Carbonyl enantioselective cyclization

A -tritylaziridine-2-(5)-carboxaldehyde. The application of a novel, sequential, trans-acetalation oxonium ene cyclization has delivered a stereoselective synthesis of the C-aromatic taxane skeleton, and a combinatorial sequence of the regioselective propiolate-ene, catalytic enantioselective epoxidation and carbonyl-ene cyclization reactions has been used to complete the synthesis of the A-ring of a vitamin D hybrid analogue. 

Cydohexenones. Carbonylation and cyclization of alkenylcyclopropanes leading to cyclohexenones with Fe(CO)j under carbon monoxide constitute an enantioselective process. 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

By tethering a,p-enones with another carbonyl-containing moiety, Rrische developed rhodium-catalyzed asymmetric 1,4-addition/aldol cyclization reactions." These reactions proceed with high diastereo- and enantioselectivity, furnishing structurally complex cyclic compounds in a single step [Eqs. (3.11-3.13)]. 

Suisse and co-workers have studied the asymmetric cyclization/silylformylation of enynes employing catalytic mixtures of a rhodium(i) carbonyl complex and a chiral, non-racemic phosphine ligand. Unfortunately, only modest enantioselectivities were realized.For example, reaction of diethyl allylpropargylmalonate with dimethylphenyl-silane (1.2 equiv.) catalyzed by a 1 1 mixture of Rh(acac)(GO)2 and (i )-BINAP in toluene at 70 °G for 15 h under GO (20 bar) led to 90% conversion to form a 15 1 mixture of cyclization/silylformylation product 67 and cyclization/ hydrosilylation product 68. Aldehyde 67 was formed with 27% ee (Equation (46)). 

Enantioselective carbonylative cyclization has been realized with o-alkenylaryl triflates in the presence of 2,2-bis(diphenyl-phosphanyl)-1,1-binaphthyl (BINAP) or TolBINAP ligands in high material yields and enantiomeric excess (Equation (41)). ... 

R)-l-[4-Methoxy-3-[(triisopropylsilyl)oxyphenyl)-2-[3-(methoxymethoxy)phenyl]ethanol 1123 undergoes selective hydrogen metal exchange followed by carbonylation to form the lithiated intermediate 1124, which undergoes cyclization in acid conditions to provide the dihydroisocoumarin 1125, a key intermediate during an enantioselective synthesis of phyllodulcin (Scheme 279) <1996JOC5371>. 

In their enantioselective total synthesis of (+)-triptocallol (3-79), a naturally occurring terpenoid, Yang and coworkers made use of a concise Mn(OAc)rmediated and chiral auxiliary-assisted oxidative free-radical cyclization [39]. Reaction of 3-77, bearing a (R)-pulegone-based chiral auxiliary, with Mn(OAc)3 and Yb(OTf)3 yielded tricyclic 3-78 in a twofold ring closure in 60% yield and a diastereomeric ratio of 9.2 1 (Scheme 3.20). A further two steps led to (-i-)-triptocallol (3-79). For the interpretation of the stereochemical outcome, the authors proposed the hypothetical transition state TS-3-80, in which chelation of the (3-keto ester moiety with Yb(OTf)3 locks the two carbonyl groups in a syn orientation. The attack of the Mn -oxidation-generated radical onto the proximate double bond is then restricted to the more accessible (si)-face, as the (re)-face is effectively shielded by the 8-naphthyl moiety. 

Carbodiimides are also used in the enantioselective synthesis of 3-substituted 4-(alkoxy-carbonyl)-2-azetidinones from malic acid. DCC is used in the the synthesis of nocardicin Penam, 4-thiazabicyclo[3.2.0]heptan-7-one, and 2,3-disubstituted derivatives utilize EDCCl in the cyclization steps. ... 

This titanocene-catalyzed procedure was immediately extended by Gansauer et al. to the enantioselective opening of meso-epoxides by employing substoichiometric quantities of titanocene complexes with chiral hgands [58-60]. It has also been applied by this group in racemic form not only for reductive epoxide openings and intermolecular additions to a,P-unsaturated carbonyl compounds, but also to achieve 3-exo, 4-exo, and 5-exo cycliza-tions, as well as tandem cyclization addition reactions featuring vinyl radicals (Scheme 9) [8,9,44,46,57,61-65]. 

Mikami and Nakai have shown that chiral titanium perchlorate 123, prepared from chiral titanium dichloride 122 and AgC104 (2 equiv.), is an asymmetric superior catalyst to 122 in terms of the diastereo- and enantioselectivity of carbonyl-ene cycliza-tion [67], AgC104 alone does not catalyze the ene cyclization. One typical example is indicated in Sch. 33. Treatment of a-alkoxy aldehyde 124 with the chiral titanium catalyst 123 in the presence of 4-A molecular sieves in CH2CI2 at 0 °C gives the trans alcohol 125 selectively with 84 % ee. Employment of the titanium dichloride 122, in contrast, results in a nearly 1 1 mixture of trans-125 and cis-i25 with lower enantioselectivity. 

The first enantioselective total synhesis of (-)-strychnine was achieved by L.E. Overman and co-workers. The carbon skeleton of the main precursor for the key aza-Cope rearrangementMannich cyclization was assembled by applying a Pd ° -catalyzed carbonylative Stille coupling reaction. Thus, the cyclic vinylstannane was coupled with the triazinone-protected ortho-iodoaniline to afford 80% yield of the aromatic enone using Pd2(dba)3 as the catalyst in the presence of carbon monoxide. 

A variety of methods are available for the synthesis of heterocyclic carbonyl compounds by radical cyclization. For example, the cyclization of alkoxycarbonyl radicals is particularly useful for the synthesis of five- and six-membered ring lactones [80]. Recent applications of this cyclization method include Zard s photoly-tical transformation of an alkoxycarbonyl dithiocarbonate having a double bond which can serve as a key step in the synthesis of ( )-cinnamolide and RA. Evans s enantioselective synthesis of 4-hydroxy butenolide terminus, which is applicable to the synthesis of mucocin [81J. Amidyl radical cyclizations are frequently utilized for the synthesis of five- and six-membered ring lactams [82]. However, this section only focuses on recent methods for heterocyclic carbonyl compounds by an n-i-1 type strategy based on radical carbonylations. 

The key step in the asymmetric synthesis of brazilin (167a), a tetracyclic homoisoflavanoid which possesses antibacterial and antiinflammatory activities, was prepared by the enantioselective a-hydroxylation of the sodium enolate of chromanone (165) in 92% ee with chloro oxaziridine (+)-(74) <93JOCl75l>. The a-hydroxy ketone (166) was converted into (167b) in 64% overall yield from (166), by reduction of the carbonyl and acid-catalyzed cyclization (Scheme 31). 

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