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Chiral 2,2’-Bipyrrolidines

By: Daniel Weibel, ChemFiles Volume 10 Article 4

Daniel Weibel, Ph.D. European Market
Segment Manager, Chemistry
daniel.weibel@sial.com

C2-symmetrical, chiral 2,2’-bipyrrolidines have recently emerged as interesting structural chiral motifs in a number of ligands for asymmetric transformations (Figure 1). When the two nitrogen atoms function either in a bidentate chelate ligand or are covalently bonded to another atom, the two pyrrolidines adopted a stair-like structure, which creates a highly asymmetric environment.

Figure 1 Commercially available chiral 2,2’-bipyrrolidines. (688622)(688746)(712116)

Prof. Denmark has exploited this feature in the development of a highly selective catalyst for asymmetric allylations.1 The addition of allylic trichlorosilanes to unsaturated aldehydes can be catalyzed by chiral bisphosphoramide derived from 2,2’-bipyrrolidine (for the corresponding chiral bisphosphoramide catalyst derived from N,N′-dimethyl-1,1′-binaphthyldiamine, (715549) to give homoallylic alcohols with excellent diastereo- and enantioselectivities (Scheme 1).

Scheme 1 Highly selective asymmetric allylic allylations using a bisphosphoramide organocatalyst

In 2007, Prof. Christina White reported on an iron-based small molecule catalyst Fe(S,S-PDP) (730459) bearing the (S,S)-1,1’-bis(2- pyridinylmethyl)-2,2’-bipyrrolidine (712361) moiety as chelating ligand that uses hydrogen peroxide to oxidize a broad range of substrates.1 Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C–H bonds, without the need for directing groups. This type of general and predictable reactivity stands to enable aliphatic C–H oxidation as a method for streamlining complex molecule synthesis (Scheme 2).

Scheme 2 Selective aliphatic iron-catalyzed C–H oxidation (730459)

On the basis of this set of selectivity rules the preferential oxidation of the electron-rich and sterically unencumbered tertiary C–H bond at C-10 of antimalarial tetracyclic compound (+)-artemisinin (361593) was predicted. In addition to the site selectivity issue posed in this substrate, a chemoselectivity challenge is present in the form of a sensitive endoperoxide moiety known to be prone to Fe(II)-mediated cleavage.3 (+)-10β-Hydroxyartemisinin was generated in diastereomerically pure form as the major product in 54% yield (after recycling of artemisinin). Interestingly, (+)-artemisinin (361593) has previously been transformed enzymatically with microbial cultures of Cunninghamella echinulata to 10β-hydroxyartemisinin in 47% yield with substantially longer reaction times and a 10-fold lower volume throughput.3 The ability of the simple, small molecule iron catalyst Fe(S,S-PDP) (730459) with broad substrate scope to achieve P-450-like tailoring enzyme selectivities is remarkable.

Recently, Prof. White reported the same bulky, electrophilic iron catalyst is capable of site-selective oxidation of isolated, unactivated secondary C–H bonds to aff ord mono-oxygenated products in preparatively useful yields without the use of directing or activating groups (Scheme 3).4

Scheme 3 Selective iron-catalyzed methylene oxidation (730459)

In 2008, Prof. Lawrence Que developed an iron catalyst bearing the optically active 6-Me2-BPBP ((R,R)-1,1’-bis(6-methyl-2- pyridinylmethyl)-2,2’-bipyrrolidine) ligand (712337) for asymmetric olefi n dihydroxylation.5 This complex is hitherto one of the most eff ective reported to date achieving up to 97% enantiomeric excess of the syn-diol product from cis-disubstituted olefi ns (Scheme 4). These ee values are comparable to those obtained with the osmium-based AD α or β mixes (392758 or 392766). These results demonstrate for the first time that a synthetic nonheme iron catalyst can approach the high enantioselectivity found in syn-dihydroxylating enzymatic systems.

Scheme 4 Iron-catalyzed asymmetric olefi n cis-dihydroxylation

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Materials

     

References

  1. Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488.
  2. Chen, M. S.; White, M. C. Science 2007, 318, 783.
  3. Zhan, J.; Guo, H.; Dai, J.; Zhang, Y.; Guo, D. Tetrahedron Lett. 2002, 43, 4519.
  4. Chen, M. S.; White, M. C. Science 2010, 327, 566.
  5. Suzuki, K.; Oldenburg, P. D.; Que, L, Jr. Angew. Chem. Int. Ed. 2008, 47, 1887.

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