Diazepane Carboxylates as Organocatalysts in the Diels–Alder Reaction of α‐Substituted Enals

Abstract

Ethyl diazepane carboxylate efficiently catalyzes the Diels–Alder cycloaddition of α‐substituted‐α,β‐unsaturated aldehydes via iminium ion organocatalysis. The reaction is applicable to a range of dienes and dienophiles and generally proceeds at room temperature in the presence of 5 mol‐% catalyst and 2.5 mol‐% triflic acid co‐catalyst. The incorporation of a stereogenic center on the diazepane backbone in combination with a menthyl carbamate produces a catalyst which affords enantioselectivities of 70–95 % ee for the cycloaddition of cyclopentadiene with a range of dienophiles. The enantioselectivity is rationalized via a transition state in which electrostatic stabilization by the carboxylate directs the diene to the more hindered face of the dienophile.

Mechanism of an Organocatalytic Cope Rearrangement Involving Iminium Intermediates: Elucidating the Role of Catalyst Ring Size

“…Figure 5 provides a comparative view down the N−N bond of the transition states for the acyclic, five-ring, six-ring, and sevenring catalysts. For example, in the five-ring catalyst, the small ring imposes a tight C(ring)−N−N−C(ring) dihedral angle of 26.8°; this forces other dihedral angles to be much greater than 90°and causes the four dihedral angles to deviate, on average, by 35.6°from their values in the model acyclic catalyst. The six-ring catalyst, with a slightly larger ring, accommodates a slightly larger C(ring)−N−N−C(ring) dihedral angle of 59.8°; this means other dihedral angles need not distort as much from 90°, and thus the four dihedral angles deviate, on average, by 14.0°from their values in the model acyclic catalyst.…”

“…Hydrazide catalysts have previously been examined as organocatalysts in the Diels−Alder reaction, and differences between fiveand six-membered ring catalysts have been previously observed. 33 We have found that the sevenmembered ring hydrazide is particularly effective in a range of reactions of α-substituted-α,β-unsaturated aldehydes, including Michael additions, 34 Diels−Alder cycloadditions, 35 and even polyene cyclizations. 36 Importantly, the formation of iminium ions with these substrates is normally quite difficult due to the development of significant A-1,3 interactions.…”

“…We measured the pK a values of the protonated hydrazides and found that acidity was directly proportional to ring size, with larger ring hydrazides being more acidic. 35 We thus hypothesized that the increase in rate with larger ring sizes might be due to the increased facility for carbonyl protonation during iminium ion formation. Separately, Tomkinson has proposed that a combination of reduced proton affinity and a decrease in LUMO energy for the intermediate iminium is responsible for the greater reactivity of six-membered ring hydrazides over five-membered ring catalysts.…”

“…Importantly, the formation of iminium ions with these substrates is normally quite difficult due to the development of significant A-1,3 interactions. We measured the p K a values of the protonated hydrazides and found that acidity was directly proportional to ring size, with larger ring hydrazides being more acidic . We thus hypothesized that the increase in rate with larger ring sizes might be due to the increased facility for carbonyl protonation during iminium ion formation.…”

Hydrazide‐Catalyzed Polyene Cyclization: Asymmetric Organocatalytic Synthesis of cis‐Decalins

“…1,S cheme 2A)a sc atalysts. [12] Preliminary calculations on this reaction suggested it proceeded in as tepwise fashion through as hallow cationic intermediate.S ince polyene cyclizationsb ear as tructural relationship to the Cope rearrangement, in that substrates for both possess 1,5-Scheme 1. Enantioselective polyene cyclizations and cis-decalin-containing natural product targets.…”