The Catalytic Asymmetric Diels–Alder Reactions and Post‐cycloaddition Reductive Transpositions of 1‐Hydrazinodienes

Dienes that enable structural rearrangements in the wake of a Diels–Alder event can afford structurally unique and complex cyclohexenes that can be inaccessible by the direct cycloaddition route.[1–4] A particular problem in natural product synthesis required a substituted cyclohexene of the type 4, and we were drawn to the idea that an initial pairing of a hypothetical diene of type 1 with an activated dienophile of type 2 might be followed by a suprafacial, reductive transposition of 3 to the desired cyclohexene 4 (Scheme 1). Scheme 1 A cyclohexene synthesis featuring a post-cycloaddition reductive transposition. In principle, the Diels–Alder chemistry of Fleming’s 1-trimethylsilyl-1,3-butadiene in conjunction with a post-cycloaddition protodesilylation step offers an attractive path to a type 4 structure.[2,5] While this strategy is feasible, 1-trimethylsilyl-1,3-butadiene displays low levels of regioselectivity in cycloadditions with unsymmetrical dienophiles, and the subsequent protodesilylation step can afford mixtures of epimers when a new stereocenter is produced. Given these circumstances, we designed a 1-hydrazinodiene that allows a stepwise realization of the concept outlined in Scheme 1.[6] For example, exo cycloadduct 6 is produced by a stereospecific union of 1-hydrazinodiene 5 with diethyl maleate and subsequently converted to the isolable hydrazine derivative 7 by a palladium-catalyzed cleavage of the two allyloxy carbonyl groups in 6 (Scheme 2). By the action of a weak base (e.g., sodium acetate), compound 7 is then transformed to the desired cyclohexene 9 via the putative allylic diazene 8; the spontaneous process that transforms 8 to 9 is formulated as a retroene rearrangement with loss of molecular nitrogen.[7–9] Interestingly, if the base-induced elimination of methanesulfinic acid from 7 is conducted in CD3OD, H–D exchange occurs and the ensuing reductive transposition stereospecifically affords the deuterated cyclohexene 10. Scheme 2 The Diels–Alder and reductive transposition chemistry of a 1-hydrazinodiene. Reaction conditions: a) diethylmaleate, Et2AlCl, 23 °C, 75%; b) Pd2(dba)3, Et2NH, THF, 23 °C; c) NaOAc, MeOH, 49% over two steps; Alloc: allyloxycarbonyl. ... A growing number of examples demonstrate that 1-hydrazinodienes undergo a range of Lewis acid-catalyzed Diels–Alder reactions that are both regio- and diastereoselective as a setup for subsequent, stereospecific reductive transpositions to rearranged cyclohexenes. In this report, we describe our more recent discovery that 1-hydrazinodienes are amenable to chiral catalyst-controlled, enantioface-selective Diels–Alder cycloadditions, as well as the cycloaddition behavior of new 1-hydrazinodienes for use in chemical synthesis.[10] In our effort to merge electron-deficient dienophiles with 1-hydrazinodiene 5 with high margins of stereoselectivity, we discovered that the chiral copper(II) bis(oxazoline) catalysts of Evans and co-workers[11] mediate efficient, regioselective, and highly stereoselective Diels–Alder reactions of N-acryloyl oxazolidinones with diene 5. Unions of 1-hydrazinodiene 5 with N-acryloyl oxazolidinone 11a were best achieved in methylene chloride at room temperature in the presence of 4 A molecular sieves and 10 mol% of the freshly prepared copper(II) bis(oxazoline) catalyst. In all cases, exo cycloadduct 13a was produced as the major diastereo-isomer with varying levels of enantioselectivity. The results summarized in Table 1, reveal the impact of the identity of the group R on the chiral bis(oxazoline) ligand and the counterion on Diels–Alder diastereo- and enantioselectivity. The tert-butyl bis(oxazoline) ligand afforded excellent levels of diastereo- and enantioselectivities. While the chloride salt of the copper(II) bis(oxazoline) catalyst was unreactive, the hexafluoroantimonate and triflate salts displayed excellent reactivities. The good-to-excellent exo diastereoselectivities exhibited in these reactions are consistent with our prior observations on the stereochemical outcomes of 1-hydrazinodiene cycloadditions to Cα-unsubstituted dienophiles.[6,12] Our hypothesis is that dienophiles lacking α-substitution should undergo exo selective Diels–Alder reactions to minimize nonbonded interactions between the Lewis acid-activated carbonyl and the substituents attached to the hydrazine moiety of the diene.[13] Table 1 Chiral copper(II) bis(oxazoline)-catalyzed Diels–Alder cycloadditions of diene 5 with N-acryloyl oxazolidinone 11a.[a] Having identified the (S,S)-(−)-2,2′-isopropylidene-bis(4-tert-butyl-2-oxazoline) chiral ligand and the hexafluoroantimonate counter ion as key components of an effective chiral catalyst, we examined a variety of β-substituted N-acryloyl oxazolidinones in asymmetric Diels–Alder reactions with 1-hydrazinodiene 5 (Table 2). Table 2 Chiral catalyst-controlled, asymmetric Diels–Alder cycloadditions of diene 5 to β-substituted N-acryloyl oxazolidinones 11a–l.[a] Although there was some variation in reaction times, all of the unions leading to exo cycloadducts 13a–l displayed diastereomer ratios of greater than 20:1 and enantiomer ratios ranging from 21–99:1. Evans’s copper(II) catalyst 14 is clearly capable of mediating cycloadditions of diverse, β-substituted N-acryloyl oxazolidinones to diene 5 with high margins of stereoselectivity. To further increase the scope of this chemistry, we leveraged our previously described method[6] to achieve syntheses of an expanded set of hydrazinodienes with diverse substitution patterns. Thus, from simple α,β-unsaturated aldehydes and monoallyloxycarbonyl (Alloc) hydrazine, 1-hydrazinodienes 15–18 (Table 3) were synthesized in three steps[14] and employed in asymmetric Diels–Alder reactions with α,β-unsaturated imides 11a, 11b, 11 f, and 11l. Table 3 Chiral catalyst-controlled, asymmetric Diels–Alder cycloadditions of additional 1-hydrazinodienes.[a] Qualitatively, these new hydrazinodienes were judged to be comparable with respect to reactivity, although dienes 16 and 18 reacted more slowly in relation to the others. All of these chiral catalyst-directed cycloadditions were regioselective and afforded exo cycloadducts 19a–k in good to excellent yields and with diastereomer ratios greater than 20:1. The major, exo diastereomers were also produced with high levels of enantioselectivity. X-ray crystallographic analysis confirmed the relative and absolute stereochemical configurations of cycloadduct 19a; this analysis was fully consistent with the prior observations of Evans and co-workers[11] on how the architecture of the dienophile-copper(II) BOX complex imparts high levels of stereoface selectivity in Diels–Alder reactions.[15] In the wake of the asymmetric Diels–Alder events, it was straightforward to execute the desired reductive transpositions to rearranged cyclohexenes (Table 4). Thus, the Diels–Alder adducts arising from diene 5 and the four dienes shown in Table 3, were smoothly transformed to the isolable hydrazine derivatives 20a–h by mild, palladium(0)-catalyzed cleavages of the Alloc protecting groups. The reductive transpositions to cyclohexenes 21a–h were subsequently achieved by warming solutions of compounds 20a–h in methanol to 50°C. Through a retroene-like rearrangement[7] of a putative allylic diazene intermediate, molecular nitrogen is expelled, the alkene is shifted to a new position within the six-membered ring, and a new stereochemical relationship is established in this pivotal step. Table 4 Deprotections and reductive transpositions of selected Diels–Alder products.[a] In the presence of Lewis acids, 1-hydrazinodienes undergo efficient [4+2] cycloadditions with fumarate and maleate esters, as well as α,β-unsaturated aldehydes, ketones, and imides. To gain some insight into the relative reactivity of 1-hydrazinodienes, the HOMO Eigenvalues for 1-dimethylamino-3-tert-butyldimethylsilyloxy-1,3-butadiene,[16] 1-methoxy-3-trimethylsilyloxy-1,3-butadiene,[17] 1-hydrazinodiene 5,[6] and isoprene were calculated as −0.172, −0.190, −0.207, and −0.226, respectively, by the method of Gaussian 03 B3LYP at the 6-31G(d) level of theory.[18] By this analysis, the HOMO energy of 1-hydrazinodiene 5 was judged to be less than the HOMO energies of the synergistic dienes of Rawal and Kozmin[16] and Danishefsky and Kitahara,[17] but greater than that of isoprene. As a class, the 1-hydrazinodienes have value in synthesis because they are easily constructed, amenable to efficient and highly stereoselective Diels–Alder reactions with a variety of dienophiles, and enable mild, post-cycloaddition rearrangements to new cyclohexenes that would likely by challenging to produce by alternative methods of synthesis. Our efforts to further extend the utility of 1-hydrazinodienes in organic synthesis are continuing.