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,r eadily available ethyl 4-bromocrotonate is deprotonated and trapped with Ellman imines selectively at the a-position to yield enantiopure 3-pyrroline products.This new method is compatible with aryl, alkyl, and vinyl imines.T he efficacy of the method is showcased by short asymmetric total syntheses of (À)-supinidine,(À)-isoretronecanol, and (+ +)-elacomine.T his novel annulation approach also works for an aldehyde,thus providing access to a2,5-dihydrofuran product in as ingle step from simple precursors.B ym odifying the structure of the carbanion nucleophile,a na symmetric vinylogous aza-Darzens reaction can be realized.

Calyciphylline B-type Alkaloids: Evolution of a Synthetic Strategy to (−)-Daphlongamine H

“…Inspired by Ellman's pioneering work, 53 we eventually decided to construct β-amino ester 75 from allylated valerolactone 76 54 and N-tertbutanesulfinyl imine 77. 55 Cursory examination of the parameters for this transformation had shown that the γsubstituent in the imine would be required to avoid undesired 1,4-addition of the enolate. 29 While we faced some uncertainty regarding the diastereoselectivity at the α-quaternary center in this Mannich reaction, we reasoned that the choice of these particular substrates would be ideal in terms of accessing a suitably functionalized and oxidized product for rapid conversion to 75.…”

“…The dried solution was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography (40% ethyl acetate in hexanes) to give alkynone 54 (685 mg, 1.97 mmol, 97% over two steps, 1,143.2,140.3,140.3*,137.7,136.11*,136.10,95.5,77.79*,77.77,72.8,43.2,40.7,37.5,33.1,31.8,28.9,23.93,23.91*,16.9,15.17*,15.16,15.10*,neat) Synthesis of 2-((S)-5-Allyl-7-methyl-5-azaspiro[2.4]heptan-4-ylidene)-1-((R)-2,6,7,7a-tetrahydro-1H-inden-5-yl)ethan-1-one (55). A solution of alkynone 54 (2.09 g, 6.03 mmol, 1.0 equiv, ∼3:1 d.r.…”

“…13 C{ 1 H} NMR (176 MHz, CDCl 3 ): δ 157.1 (q, J = 35.6 Hz), 132.2,131.3*,119.0,118.6*,116.5 (q,J = 287.9 Hz),86.5,85.7*,67.4*,67.2,51.4 (q,J = 3.3 Hz),51.3,50.3* (q, J = 2.9 Hz), 50.0*,41.0*,38.3,16.4,15.74*,15.71*,15.41,15.38*,15.26,14.3*,13.4. 19 F NMR (376 MHz,CDCl3) , 143.2, 140.3, 140.3*, 137.7, 136.11*, 136.10, 95.5, 77.79*, 77.77, 72.8, 43.2, 40.7, 37.5, 33.1, 31.8, 28.9, 23.93, 23.91*, 16.9, 15.17*, 15.16, 15.10*, 15.08 Synthesis of 2-((S)-5-Allyl-7-methyl-5-azaspiro[2.4]heptan-4-ylidene)-1-((R)-2,6,7,7a-tetrahydro-1H-inden-5-yl)ethan-1-one (55). A solution of alkynone 54 (2.09 g, 6.03 mmol, 1.0 equiv, ∼3:1 d.r.…”

Efforts Toward a Unified Kainoid Family Synthesis Approach: Unexpected Sulfinamide‐Directed Conjugate Addition Results

“…Inspired by the structural homology of the kainoid natural products, and the reliability and flexibility of our recently disclosed method for assembling chiral 3‐pyrrolines, we postulated that these kainoids could be rapidly assembled from a common precursor. To establish the feasibility of our synthetic hypothesis we chose to first study kainic acid.…”

Calyciphylline B-Type Alkaloids: Total Syntheses of (−)-Daphlongamine H and (−)-Isodaphlongamine H

“…While Ellman’s pioneering studies have revealed that adding ester enolates to N - tert -butanesulfinyl imines result in good diastereoselectivities at the β -amino stereocenter, 19 the selectivity outcome at the α -center remains difficult to predict when fully substituted, unsymmetrical enolates are employed. Following an initial survey of imines and enolates, 20 allylated valerolactone 8 21 and sulfinyl imine 9 22 were identified as suitable precursors (Scheme 1). Thus, reaction of 9 with the lithium enolate derived from 8 led to an intriguing Mannichretro–Mannich equilibration of the β -amino lactones ( SS - 10 and SR - 10 ), and optimization studies eventually yielded an ~1:1 mixture of C8 epimers in 82% combined yield on multigram scale.…”