PDE) IVb inhibitor 90 (Scheme 13). 41 Initially, the aldehyde 87 and the nitro compound 89 were Examples of scaffolds that may be prepared using a related two-component process exploiting cyclic imines. 40 The power of approaches to small molecule scaffolds further increases with the connectivity of the building blocks used.…”

“…For example, three bi-connective building blocks -the aldehyde 87, the enol ether 88, and the methoxycarbonyl-substituted nitro compound 89 -were exploited in the synthesis of the phosphodiesterase (PDE) IVb inhibitor 90 (Scheme 13). 41 Initially, the aldehyde 87 and the nitro compound 89 were condensed to yield the a,b-unsaturated nitro compound 91. The nitroalkene 91 underwent efficient cycloaddition with the chiral enol ether 88a to give the nitronate 92 with good diastereoselectivity.…”