Reaction Discovery Employing Macrocycles: Transannular Cyclizations of Macrocyclic Bis-lactams

Abstract

Macrocyclic bis-lactams have been synthesized by cyclodimerization of homoallylic amino esters employing a Zr(IV)-catalyzed ester-amide exchange protocol. Base-mediated transannular cyclizations have been identified to access both bicyclic [5][6][7][8][9][10][11] and tricyclic [5-8-5] frameworks in good yield and diastereoselectivity. Preliminary mechanistic studies support an olefin isomerizationintramolecular conjugate addition pathway.Macrocyclic natural products often exhibit important biological activities and have thus inspired a number of studies involving diversity-oriented synthesis of macrocyclic frameworks. 1 Recent studies have also highlighted elegant examples of transannular cyclizations enroute to complex natural products. 2 As part of our studies, we considered preparation of macrocycles as substrates for reaction discovery 3 and potential complexity-generating transannular cyclizations. 4,5 In this communication, we report the preparation of 14-membered ring bislactams 6 and their conversion to polycyclic frameworks by divergent, transannular reaction processes as well as preliminary computational studies to probe the reaction mechanism.In order to access macrocyclic bis-lactam substrates, we utilized cyclodimerization of stereochemically well-defined homoallylic amino esters 7 using Zr(IV)-catalyzed ester-amide exchange. 8 Alloc-protected amino esters 1a-d were prepared using asymmetric crotylation 7 of the iminium species derived from condensation of allyl carbamate with aromatic aldehydes (Scheme 1). Subsequent alloc removal 9 using a polymer-bound Pd (0) reagent (PS-PPh 3 -Pd) 10 simplified product purification and afforded amino ester monomers 2a-d. As cyclodimerization of 2 involves consecutive intermolecular and intramolecular amidations, we anticipated that concentration may play an important role in reaction efficiency. Therefore, a range of concentrations (0.10-0.80 M) were examined for cyclodimerization of 2a using Zr (Ot-Bu) 4 -2-hydroxypyridine (HYP) 8 as catalyst (Scheme 2). Based on these studies, an optimal concentration for production of 14-membered bis-macrolactam 3a was found to be 0.60 M.Macrocyclic bis-lactams 3b-d were also prepared in moderate to good yield using the optimized conditions. The structure and stereochemistry of bis-lactam 3b was confirmed by single x-ray crystal structure analysis (one conformer shown). 10With the target macrolactams in hand, we focused on reaction discovery to identify complexitygenerating transannular cyclizations. Initial attempted intramolecular hydroamidation 11 of bislactam 3b utilizing carbophilic late-transition metal catalysts including Pd(II), Ag(I), Pt(II), Au(I), and Au(III) 12 failed to afford any cyclized products. After reaction screening, use of NaH as base 13 in DMF at 60 °C was found to provide tricyclic [5-8-5] product 5 (dr= 5:1:1) (Scheme 3, entry 1). Reaction at room temperature using NaH gave no conversion indicating a high activation energy for transannular cyclization (Scheme 3, entry 2). Further optimization ...

Remodelling of the natural product fumagillol employing a reaction discovery approach

“…A reaction screen 15 , 16 was first undertaken to explore sequential aminolyses of the 1,4- bis -epoxide. We anticipated that the sequence would be initiated at the spirocyclic epoxide, thereby mimicking the reactivity of fumagillin with aminopeptidase MetAP-2, the putative mode of its antiangiogenic activity.…”

Synthesis and structure of a carbohydrate-fused [15]-macrodilactone

“…1 H and 13 C NMR spectra of epoxide 16 were consistent with the structure shown, where epoxidation took place only at the 9,10-alkene, located away from carbohydrate fused region of the macrolide 8. However, at this point the reason behind the observed regioselectivity in the epoxidation of 8 is not fully apparent.As observed earlier for other[13]-macrodilactones and[15]-macrodilactones, facial selectivities of the alkene and diene units originated via macrocyclic diastereocontrol[36][37][38][39][40]. Being present in a rigid cyclic structure, the planar 1,3-diene unit in macrocycle 8 was not able to rotate around its own axis.…”

“…On the basis of all the above observations,[15]-macrodilactone 8 displayed a narrow, elongated, and rigid structure compared to macrodilactone 7. Perhaps it was because of the rigidity of the overall system that macrocyclic ring closure became comparatively more difficult and it reflected in the lower yield of the intramolecular Stille coupling for[15]macrodilactone 8 compared to its non-sugar analogs.2.3 Regio-and diastereoselective epoxidation of the macrocyclic diene unitAnalogous to 7, however, glucose-fused macrocycle 8 was found to expose only one face of its diene to the outer environment[36][37][38][39][40]. Macrocycle 8 positioned the opposite face of the diene outward even though the configuration at C2 (that in 7 was the key center controlling the planar chirality) was the same in both the macrocycles.…”

Biologically Active Macrocyclic Compounds – from Natural Products to Diversity‐Oriented Synthesis

“…Analogous to the above described method, macrocyclic bislactams have recently been synthesized by zirconium‐catalyzed cyclodimerization of homoallylic amino esters with the aim to facilitate transannular cyclizations leading to polycyclic frameworks 27…”