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. 2013 Aug 14;135(32):11799-802.
doi: 10.1021/ja407277a. Epub 2013 Aug 1.

Cyclopropenimine-catalyzed enantioselective Mannich reactions of tert-butyl glycinates with N-Boc-imines

Jeffrey S Bandar  1 , Tristan H Lambert
Affiliations

Cyclopropenimine-catalyzed enantioselective Mannich reactions of tert-butyl glycinates with N-Boc-imines

Jeffrey S Bandar et al. J Am Chem Soc. .

Abstract

Cyclopropenimine 1 is shown to catalyze Mannich reactions between glycine imines and N-Boc-aldimines with high levels of enantio- and diastereocontrol. The reactivity of 1 is shown to be substantially greater than that of a widely used thiourea cinchona alkaloid-derived catalyst. A variety of aryl and aliphatic N-Boc-aldimines are effective substrates for this transformation. A preparative-scale reaction to deliver >90 mmol of product is shown using 1 mol % catalyst. The products of this transformation can be converted into several useful derivatives.

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Figures

Figure 1
Figure 1
Vincinal diamino stereocenters via direct glycinate Mannich reaction.
Figure 2
Figure 2
Proposed catalytic cycle for cyclopropenimine-catalyzed Mannich reaction. The red double-headed arrow indicates conformational locking of the stereocenter due to steric conflict with a cyclohexyl ring.
Scheme 1
Scheme 1
Preparative scale synthesis and derivatization of diamine 8. See supporting information for full experimental details. (a) TFA, CH2Cl2, rt; (b) dimethyloxylate, MeOH, reflux; (c) CBzCl, Na2CO3 (aq), PhMe, rt; (d) TMSCl, CH2Cl2, 0 ºC then tBuMgCl; (e) 4-bromobenzaldehyde, TEA, CH2Cl2, rt then NBS, 0 ºC; (f) Z-Ala-OH, EDC, HOBt, TEA, CH2Cl2, 0 ºC to rt; (g) Boc-Phe-OH, EDC, HOBt, TEA, CH2Cl2, 0 ºC to rt.
See this image and copyright information in PMC

References

    1. Viso A, de la Pradilla RF, Garcia A, Flores A. Chem Rev. 2005;105:3167. - PubMed
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    1. For a review, see: Gómez Arrayás R, Carretero JC. Chem Soc Rev. 2009;38:1940.

    1. Bandar JS, Lambert TH. J Am Chem Soc. 2012;134:5552. - PubMed

    1. See supporting information for an improved synthesis of cyclopropenimine 1 directly from pentachlorocyclopropane.

    1. (S)-2-(2,3-bis(dicyclohexylamino)cyclopropenimine)-3-phenylpropan-1-ol hydrochloride (1•HCl) can be purchased from Sigma-Aldrich (product #L511188).

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