Iterative Multifunctionalization of Unactivated C−H Bonds in Piperidines by Way of Intramolecular Rh(II)-Catalyzed Aminations

Abstract

Efficient stereocontrolled synthesis of di-, tri-, tetra-, and pentasubstituted piperidines from simple 2-sulfamoyloxymethyl piperidine derivatives has been performed by way of intramolecular Rh-catalyzed amination of saturated C-H bonds. In this process, the sulfamoyloxymethyl arm was directly or indirectly involved in the functionalization of every saturated methylene group of the piperidine ring at C-3, C-4, C-5, and C-6. Direct application to the total synthesis of iminosugars and related compounds demonstrated the synthetic potential of this strategy.

Metal-Catalyzed Nitrogen-Atom Transfer Methods for the Oxidation of Aliphatic C–H Bonds

“…A wide range of common nucleophiles (allylsilanes, alkynylzinc reagents, silyl enol ethers, silylhydrides, tethered phenols) will engage in this process. 37,38 Product diastereoselectivity in many instances is exceptional (>20:1), and has been rationalized through a combined Stevens/Felkin-Ahn model.…”

Searching for Glycomimetics That Target Protein Misfolding in Rare Diseases: Successes, Failures, and Unexpected Progress Made in Organic Synthesis

“…The versatility of bicyclic intermediate 64 was further probed by stepwise functionalization into more-complex structures such as 65 (in racemic form). 89 This amino iminosugar, obtained after a journey in the fascinating world of C-H functionalization, was not the product we originally desired. The synthetic target I was missed this time, but relevant progress was made in the field of metal-catalyzed nitrene insertion reactions.…”

“…On the basis of this starting point, we have devised unique bond-construction strategies in nitrogen-containing heterocycles involving iterative multifunctionalization of non-activated C-H bonds. 89 In this process, the sulfamoyloxymethyl group is used several times as a molecular activating arm, permitting the formation of a C-C or C-N bond or a C=C double bond. We have, for example, designed a strategy in which the sulfamoyloxy activating arm was directly or indirectly involved in the functionalization of every saturated methylene group of a monosubstituted piperidine (Scheme 24).…”

“…We have, for example, designed a strategy in which the sulfamoyloxy activating arm was directly or indirectly involved in the functionalization of every saturated methylene group of a monosubstituted piperidine (Scheme 24). 89 This approach exploited the reactivity of cyclic enamine 61, which was readily obtained from 41′ by reaction in acetic acid. Iodomethoxylation of the α,β-unsaturated N-tosylpiperidine 61 with molecular iodine and sodium methoxide in methanol, followed by 1,8-diazabicyclo [5.4.0]undec-7-ene-mediated dehydroiodination provided the desired 6-methoxy-tetrahydropyridine 62 with a double bond tactically positioned at C(4)-C(5).…”

“…92 The unexpected regioselectivity observed with piperidine 40 led eventually to a new original bond-construction strategy based on iterative multifunctionalization of nonactivated C-H bonds in nitrogen-containing heterocycles. 89,93 …”