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Enantioselective Synthesis of Cyclopropenes

Virginie Carreras and Thierry Ollevier

Université Laval, Département de chimie, 1045 avenue de la Médecine, Québec, QC, G1V 0A6, Canada

1.1 Introduction

Cyclopropene is the smallest unsaturated cyclic hydrocarbon. Its preparation is relatively tricky because it is an unstable compound that has a high ring strain. This strain energy of cyclopropene (228?kJ?) is basically double of the one of cyclopropane (115?kJ?), mainly because of the high angular strain present in the former [1, 2]. However, cyclopropenes containing one or two substituents on the aliphatic position are relatively stable and easily accessible compounds.

1.1.1 Synthesis of Cyclopropenes

The synthesis of the first cyclopropene was carried out by Demyanov and Doyarenko in 1922 via the thermal decomposition at high temperature (C) of trimethylcyclopropylammonium hydroxide under a carbon dioxide atmosphere. After the Hofmann elimination step, cyclopropene was obtained with low yield [3, 4]. An improved procedure was reported starting from allyl chloride and sodium bis(trimethylsilyl)amide that allowed to isolate cyclopropene in a better yield (40%) than in the previously published procedure [5]. An enantioenriched cyclopropene was prepared for the first time by Breslow and Douek via a resolution using cinchonine [6].

Cyclopropenes possessing various substitutions can be prepared: (i) by [2+1] cycloaddition between an alkyne and a free carbene or a metal carbene, most often resulting from the decomposition of diazo compounds; by cycle contraction, by retro-Diels-Alder reaction; from the nucleophilic attack on a previously synthesized cyclopropene; by isomerization; by rearrangement initiated by photochemistry; and finally, via elimination reactions induced by strong bases [7].

Diazo compounds have also been used in the development of asymmetric versions of cyclopropenations of alkynes. The various catalytic asymmetric methods are reviewed in this chapter.

1.1.2 Reactivity of Cyclopropenes

Cyclopropenes can be involved in a large variety of chemical transformations, whose driving force is the release of the ring strain. A few reviews highlighting the synthetic potential of cyclopropenes have been published [8-14].

The reactivity of cyclopropenes has been illustrated in various synthetically useful transformations. Releasing the strain energy enables cyclopropenes to undergo reactions that would be more challenging in other alkenes, e.g. hydrofunctionalization and cycloaddition reactions.

The catalytic stereoselective functionalization of cyclopropenes has been reported throughout various synthetic transformations (Scheme 1.1), i.e. carbocupration [15], carbozincation [16, 17], carbomagnesiation [18], Fe- [19] and Pd-catalyzed carbozincation [20], hydroboration [21], hydroformylation [22], hydroacylation [23], hydroalkylation [24], hydroalkynylation [25], and hydrosilylation [26, 27]. Also, chiral cyclopropylamines have been obtained via highly enantioselective Cu-catalyzed three-component cyclopropene alkenylamination [28]. Using these methods, a large diversity of enantioenriched cyclopropanes can be accessed. Getting high selectivities, i.e. ring-retention vs. ring-opening processes, is often a challenge. In this regard, Dong and coworkers elegantly demonstrated that the choice of a bisphosphine ligand could orient the hydrothiolation of cyclopropenes toward the formation of cyclopropyl sulfides or allylic sulfides [29]. The Pd-catalyzed selective alkynylallylation of the C-C bond of tetrasubstituted cyclopropenes has also been disclosed [30].

Cyclopropenes undergo a ring-opening process to generate rhodium carbenes due to the ring strain. This approach has been used in various synthetic transformations, e.g. the synthesis of dicarbonyl-functionalized 1,3-dienes by the reaction of enaminones with cyclopropenes in the presence of a rhodium catalyst [31].

Cyclopropenes have been used in copper-catalyzed [3+2] cycloaddition reactions as dipolarophiles [32]. Donor-acceptor cyclopropenes have been used in [4+3]-cycloaddition reactions with benzopyrylium salts [33], and in Favorskii-type ring opening [34].

Cyclopropenes have also been used in radical chemistry. Waser has reported the radical azidation of cyclopropenes leading to alkenyl nitriles and polycyclic aromatic compounds [35]. A visible-light-promoted addition of -bromoacetophenones onto the cyclopropene -system in the presence of the has been described by Landais and coworkers [36].

The synthesis of difluoro- and trifluoromethylated derivatives of cyclopropenes has been disclosed using diazo compounds [37-39]. Continuous-flow methods have been reported for the difluorocyclopropenation of alkynes using trimethylsilyl trifluoromethane () [40] and for the photochemical cyclopropenation of alkynes using trifluoromethyl diazirines [41].

Cyclopropenes have appeared to be key intermediates in various total syntheses. The intramolecular Pauson-Khand reaction of a cyclopropene with an alkyne has been used in the synthesis of ()-pentalenene and ()-spirochensilide A [42, 43].

The polymerization of cyclopropenes, in particular the well-developed ring-opening metathesis polymerization, takes advantage of their high strain energy [44]. Recent uses of cyclopropene units have recently emerged in the study of biological systems. Cyclopropenes can react quickly in tetrazine and photoclick ligation reactions [43].

Scheme 1.1 Catalytic stereoselective functionalization of cyclopropenes.

1.2 Metal-Catalyzed Enantioselective Syntheses of Cyclopropenes

The [2+1] cycloaddition between an alkyne and a metal carbene is the main enantioselective approach to prepare cyclopropenes. The metal carbene usually results from the decomposition of a diazo compound using a chiral metal catalyst.

A practical non-enantioselective method was first published by Teyssié and coworkers using a Rh-catalyzed [2+1] cycloaddition of methyl diazoacetate with alkynes [45].

1.2.1 Rhodium Catalysis

Asymmetric versions of these transformations came out with pioneering work of Doyle and coworkers and Müller with the use of chiral complexes based on rhodium [46-61]. Doyle and coworkers focused their work on the cyclopropenation of terminal alkylated alkynes with the use of chiral dirhodium(II) tetrakis[methyl 2-oxopyrrolidine-5(R)-carboxylate] . This method was applied to various diazoacetates and was even extended to chiral diazo possessing auxiliaries derived from menthol (Scheme 1.2) [46, 47]. Using a significant excess of alkyne (20 equiv), cyclopropenes were obtained in high enantioselectivities.

Scheme 1.2 Asymmetric cyclopropenation of terminal alkynes with catalyst.

Müller used for the cyclopropenation of propargylamines bearing two carboxyl or sulfonyl protecting groups using ethyl diazoacetate [48, 49]. The cycloaddition reaction proceeds smoothly at room temperature in with a slow addition of the diazo compounds via a syringe pump to 10 equiv of the alkyne. This method employing 3-7% of rhodium affords high yields and excellent enantioselectivities in the range of 90-97% ee (Scheme 1.3). Further derivatizations via selective deprotection of the TEOC derivatives (N,N-di-(2-trimethylsilyl ethoxycarbonyl)) could be illustrated by the synthesis of -aminobutyric acid (GABA) analogues containing the cyclopropene ring.

Scheme 1.3 Asymmetric cyclopropenation of terminal alkynes with .

These transformations were initially conducted with diazoesters, i.e. ethyl diazoacetate. As shown in Scheme 1.4, Davies' work with dirhodium tetrakis (S)-N-(dodecylbenzenesulfonyl) prolinate demonstrated that the catalyst was efficient for this transformation to get high enantioselectivities of the cyclopropenes via the asymmetric cyclopropenation of terminal alkynes using aryl or vinyl diazoacetates [62, 63]. A large excess of aromatic alkynes is used vs. the aliphatic ones, showing an improved reactivity of the latter. Computational studies demonstrated that the chiral induction of the process is governed by the specific orientation of the alkyne as it approaches the metal carbene. Specific orientation occurs due to the presence of a binding interaction between the alkyne hydrogen and the carboxylate ligand on the dirhodium catalyst.

Scheme 1.4 Asymmetric cyclopropenation of terminal alkynes with .

A closely related observation was made by Hashimoto and coworkers with dirhodium carboxylate catalyst [] emerging as a catalyst of choice for enantioselective cyclopropenation reactions of terminal alkynes with various alkyl-diazoacetates, in which high levels of asymmetric induction (up...