Stereoselective Synthesis of Highly Substituted Tetrahydrofurans through Diverted Carbene OH Insertion Reaction

Abstract

Abstract:Copper or rhodium catalyzed reaction of diazocarbonyl compounds with β-hydroxyketones gives highly substituted tetrahydrofurans with excellent diastereoselectivity, under mild conditions, in a single step process that starts as a carbene O-H insertion reaction but is diverted by an intramolecular aldol reaction.The tetrahydrofuran ring is a commonly found motif in naturally occurring bioactive compounds, and occurs in structural classes such as lignans, [1] acetogenins, [2] ionophores, [3] and macrolides. [4] Examples include (+)-fragransin A2 [5] and amphidinolide F [6] (Figure 1). As a consequence, a number of strategies have been employed for the stereoselective synthesis of tetrahydrofurans. [7][8][9] However, despite advances in synthetic methodology, highly substituted tetrahydrofurans remain difficult to access, and new approaches are needed. We now describe a new route to highly substituted tetrahydrofurans that proceeds with excellent diastereoselectivity, under mild conditions in a single step (Scheme 1) by a novel process initiated by metallocarbene O-H insertion but diverted by intramolecular aldol reaction.

Stereoselective Synthesis of Functionalized Pyrrolidines by the Diverted N−H Insertion Reaction of Metallocarbenes with β‐Aminoketone Derivatives

“…In line with previous reports from our group [14] and others, [10f,i] we propose that the formation of pyrrolidine products by the metal-catalyzed reaction of b-aminoketone derivatives with diazo compounds results from the intramolecular trapping of an intermediate ylide species (Scheme 6). Ammonium ylide B is proposed to arise from the attack of the carbamate/aniline NÀHo f4d/2a onto the electrophilic metallocarbene A,asgenerally accepted in NÀH insertion processes.…”

“…We now describe a new route to highly substituted pyrrolidines that proceeds with excellent diastereoselectivity under mild conditions in a single step (Scheme 1) by a process initiated by metallocarbene N-H insertion, but diverted by an intramolecular aldol reaction. [13] Following our interest in the use of bifunctional reagents for the preparation of heterocycles by diverted carbene insertion reactions, [14] we started investigating the use of β-aminoketone derivatives for the preparation of substituted pyrrolidines. Our initial study focused on the reaction of ethyl phenyldiazoacetate 1a with N-(4-methoxyphenyl)-β-aminoketone 2a, the p-methoxyphenyl (PMP) group serving both to provide a suitably nucleophilic nitrogen atom and to allow for later N-deprotection of the product.…”

“…[10f,13] Despite this recent progress, some limitations remain, including the absence of routes to C4-substituted pyrrolidines,t he variable diastereoselectivity, and the preponderance of N-phenyl precursors,w hich seriously limits the utility of the resulting heterocycles.W en ow describe an ew route to highly substituted pyrrolidines that proceeds with excellent diastereoselectivity under mild conditions in asingle step (Scheme 1) by aprocess that is initiated by am etallocarbene NÀHi nsertion, but is diverted by an intramolecular aldol reaction. [13] Following our interest in the use of bifunctional reagents for the preparation of heterocycles by diverted carbene insertion reactions, [14] we started investigating the use of b-aminoketone derivatives for the preparation of substituted pyrrolidines.Our initial study focused on the reaction of ethyl phenyldiazoacetate (1a)with N-(4-methoxyphenyl)-b-aminoketone 2a;the para-methoxyphenyl (PMP) group serves both to provide asuitably nucleophilic nitrogen atom and to allow for later Ndeprotection of the product. [15] We rapidly established that diazoester 1a and b-aminoketone 2a gave N-PMP protected pyrrolidine 3a exclusively as the cis isomer under rhodium(II) or copper(I) catalysis ( Table 1, entries 1-4), with the (Cu I OTf) 2 ·toluene complex giving the best result (entry 4).…”

“…In particular,alkyl diazoacetate 1c gave pyrrolidine 3d in 55 %y ield under copper triflate catalysis,animportant result given that diazo compounds with a b-hydrogen atom, such as 1b,a re prone to give alkenes by a [1,2]-H shift. [14,16] Ethyl diazoacetate (1b)can also be used in this reaction, and the pyrrolidines 3fand 3g were obtained in excellent yields provided that iron(III) tetraphenylporphyrin (TPT) [17] was used as the catalyst. In fact, iron(III) tetraphenylporphyrin was found to be an active catalyst in this process only when ethyl diazoacetate (1b)w as used, and failed to react with the diazo compounds 1a and 1c under the same conditions.M oreover, when a-substituted aminoketone 2c was used, the pyrrolidine products 3e and 3g were obtained stereoselectively as the cis/ cis isomers exclusively.…”

Divergent Synthesis of Multisubstituted Tetrahydrofurans and Pyrrolidines via Intramolecular Aldol‐type Trapping of Onium Ylide Intermediates

“…[9e] Very recently,M oody and co-workersr eported aR h II -o rC u IIcatalyzed reactiono fd iazo compounds and b-hydroxyketones for the synthesis of tetrahydrofurans by intramolecular aldoltype trapping of oxonium ylides. [12] To extend this ylide-trapping strategy,w ed esigned aR h II -catalyzed transformation startingf rom simple b-hydroxyketones or b-aminoketones and diazo compounds. Wee xpect that the metal-carbene-induced oxoniumo ra mmonium ylides would undergo an intramolecular aldol-type interception by tethered ketones to give tetrahydrofurans or pyrrolidines in adivergentmanner (Scheme 1).…”