(−)-Cytisine: Access to a stereochemically defined and functionally flexible piperidine scaffold

Abstract

N-Benzyl cytisine undergoes an efficient C(6)-N(7) cleavage via directed C(6) lithiation, borylation and oxidation to provide a "privileged" heterocyclic core unit comprising a highly functionalised, cis-3,5-disubstituted piperidine in enantiomerically pure form. The potential offered by this unit as a means to explore chemical space has been evaluated and methods have been defined (and illustrated) that allow for selective manipulation of N(1), C(3'), and the pyridone N. The pyridone core can also be diversified via bromination (at C(3'') and C(5'')) which is complementary to direct C-H activation based on Ir-catalyzed borylation to provide access to C(4''). The use of a boronate-based 1,2-migration as an alternative trigger to mediate C(6)-N(7) cleavage of cytisine was evaluated but failed. However, the stability of the intermediate boronate opens a new pathway for the elaboration of cytisine itself using both Matteson homologation and Zweifel olefination.

Oxidative Fragmentation of Cytisine as an Entry to the Bis(piperidine) Scaffold of Virgidivarine

“…The lithiation of N-alkylcytisine (first reported by Rouden 15 ) is achieved under remarkably mild conditions using LDA and trapping of the resulting C10-lithiated intermediate with a boron (or silyl) electrophile provides an effective vehicle for subsequent oxidative cleavage of the C10-N1 bond. Details have been reported previously 4,8 but C10 metalation does require use of an N-alkyl (Me or Bn) derivative; in our hands cytisine itself fails to lithiate and use of N-Boc cytisine leads preferentially to α-lithiation (at C11/C13) adjacent to the piperidine N.…”

“…1,2 These encompass "de novo" in silico approaches based on understanding the structural requirements of a drug target and "evolving" a core fragment or fragments and are exemplified by widely available commercial products such as SPOUT, 3a SPARK 3b and LigBuilder 2 3c (and others), and well-established combinatorial methodologies and, more recently, diversity-oriented and chemical genetics approaches. 4 These approaches often rely on use of a molecular scaffold as a starting point, where that scaffold is (i) known to be synthetically accessible and (ii) well-positioned in terms of its downstream versatility; so readily manipulated at a variety of different sites within the scaffold. In that regard, natural products have long inspired drug discovery efforts, either directly or indirectly serving as a guide to crucial structure-activity profiles.…”

“…11 The utility of the core cis-3,5-disubstituted piperidine in terms of further scaffold elaboration was illustrated further using N-benzylcytisine 5 which allows access to a range of variants (6) with functionality available at a number of different sites: the piperidine amine, pyridone N, introduction of a carboxylic acid and exploiting the intrinsic reactivity of the 2-pyridone unit at C3′/C5′ (via electrophilic bromination) and at C4′ (via Ir-mediated CH activation) (Scheme 1). 4,12 Scheme 1. Scaffold elaboration via fragmentation of (-)-cytisine In this paper, this chemistry is further developed to provide a fully-reduced, stereochemically defined bis(piperidine) that was prompted by the structure of virgidivarine 7, 13 which is structurally related to cytisine and fully reduced lupin alkaloid sparteine.…”

The Symbiotic Relationship Between Drug Discovery and Organic Chemistry

“…[195] One more recent example describes as imilara pproacht o designaNP-derived compound library that also utilizes aspects of DOS. [196] In particular, the degradation-functionalization synthetic sequence is applied to the alkaloid cytisine through efficient C-6ÀN-7 bond cleavage (Scheme 11). As a result,alibrary with five diversity points was generated around the chiral piperidine-derived scaffold.…”

“…One more recent example describes a similar approach to design a NP‐derived compound library that also utilizes aspects of DOS . In particular, the degradation–functionalization synthetic sequence is applied to the alkaloid cytisine through efficient C‐6−N‐7 bond cleavage (Scheme ).…”