Asymmetric [3+2] Annulation Approach to 3‐Pyrrolines: Concise Total Syntheses of (−)‐Supinidine, (−)‐Isoretronecanol, and (+)‐Elacomine

Abstract

An asymmetric [3+2] annulation reaction to form 3-pyrroline products is reported. Upon treatment with lithium diisopropylamide, readily available ethyl 4-bromocrotonate is deprotonated and trapped with Ellman imines selectively at the α-position to yield enantiopure 3-pyrroline products. This new method is compatible with aryl, alkyl, and vinyl imines. The efficacy of the method is showcased by short asymmetric total syntheses of (-)-supinidine, (-)-isoretronecanol, and (+)-elacomine. This novel annulation approach also works for an aldehyde, thus providing access to a 2,5-dihydrofuran product in a single step from simple precursors. By modifying the structure of the carbanion nucleophile, an asymmetric vinylogous aza-Darzens reaction can be realized.

Recent Advances in the Application of Ring-Closing Metathesis for the Synthesis of Unsaturated Nitrogen Heterocycles

“…Other cyclization strategies include Heck-aza-Michael reactions, 12 in situ formation of alkylidene carbenes from vinyl bromides resulting in 1,5-C-H insertion, 13 the use of azomethine ylides, 14 and Lewis acid mediated cyclizations. 15 Another interesting approach includes the ring expansion of aziridines 16 to the corresponding pyrroline, or alternatively the ring contraction of diazo-oxazepanes. 17 Tetrahydropyridines present a greater challenge, however many versatile methods have been developed including 6πcyclization strategies 18 such as the aza-Diels-Alder reaction 19 (Scheme 1).…”

Asymmetric [3+2] Annulation Approach to 3‐Pyrrolines: Concise Total Syntheses of (−)‐Supinidine, (−)‐Isoretronecanol, and (+)‐Elacomine

“…Presented in Scheme 6i st he shortest asymmetric total synthesis of (+ +)-elacomine,a nd it makes use of as ubstratecontrolled Heck cyclization step to form the spirooxindole core.W ef irst treated the Ellman imine (11 d)o fi sovaleraldehyde with the enolate of ethyl 4-bromocrotonate under our new annulation conditions.T he ester of the resulting pyrroline (9d)was then converted into the iodo arylamide 25 using Weinrebs protocol and aniline 24. [19] Heck cyclization to form the spirooxindole core (26)p roceeded in very good yield and with complete substrate control as evident from X-ray crystallographic analysis.I nterestingly,r adical cyclization approaches failed to produce the spirooxindole,a sd id palladium cyclizations employing an aryl bromide.T reatment of the protected enamine functionality with zinc in acetic acid deprotected the nitrogen atom and reduced the resulting imine,t hus affording the methoxy-protected elacomine 27. Standard deprotection conditions then afforded (+ +)-elacomine in only six steps from isovaleraldehyde.…”

“…Palladium-mediated cyclization affords au seful 2-pyrroline moiety (19)f or further functionalization. Such strategies are currently being used in our laboratory to build diverse collections of enantiopure nitrogen heterocycles.…”

Practical Stereoselective Synthesis of C3‐Spirooxindole‐ and C2‐Spiropseudoindoxyl‐Pyrrolidines via Organocatalyzed Pictet‐Spengler Reaction/Oxidative Rearrangement Sequence

“…Among the large family of biologically active spirooxindoles, [1] C3-spirooxindole-pyrrolidines are found in a variety of natural compounds and pharmaceuticals, such as horsfiline, [2] elacomine, [3] and spirotryptastatin A [4] (Figure 1a). In addition, C2-spiropseudoindoxyl-pyrrolidines, which are structural analogs of C3-spirooxindole-pyrrolidines, have recently received increasing attention in the fields of organic chemistry and drug discovery because of their potent pharmacological activities, with example compounds including fluorocurine, [5] mitragynine pseudoindoxyl, [6] and rauniticine pseudoindoxyl [7] (Figure 1a).…”