Excess Substrate is a Spectator Ligand in a Rhodium-Catalyzed Asymmetric [2 + 2 + 2] Cycloaddition of Alkenyl Isocyanates with Tolanes

Abstract

Excess substrate has been identified as an unintended spectator ligand affecting enantioselectivity in the [2+2+2] cycloaddition of alkenyl isocyanates with tolanes. Replacement of excess substrate with an exogenous additive affords products with consistent and higher ee's. The increase in enantioselectivity is the result of a change in composition of a proposed rhodium(III) intermediate on the catalytic cycle. The net result is a rational probe of a short-lived rhodium(III) intermediate, and gives insight that may have applications in many rhodium catalyzed reactions.The efficacy of transition-metal catalyzed transformations relies ultimately on the ability to finetune the chemical environment of a metal catalyst in different ways. One can alter catalyst activity both electronically and sterically by manipulating the ligand environment, which can lead to changes in product, chemo-, regio-and enantioselectivity. Understanding the mechanistic details of these observed changes can lead to synthetically useful solutions resulting from manipulation of unobserved reaction intermediates. Additives have been recognized as indispensible tools in an effort "towards perfect asymmetric catalysis". 1 A handful of reports describe changes in selectivity with the introduction of spectator (chiral or achiral) ligands, but the source of these effects remains unaddressed. In the context of our recent studies on asymmetric rhodium-catalyzed [2+2+2] cycloadditions involving alkenyl isocyanates, 5,6 we had occasion to study diaryl acetylenes (tolanes). The advent of GUIPHOS (L1) proved crucial for obtaining high enantioselectivities with product selectivity favoring vinylogous amide adduct 3 (Fig. 1). 7 An initial substrate screen revealed extreme variation in enantioselectivity (Fig. 1). No linear trend was reconcilable on the basis of either sterics or electronics. Sterically, the parasubstituent is much too distant to undergo through-space interactions with either the ligand or the olefin-metal bond, while electronic communication through π bonds is restricted since the arene rings are likely bent out of coplanarity due to strong A 1,3 strain (I in Fig. 2). Alternately, this variation may be explained by coordination of a second alkyne on an octahedral rhodium (III) intermediate (II or III) rather than a 5-coordinate intermediate (I) (Fig. 2). 8Olefin insertion into the rhodacycle thus occurs through several possible diastereomers, via transition states whose relative energy is affected by the close electronic and steric communication with the spectator alkyne, leading to product with variant ee's. 9As a test of this hypothesis, we designed a competition experiment between two different alkynes, which alone give products of different ee (Fig. 3). In this experiment, the ee of 3a was affected by the presence of 2f in the reaction mixture. This result is consistent with a second alkyne present during the enantiodetermining step (Fig. 2).During the course of these studies, we noted that electronically similar substrates 2e ...

A Catalytic Asymmetric Synthesis of Polysubstituted Piperidines Using a Rhodium(I)‐Catalyzed [2+2+2] Cycloaddition Employing a Cleavable Tether

“…[1f] As with previous rhodium (I) catalyzed [2+2+2] cycloadditions, [Rh(C 2 H 4 ) 2 Cl] 2 proved to be the most efficient precatalyst. [16,17] A variety of TADDOL based phosphoramidite ligands provided the vinylogous amide.…”

“…This catalytic, asymmetric method allows facile access to indolizidines and quinolizidines, important scaffolds in natural products and pharmaceutical targets, in good yields with high enantioselectivities. [1,2] Extension of this methodology to the synthesis of monocyclic nitrogen containing heterocycles would be useful, as piperidines are present in numerous compounds with interesting biological activities, [3] such as alkaloid 241D, [4] isosolenopsin A [5] and palinavir [6] (Figure 1). Recently, several new methods have been reported for the synthesis of poly-substituted piperidines, [7,8] highlighted by Bergman and Ellman’s recent contribution.…”

“…[1c] These reactions proceed in slightly lower yield and enantioselectivity. A variety of alkynes are tolerated, including aryl alkynes with electron donating or withdrawing substituents and enynes.…”

“…5% Palladium on carbon under a hydrogen atmosphere affords bicyclic aminals with high diastereoselectivity (>19:1, Table 5). [1b] …”

Enantioselective Synthesis of the Tricyclic Core of FR901483 Featuring a Rhodium-Catalyzed [2+2+2] Cycloaddition

“…7–9 Extensive phosphoramidite ligand (L*) optimizations has led to a broader scope of heterocycles since one can control the selective formation of bicyclic lactams ( 4 ) or vinylogous amides ( 5 ), the latter arising from a CO migration. With terminal alkynes ( I, II ) 7 and unsymmetrical internal alkynes ( III, IV ), 8a single regioisomeric products are obtained in good yields and excellent enantioselectivities.…”