Catalytic diastereo- and enantioselective additions of versatile allyl groups to N-H ketimines

Abstract

There are many biologically active organic molecules that contain one or more nitrogen-containing moieties, and broadly applicable and efficient catalytic transformations that deliver them diastereoselectively and/or enantioselectively are much sought after. Various methods for enantioselective synthesis of α-secondary amines are available (for example, from additions to protected/activated aldimines), but those involving ketimines are much less common. There are no reported additions of carbon-based nucleophiles to unprotected/unactivated (or N-H) ketimines. Here, we report a catalytic, diastereo- and enantioselective three-component strategy for merging an N-H ketimine, a monosubstituted allene and B₂(pin)₂, affording products in up to 95% yield, >98% diastereoselectivity and >99:1 enantiomeric ratio. The utility of the approach is highlighted by synthesis of the tricyclic core of a class of compounds that have been shown to possess anti-Alzheimer activity. Stereochemical models developed with the aid of density functional theory calculations, which account for the observed trends and levels of enantioselectivity, are presented.

Figure 1. State-of-the-art in allyl additions to ketimines and goals of this study

There are significant exisiting limitations and a number of compelling issues remain unaddressed. a, There are only a small number of methods for catalytic enantioselective addition of an allyl group to a ketimine. The substrate is typically equipped with an activating/protecting group, which might prove difficult to remove in the presence of similar functional groups within a product structure (e.g., another N-benzylamine). b, A direct approach to synthesis of α-tertiary amines may entail preparation of the requisite unprotected N-H ketimine through alkylation of readily available nitriles followed by catalytic site-, diastereo- and enantioselective multicomponent addition of 2-boryl-substituted allyl groups. One application relates to synthesis of the core tricyclic structure of a set of heterocyclic molecules that exhibit strong anti-Alzheimer activity. Bn, benzyl; Ts, tosyl; Ac, acyl; pin, pinacolato; G, R, L, functional groups; Pg, protecting group.

Figure 2. Further exploration of scope and illustration of utility

A variety of desirable products can be synthesised. a, The method is applicable to a variety of heterocyclic substrates and allenes. Products derived from ketimines containing n-alkyl or iso-alkyl substituents (vs. methyl) can be obtained efficiently, in >98:2 d.r. and 85.5:14.5–96:4 e.r., depending on the substituent identity. For results with achiral imidazolinium salt 4c, see the Supplementary Information Table 1. b, Oxidation of the alkenylboronate moiety within the products derived from the NHC–Cu-catalyzed multicomponent reactions proceed efficiently to deliver the corresponding β-amino ketones (e.g., 9a), which represent the products of diastereo- and enantioselective Mannich-type additions. c, The method may be applied to the synthesis of the polycyclic core of compounds recently implicated in the fight against Alzheimer’s disease. Conversion of the C–B(pin) to a C–H bond promoted by a readily accessible NHC–Cu complex afforded 10. Formation of the derived thiourea and another NHC–Cu-catalyzed reaction generated the oxepane ring of 12. A two-step procedure involving oxidative cleavage/reduction and activation of the resulting primary alcohol delivered the desired aminothiazine ring and the strained tricyclic 13. Reactions were performed under N₂; there was >98% disappearance of ketimine in all cases (might include decompositiopn products). Yields correspond to isolated and purified products and represent an average of at least three runs (±5%). Diastereomeric ratios were determined by analysis of the 400 MHz ¹H NMR spectra of unpurified product mixtures (±2%). Enantiomeric ratios were determined by HPLC analysis (± 1%). See the Supplementary Information for experimental details and spectroscopic analyses.

Figure 3. Stereochemical models

DFT calculations shed light on the origins of enantioselectivity. a, Transition states with a N→Na interaction account for high e.r.; I represents the preferred mode. b, The model suggests that disruption of the N→Na coordination by the long, flexible alkyl ketimine chain (3w,x Figure 2) in V might render mode VI competitive, leading to lower e.r. Free energy values relative to the major pathway refer to the MN12SX/Def2TZVPP_THF(PCM) level after geometry optimization performed with either MN12SX/Def2SVP_THF(PCM) (for a) or M06L/Def2SVP_THF(PCM) (for b and c). For details, see Sections 4 and 5 of the the Supplementary Information. Abbreviations: NHC, N-heterocyclic carbene; THF = tetrahydrofuran.