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Diastereoselective Aldol reaction of Zincated 3-Chloro-3-methyl-1-azaallylic anions as key step in the synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines

Sven Mangelinckx (UGent) , Bart De Sterck (UGent) , Filip Colpaert (UGent) , Saron Catak (UGent) , Jan Jacobs (UGent) , Stijn Rooryck, Michel Waroquier (UGent) , Veronique Van Speybroeck (UGent) and Norbert De Kimpe (UGent)
(2012) JOURNAL OF ORGANIC CHEMISTRY. 77(7). p.3415-3425
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Abstract
Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn alpha-chloro-beta-mesyloxyketimines, which were isolated in 80-84% yield and high diastereomeric excess (dr > 97/3) after purification via flash chromatography. The syn alpha-chloro-beta-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.
Keywords
3-HALO-1-AZAALLYLIC ANIONS, THEORETICAL RATIONALIZATION, RING-OPENING REACTIONS, STEREOSELECTIVE-SYNTHESIS, 1, 3-ASYMMETRIC INDUCTION, HETEROCYCLIC CHEMISTRY, CONVENIENT SYNTHESIS, ASYMMETRIC-SYNTHESIS, ADDITION-REACTIONS, ORGANIC-CHEMISTRY

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Chicago
Mangelinckx, Sven, Bart De Sterck, Filip Colpaert, Saron Catak, Jan Jacobs, Stijn Rooryck, Michel Waroquier, Veronique Van Speybroeck, and Norbert De Kimpe. 2012. “Diastereoselective Aldol Reaction of Zincated 3-Chloro-3-methyl-1-azaallylic Anions as Key Step in the Synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines.” Journal of Organic Chemistry 77 (7): 3415–3425.
APA
Mangelinckx, S., De Sterck, B., Colpaert, F., Catak, S., Jacobs, J., Rooryck, S., Waroquier, M., et al. (2012). Diastereoselective Aldol reaction of Zincated 3-Chloro-3-methyl-1-azaallylic anions as key step in the synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines. JOURNAL OF ORGANIC CHEMISTRY, 77(7), 3415–3425.
Vancouver
1.
Mangelinckx S, De Sterck B, Colpaert F, Catak S, Jacobs J, Rooryck S, et al. Diastereoselective Aldol reaction of Zincated 3-Chloro-3-methyl-1-azaallylic anions as key step in the synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines. JOURNAL OF ORGANIC CHEMISTRY. 2012;77(7):3415–25.
MLA
Mangelinckx, Sven, Bart De Sterck, Filip Colpaert, et al. “Diastereoselective Aldol Reaction of Zincated 3-Chloro-3-methyl-1-azaallylic Anions as Key Step in the Synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines.” JOURNAL OF ORGANIC CHEMISTRY 77.7 (2012): 3415–3425. Print.
@article{2094885,
  abstract     = {Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn alpha-chloro-beta-mesyloxyketimines, which were isolated in 80-84\% yield and high diastereomeric excess (dr {\textrangle} 97/3) after purification via flash chromatography. The syn alpha-chloro-beta-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions.},
  author       = {Mangelinckx, Sven and De Sterck, Bart and Colpaert, Filip and Catak, Saron and Jacobs, Jan and Rooryck, Stijn and Waroquier, Michel and Van Speybroeck, Veronique and De Kimpe, Norbert},
  issn         = {0022-3263},
  journal      = {JOURNAL OF ORGANIC CHEMISTRY},
  keyword      = {3-HALO-1-AZAALLYLIC ANIONS,THEORETICAL RATIONALIZATION,RING-OPENING REACTIONS,STEREOSELECTIVE-SYNTHESIS,1,3-ASYMMETRIC INDUCTION,HETEROCYCLIC CHEMISTRY,CONVENIENT SYNTHESIS,ASYMMETRIC-SYNTHESIS,ADDITION-REACTIONS,ORGANIC-CHEMISTRY},
  language     = {eng},
  number       = {7},
  pages        = {3415--3425},
  title        = {Diastereoselective Aldol reaction of Zincated 3-Chloro-3-methyl-1-azaallylic anions as key step in the synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines},
  url          = {http://dx.doi.org/10.1021/jo300203t},
  volume       = {77},
  year         = {2012},
}

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