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. 2012 Mar 14;134(10):4941-54.
doi: 10.1021/ja210981a. Epub 2012 Mar 2.

Enantioselective construction of pyrrolidines by palladium-catalyzed asymmetric [3 + 2] cycloaddition of trimethylenemethane with imines

Barry M Trost  1 , Steven M Silverman
Affiliations

Enantioselective construction of pyrrolidines by palladium-catalyzed asymmetric [3 + 2] cycloaddition of trimethylenemethane with imines

Barry M Trost et al. J Am Chem Soc. .

Abstract

A protocol for the enantioselective [3 + 2] cycloaddition of trimethylenemethane (TMM) with imines has been developed. Central to this effort were the novel phosphoramidite ligands developed in our laboratories. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of imine acceptors to provide the corresponding pyrrolidine cycloadducts with excellent yields and selectivities. Use of a bis-2-naphthyl phosphoramidite allowed the successful cycloaddition of the parent TMM with N-Boc imines, and has further permitted the reaction of substituted donors with N-tosyl aldimines and ketimines in high regio-, diastereo-, and enantioselectivity. Use of a diphenylazetidine ligand allows the complementary synthesis of the exocyclic nitrile product shown, and we demonstrate control of the regioselectivity of the product based on manipulation of the reaction parameters.

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Figures

Figure 1
Figure 1
ORTEP illustration of (R)-tert-buty12-(4-chlorophenyl)-4- methylenepyrrolidine-1-carboxylate (8f) with thermal ellipsoids drawn at the 50% probability level.
Figure 2
Figure 2
Structures of additional ligands studied in the reaction of cyano donor 10 with tosyl imine 12.
Figure 3
Figure 3
ORTEP illustration of (2S,3R)-2-(benzo[d][1,3]dioxol-5-yl)-4-methylene-1-tosylpyrrolidine-3-carbonitrile (13d) with thermal ellipsoids drawn at the 50% probability level.
Figure 4
Figure 4
ORTEP illustration of (2S,3R)-2-(2-methoxyphenyl)-2-methyl-4-methylene-1-tosylpyrrolidine-3-carbonitrile (23f) with thermal ellipsoids drawn at the 50% probability level.
Figure 5
Figure 5
Proposed stereochemical model for diastereoselectivity of ketimine TMM reaction.
Figure 6
Figure 6
Crystal structure of saccharine imine derived cycloadduct 25.
Scheme 1
Scheme 1
Achiral TMM reaction of donors 1 and 2 with tosyl imines.
Scheme 2
Scheme 2
Marrs' catalytic, asymmetric pyrrolidine synthesis.
Scheme 3
Scheme 3
Catalytic cycle for the palladium-catalyzed [3+2] TMM cycloaddition with imines.
Scheme 4
Scheme 4
Performance of phosphoramidite ligands in the reaction with benzylidene aniline.
Scheme 5
Scheme 5
Initial reaction of donor 10 with N-Boc imine 9.
Scheme 6
Scheme 6
Expanded catalytic cycle depicting the mechanism of formation of exocyclic cycloadduct 15.
Scheme 7
Scheme 7
Control over TMM reaction chemoselectivity by selection of reaction parameters.
Scheme 8
Scheme 8
Reaction of cyano donor 10 with saccharin-derived imine 24.
Scheme 9
Scheme 9
Formation of exo-product through cycloaddition of TMM donor 10 with nosyl ketimine.
Scheme 10
Scheme 10
Functionalization and removal of the tosyl protecting group from ketimine cycloadduct 21f.
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References

    1. O'Hagan D. Nat Prod Rep. 2000;17:435. - PubMed
    2. Michael JP. Nat Prod Rep. 2005;22:603. - PubMed
    1. Willstatter R. Annalen. 1903;317:204.
    2. Robinson R. J Chem Soc Trans. 1917;111:762.
    3. Humphrey AJ, O'Hagan D. Nat Prod Rep. 2001;18:494. - PubMed

    1. Some selected examples of classical pyrrolidine syntheses include Wojcik B, Adkins H. J Am Chem Soc. 1934;56:2419–2424.

    2. Karrer P, Portmann P. Helv Chim Acta. 1948;31:2088–2092. - PubMed
    3. Dolfini JE, Dolfini DM. Tetrahedron Lett. 1965:2053–2058. - PubMed
    4. Basha FZ, DeBernardis JF. Tetrahedron Lett. 1984;25:5271–5274.
    5. Jiang C, Frontier AJ. Org Lett. 2007;9:4939–4942. - PubMed
    6. Lorthiois E, Marek I, Normant JF. J Org Chem. 1998;63:2442–2450. - PubMed
    7. Overman LE, Kakimoto MA. J Am Chem Soc. 1979;101:1310.
    1. Fache F, Schulz E, Tommasino ML, Lemaire M. Chem Rev. 2000;100:2159. - PubMed
    1. Dalko PI, Moisan L. Angew Chem Int Ed. 2004;43:5138. - PubMed

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