Vicinal and 1,3-diamines are important structural motifs in natural products and pharmaceuticals, with useful applications in asymmetric catalysis and supramolecular chemistry.1 Recently, one of our labs has disclosed a method that takes advantage of Rh-catalyzed C–H insertion to synthesize differentially substituted 1,2-diamines from hydroxylamine-derived sulfamate esters.2 With an interest in facilitating access to optically active, polyfunctionalized diamines, we envisioned a sequential process featuring asymmetric synthesis of N-allyl hydroxylamine-O-sulfamates and catalytic intramolecular aziridination (Figure 1). Palladium-catalyzed allylic amination was viewed as a particularly attractive means for preparing allylic hydroxylamine-derived sulfamate esters in enantioenriched form.3 Diastereoselective oxidative cyclization of these materials under Rh catalysis would then afford aziridine products. Accordingly, the successive application of these selective transition metal-catalyzed processes makes available complex polyamine architectures from readily available, racemic starting materials. The power of these combined tactics for streamlining chemical synthesis is highlighted below.
Figure 1.
Asymmetric synthesis of polyfunctionalized diamines through sequential Pd- and Rh-catalyzed transformations.
Initial studies on the Pd-catalyzed amination using chiral ligand L1, Pd2dba3•CHCl3, cyclohexenol-derived carbonate 1, and sulfamate nucleophile 2 (Mbs = p-MeOC6H4SO2–) afforded the product 3 in good yield and in high enantiomeric excess (Table 1, entry 1). The catalyst loading, the addition of either acid or base, and the solvent had minimal influence on enantioselectivity (Table 1, entries 2-6), although, the use of 5 mol % catalyst resulted in a significantly higher product yield (Table 1, entry 4). Changing to ligand L2 improved asymmetric induction to >90% ee (Table 1, entries 8-10).
Table 1.
Optimization of Pd-catalyzed allylic amination.
| Entrya | X mol % | Solvent | Ligand | % Yield | % eeb |
|---|---|---|---|---|---|
| 1 | 1.0 % | THF | L1 | 76 | 86 |
| 2 c | 1.0 % | THF | L1 | 63 | 88 |
| 3 d | 1.0 % | THF | L1 | 60 | 87 |
| 4 | 5.0 % | THF | L1 | 94 | 84 |
| 5 | 1.0 % | Dioxane | L1 | 71 | 82 |
| 6 | 1.0 % | CH2Cl2 | L1 | 18 | 87 |
| 7 | 2.5 % | DME | L1 | 54 | 88 |
| 8 e | 2.5 % | THF | L2 | 56 | −92 |
| 9 e | 2.5 % | DME | L2 | 40 | −93 |
| 10e,f | 2.5 % | DME | L2 | 66 | −91 |
Reactions conducted on a 0.25 mmol scale using 1.1 equiv carbonate and 1.0 equiv nucleophile at 0.1 M.
Determined by chiral HPLC.
Reaction performed using 20 mol % PhCO2H.
Reaction performed using 20 mol % Cs2CO3.
Reaction performed at 0.23 M.
Reaction performed at 50 °C.
Evaluation of the reaction scope revealed that several types of allylic derivatives participate in Pd π-allyl reactions with MbsNHOSO2NH2 as the nitrogen nucleophile (Table 2). In all cases, sulfamate products were formed with high levels of enantioinduction exclusively at the more hindered nitrogen.4 Dynamic kinetic asymmetric transformations (DYKAT) were accomplished with both the 5- and 6-membered ring allylic carbonates (Table 2, entries 1-3). Entry 3 highlights the reaction of C2-symmetric conduritol B tetracarbonate, which afforded the mono-substituted product exclusively in 96% ee.5 A related reaction involving the asymmetric desymmetrization of a meso-dibenzoate also furnished the mono-substituted product (Table 1, entry 4). Finally, acyclic substrates, which include both the allyl carbonate and butadiene mono-epoxide, were found to couple efficiently with 2 (Table 1, entries 5 and 6). Using the latter starting material, the DYKAT proceeded with outstanding regiocontrol and furnished a protected 1,2-amino alcohol. Oxidation of related 1,2-amino alcohols has enabled the synthesis of enantiomerically pure α-amino acids.6 Collectively, these data establish 2 as a unique and particularly effective nitrogen nucleophile for Pd-catalyzed allylic alkylation. By way of analogy to reactions with (S,S)-L1 and other amine surrogates, the stereochemical configuration of the products shown in Table 2 has been assigned.7
Table 2.
Pd-catalyzed asymmetric allylic amination.
Reactions were performed in THF using 2.5 mol % Pd2(dba)3•CHCl3, 7.5 mol % (S,S)-L1, at 0.2 M; yields based on limiting amounts of nucleophile 2.
Reaction conducted using (R,R)-L2.
Reaction conducted in dioxane.
The products of Pd-catalyzed asymmetric allylic amination can be readily transformed into differentially-substituted amino aziridines upon treatment with a dinuclear Rh(II)-tetracarboxylate catalyst, a hypervalent iodine oxidant, and MgO.8 Subsequent SN2 ring opening of the resultant aziridines occurred with modest levels of regioselectively to yield the 7-membered ring heterocycles (Figure 2).9,10 Both cyclic and acyclic olefins underwent oxidative cyclization using 2 mol % Rh2(esp)2.11 In general, substrate-controlled diastereoselectivity was quite high. The unusual aziridine products were readily isolated by chromatography, and reacted smoothly and at ambient temperatures in the presence of nucleophiles such as N3−. Remarkably, ring opening to give the 7-membered heterocycle occurred even when the carbon undergoing attack was tetrasubstituted. Use of azide in the two examples shown in Figure 2 made possible the synthesis of differentially masked, stereodefined 1,2,3-triamines.
Figure 2.
Aziridine formation and subsequent ring opening.
Cleavage of the N–O bond in either cyclic or acylic sulfonamide products was easily effected with Zn(Cu) (Figure 3).2 In the first example, reduction of the heterocycle and the azido group in 4 unveiled the singly protected triamino ester 5. The availability of this material in optically active form in just four steps starting from the racemic allylic carbonate underscores the effectiveness of these combined methods. Similarly, reduction of 6 resulted in a concise enantioselective synthesis of the protected conduramine B 7 (3 steps from (±)-conduritol).12
Figure 3.
Reductive N–O cleavage affords novel amine derivatives. Product 5 purified by HPLC using H2O/CH3CN/CF3CO2H.
The sequential application of two efficient and selective transformations, Pd-catalyzed allylic amination and Rh-catalyzed alkene aziridination, makes possible the rapid assembly of complex polyamine structures. Conjoining these two methods reveals opportunities to identify alternative nitrogen-based nucleophiles that will engage in both processes, further augmenting substrate scope and selectivity. The advancement of such technologies should diminish the effort generally needed to access structurally intricate, optically active nitrogen derivatives.
Supplementary Material
Acknowledgment
This work has been supported by the National Institutes of Health and the National Science Foundation. S.M. gratefully acknowledges Stanford University for a graduate fellowship. D.E.O acknowledges Eli Lilly for a graduate fellowship. Palladium salts were generously supplied by Johnson-Matthey.
Footnotes
Supporting Information Available: Experimental details and analytical data for all new compounds (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
References
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