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A convergent process for the assembly of stereodefined mono- and bicyclic exo-alkylidene γ-lactams is described that proceeds through the union of β-halo allylic alcohols, aromatic imines and CO. Overall, regio- and stereoselective Ti-mediated reductive cross-coupling, followed by Pd-catalyzed carbonylation can be performed in a one or two-pot procedure, defining a highly selective three-component coupling process for heterocycle synthesis.
Nitrogen-containing heterocycles are ubiquitous structural motifs in natural products and small molecules of biomedical relevance.1 Among this class, stereodefined pyrrolidines and γ-lactams are abundant (Figure 1). A wealth of chemical pathways are indeed available for the synthesis of these functionalized heterocycles.2 However, strategic considerations for the preparation of highly substituted and stereodefined systems often limit the utility of many available methods. In a program aimed at defining convergent coupling reactions for complex molecule synthesis, we have been investigating the potential of reductive cross-coupling processes between imines and alkynes, alkenes or allenes to serve as a general foundation for heterocycle synthesis.3 Recently, we set our sights on the development of a multicomponent coupling reaction suitable for the synthesis of exo-alkylidene γ-lactams (Figure 2A). These architectures, while representing interesting heterocycles in their own right, possess a rich reactivity profile suitable for diverse elaboration (Figure 2B). Herein, we report the realization of a stereoselective synthesis of exo-alkylidene γ-lactams from the convergent and stereoselective union of homoallylic alcohols, imines and carbon monoxide.
Recently, we reported a stereoselective synthesis of homoallylic amines that proceeds by regioselective reductive cross-coupling of allylic alcohols with aromatic imines.3d Of particular interest to our goals here, coupling of 2-halo allylic alcohols to aromatic imines was found to provide stereoselective access to anti-homoallylic amines that contain a stereodefined vinyl halide (dr ≥ 20:1; E:Z ≥ 20:1; Figure 3). While the mechanistic details that result in these high levels of stereoselection remain undefined, an emperical model has emerged to explain the patterns of reactivity and selectivity observed. The proposed model, based on a sequence of directed carbometalation and syn-elimination (A → B; Figure 3), embraces a boat-like geometry in the transition state for C–C bond formation to reflect the presumed mechanistic requirement of preassociating the allylic alkoxide to the Ti-center of the azametallacyclopropane and the orbital requirements for carbometalation (coplanarity of the σTi–C and the πC=C). A key factor for stereocontrol then derives from the minimization of A-1,2 strain in the boat like orientation A (minimize steric interaction between R3 and X). As a consequence, high selectivity is observed for the formation of products containing a pendant E-alkene. Overall, the general reactivity pattern is consistent with formal metallo-[3,3] rearrangement by way of C.4
While having a stereoselective coupling reaction in place for the synthesis of highly functionalized homoallylic amines, we were aware of the potential of halogenated homoallylic amines to participate in Pd-catalyzed carbonylation chemistry.5, 6 As depicted in Figure 4, this was indeed the case. Carbonylation of vinylbromide 1 and vinyliodide 2 resulted in the production of the exo-methylene γ-lactam 3 in ≥ 93% yield.
With the knowledge gleaned from these initial studies, we moved on to explore the compatibility of more complex substrates in this two-step reductive cross-coupling/carbonylation process as a means to access a variety of stereodefined γ-lactams (Table 1).7 As depicted in entries 1–3, the size of the alkyl group at the allylic position plays an important role in stereoselection. While reductive cross coupling of allylic alcohol 5 with imine 4 proceeds in a fairly unselective manner (E:Z = 1.5:1), union of imine 4 with allylic alcohol 7 occurs with increased levels of stereoselection and produces the homoallylic amine 8 in 76% yield (E:Z ≥ 4:1). Subsequent carbonylation then delivers the stereodefined unsaturated γ-lactam 9 in 99% yield. As depicted in entry 3, branched alkyl substitution on the allylic alcohol leads to the highest levels of E-selectivity in this coupling reaction. Here, the homoallylic amine 11 is forged in 58% yield with greater than 20:1 selectivity for the formation of the stereodefined E-alkene. Palladium catalyzed carbonylation then furnishes γ-lactam 12 in 94% yield. Moving on to a more highly substituted allylic alcohol, the conversion of 13 to homoallylic amine 14 proceeds in 53% yield and delivers the stereodefined anti-product as essentially a single isomer. Similarly, carbonylation then provides the highly substituted exo-alkylidene γ-lactam 15 in 66% yield.
Finally, this two-step three-component heterocycle synthesis is useful for the synthesis of stereodefined bicyclic lactams. As illustrated in entries 5 and 6, reductive cross-coupling of cyclic allylic alcohols 16 and 17 with imine 4 can be accomplished in a highly stereoselective manner to deliver vinyliodides 17 and 20 (dr up to ≥ 20:1) These substrates are equally effective in the Pd-catalyzed carbonylative cyclization and deliver the bicyclo[4.3.0] and [5.3.0] systems 18 and 21 in 87% and 92% yield.
While this two-step procedure is effective for the stereoselective convergent synthesis of mono- and bicyclic γ-lactams, this multi-component coupling sequence can be streamlined. Specifically, we have defined a one-pot three-component coupling reaction that converts 2-halo allylic alcohols, imines and carbon monoxide directly to stereodefined exo-alkylidene γ-lactams. Aware of the the compatibility of Pd-catalyzed coupling processes with water and base, we speculated that aqueous quenching of the titanium-mediated reductive cross-coupling reaction may directly furnish a suitable environment for Pd-catalyzed carbonylation. This expectation was indeed the case.
As depicted in Figure 5, this sequential multicomponent coupling process for the synthesis of substituted γ-lactams can be conducted in a single reaction vessel. Here, union of imine 4 with allylic alcohol 2 furnishes lactam 3 in 69% yield. Similarly, union of imine 4 with allylic alcohol 22 provides the stereodefined bicyclic lactam 18 in 73% yield.8 Notably, avoiding the requirement for purification of the intermediate homoallylic amines substantially improves the overall yield for this γ-lactam forming annulation process.
Overall, we have described studies that have culminated in the elucidation of a multi-component coupling process for the synthesis of stereodefine exo alkylidene γ-lactams. In short, titanium-mediated regio- and stereoselective coupling of aromatic imines with 2-halo allylic alcohols furnishes intermediate homoallylic amines that are well-suited for palladium-catalyzed carbonylation. This two-step process has been demonstrated with a variety of allylic alcohols and has defined a convergent and stereoselective pathway to mono- and bicyclic γ-lactams. Finally, a one-pot procedure has been developed that enables direct preparation of stereodefined lactams from allylic alcohols and imines. Given the flexibility of the titanium-mediated coupling with respect to imine structure,3d and the ability to translate stereochemical information from the allylic alcohol to the homoallylic amine intermediates,3d we anticipate that this heterocycle-forming annulation will be of utility in medicinal chemistry and natural product synthesis.
We gratefully acknowledge financial support of this work by the Arnold and Mabel Beckman Foundation, JSPS Research Fellowship for Young Scientists (to SU), the G-COE in Chemistry from Nagoya University, and the National Institutes of Health -–NIGMS (GM80266 and GM80266-04S1).
Supporting Information Available Experimental procedures and tabulated spectroscopic data for new compounds (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.