Stereocontrolled Annulations of Indolo[2,3‐a]quinolizidine‐Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine‐Type Derivatives

Abstract

Abstract:The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3-a]quinolizidine lactams 3 is studied. Pentacyclic 3-H/15-H trans adducts 5 are generated from Nind-unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen bears a Boc substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarovderived adducts is demonstrated by their conversion to allo and epiallo yohimbine-type targets.

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

“…The asymmetric synthesis of indoloquinolizidines was achieved starting from enantiopure tryptophanol, a methodology used previously by the groups of Allin [19,20] and Amat-Bosch [21,22,23,24,25,26,27] for the synthesis of several indole alkaloids. In this synthetic strategy, tryptophanol is used not only as the source of chirality, but is also used to incorporate the tryptamine moiety present in the target alkaloids [28,29].…”

Origin of the Base‐Dependent Facial Selectivity in Annulation Reactions of Nazarov‐Type Reagents with Unsaturated Indolo[2,3‐a]quinolizidine Lactams

“…Reaction of Unsaturated Lactams 5 and 8 with Nazarov Reagent 4 Using Cs 2 CO 3 : A solution of unsaturated lactam 5a , 5b , 8a or 8b (1 equiv.) in anhydrous CH 2 Cl 2 (0.02–0.005 m ) was added at 0 °C under an inert gas to a solution of the Nazarov reagent 4 (3 equiv.)…”

“…Derivative 3 can participate in base‐promoted double Michael annulations (Scheme ), avoiding the polymerization problem associated with 1 . Using unsaturated indolo[2,3‐ a ]quinolizidine lactams A , this reagent opened up straightforward stereodivergent routes to yohimbine‐type derivatives , . Interestingly, pentacyclic 3‐H/15‐H trans adducts B were generated from N ind ‐unsubstituted lactams, but the corresponding cis isomers C were formed when the indole nitrogen atom bears a Boc substituent (Scheme ) .…”

“…Interestingly, pentacyclic 3‐H/15‐H trans adducts B were generated from N ind ‐unsubstituted lactams, but the corresponding cis isomers C were formed when the indole nitrogen atom bears a Boc substituent (Scheme ) . This dramatic reversal in the facial selectivity was rationalized based on theoretical calculations, which indicated that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group . The reactions were performed using either 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) [in tetrahydrofuran (THF)] or Cs 2 CO 3 (in CH 2 Cl 2 ) as the base, although with the latter, when E = SO 2 C 6 H 5 , the stereoselectivity was lower and dependent on the concentration of Cs 2 CO 3 .…”

A Straightforward Synthesis of Functionalized cis-Perhydroisoquinolin-1-ones

“…In the former, the reagent sequentially acts as an electrophilic Michael acceptor and as a nucleophile to promote an aldol condensation. In the latter, however, it successively acts as a nucleophilic Michael donor and an electrophilic Michael acceptor, a reactivity pattern that has been successfully applied to assemble pentacyclic yohimbine-type derivatives from unsaturated indolo[2,3- a ]quinolizidine-derived lactams [17,18,19].…”