Carbonyl tandem reactions

The enyne bicyclization-carbonylation tandem reaction is of great interest to synthesize various organic compounds. Possible mechanisms have been proposed as follows (Scheme 27). 

SCHEME 15 Negidii s Pd(0)-catalyzed cyclic carbopaUadation-carbonylative tandem reaction of (2Z,11S)-111. 

Carbonyl ylides continue to be targets of opportunity because of their suitability for trapping by dipolar addition. High enantiocontrol has been achieved in the process described by Eq. 16 [109], but such high enantioselectivity is not general [110] and is dependent on those factors suggested by Scheme 11. Using achiral dirhodium(II) catalysts, Padwa and coworkers have developed a broad selection of tandem reactions of which that in Eq. 17 is illustrative [111] these... 

Carbonylation can also be carried out as a tandem reaction in intramolecular Heck reactions. 

Section 10.1.2.2 describes another tandem reaction sequence involving a carbonyl-ene reaction. 

Pinacol Rearrangement in Tandem with the Carbonyl-Ene Reaction. Overman and co-workers have developed protocols in which pinacol rearrangement... 

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. 

The key features of the catalytic cycle are trapping of the radical generated after cycliza-tion by an a,P-unsaturated carbonyl compound, reduction of the enol radical to give an enolate, and subsequent protonation of the titanocene alkoxide and enolate. The diaster-eoselectivity observed is essentially the same as that achieved in the simple cyclization reaction. An important point is that the tandem reactions can be carried out with alkynes as radical acceptors. The trapping of the formed vinyl radical with unsaturated carbonyl compounds occurs with very high stereoselectivity, as shown in Scheme 12.21. 

Among all tandem hydroformylation sequences the ones involving additional C,C-bond formations are the most synthetically valuable tandem hydroformylation sequences. These C,C-bonds can be formed by adding nucleophiles, which attack the carbonyl carbon, or by adding electrophiles, which attack the a-position. Furthermore, tandem reactions in which the aldehyde or an aldehyde derivative is involved in sigmatropic rearrangement are described. 

A tandem hydroformylation/carbonyl ene reaction can be observed in cases, in which substrates with at least two isolated oleftnic bonds are hydro-formylated at only one double bond selectively. Thus hydroformylation of limonene with PtCkCPPlH /SnCk/PPlH or PtCl2(diphosphine)/SnCl2/PPh3 gives a mixture of two diastereomeric alcohols upon carbonyl ene reaction of the intermediate aldehyde, (Scheme 36). Best results are achieved with a PtC Cdppb) complex. The mechanism of the final intramolecular cycli-zation step resembles an acid catalyzed carbonyl ene reaction [89]. 

The vast majority of the work described in this chapter was reported since 1995. Rho-dium( I)-catalyzed hydroformylation and silylformylation reactions have only very recently been adapted and developed for use in the efficient synthesis of stereochemi-cally complex natural products. In addition, the recent development of tandem reactions that take advantage of the direct production of aldehydes in these carbonylation reactions have only begun to demonstrate the versatility of this chemistry. Rhodium(I)-catalyzed hydroformylation and silylformylation, venerable reactions that have primarily been associated with organometaUic chemistry, must now be considered important tools for natural product synthesis. The continued development of these methodologies for that purpose may be expected. 

In principle, bifunctional aldehydes should be able to engage in twofold enzymatic aldol additions to both of their acceptor carbonyls in a fashion to be classified as a tandem reaction, that is, without the need for isolation of intermediates. Depending on the specificity of the enzyme used and on the functionalization in the starting material, the isomeric constitution as well as the absolute and relative stereochemistry should be deliberately addressable. Therefore, we engaged in a program to evaluate the scope and the Hmitations of such two-directional chain elongation processes for the construction of extended poly functional molecules [36]. 

The reaction of (R)- or (3)-dihydrodinaphthothiepines 23 with an excess of lithium and a catalytic amount of DTBB, under the same reaction conditions shown in Equation (15), after treatment with a carbonyl compound [(Et2CO or (CH2)sCO] or H20 as electrophile, gave enantiomerically pure 127 and 133, respectively. No racemiza-tion occurred during the whole process of the tandem reaction. 

When the activated carbonyl is a 1,3-dicarbonyl compound, some tandem reactions have been described. 

The Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes gave homoallylic alcohols, which have been used for the diastereoselective preparation of fused bicyclic, tricyclic and tetracyclic p-lactams of non-conventional structure 49 and 50, using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences <03JOC3106>. 

A stereoselective tandem Sakurai-carbonyl-ene reaction for the synthesis of steroid derivatives has been reported [48]. When LtAlCl2 and la were employed in this cyclization, stereochemical control was different. The cyclization product obtained with la is only 19 (Sch. 17), even though the starting material contained all four geometrical isomers use of LtAlCl2 resulted in a mixture of two different stereoisomers in lower yield. 

---