Hydroformylation alkaloids

In the presence of tetramethyltin, 1-bromonauclefine reacts with CO in a Pd-catalyzed carbonylation to give the alkaloid naucletine [202], Dong and Busacca effected a new synthesis of tryptamines and tryptophols via a Rh-catalyzed hydroformylation of functionalized anilines that are prepared by a standard Heck reaction, as shown for the preparation of tryptamine sulfonamide 325 [423]. This reaction is applicable to ring-substituted tryptamines (Cl, Br, F. OMe, CF3). Likewise, the Rh-catalyzed carbonylation of o-alkynylanilines, which were prepared by a Pd-catalyzed Sonogashira coupling, leads to oxindoles (60-86% yields) [424],... 

The combination of rhodium dicarbonyl acetylacetonate complex (Rh(acac)(CO)2) and a diphosphite ligand, (2,2 -bis[(biphenyl-2,2 -dioxy)phosphinoxy]-3,3 -di-/i t/-butyl-5,5 -dimethoxy-l,T-biphenyl (BIPHEPHOS), is an excellent catalyst system for the linear-selective hydroformylation of a wide range of alkenes. This catalyst system has been successfully applied to the cyclohydrocarbonylation reactions of alkenamides and alkenylamines, which are employed as key steps for the syntheses of piperidine,indolizidine, and pyrrolizidine alkaloids. ... 

A quinazoline alkaloid skeleton has been synthesized by means of the Rh-catalyzed cyclohydrocarbonylation of diaminoalkenes. The reaction of 2-(A -allylaminomethyl)aniline 55 gave quinazoline 59 in excellent yield through the highly linear-selective hydroformylation of 55 to aldehyde 56, followed by the sequential formations of hemiaminal 57 and iminium ion 58 as intermediates and then the subsequent intramolecular amine addition (Scheme In the same manner, the reaction of A -allyl-2-aminomethylaniline 60 afforded 61 in 96% yield. ... 

Draw structures of ligands derived from the chiral framework of glucose, tartaric acid, binaphthol, and cinchona alkaloids that are used for efficient asymmetric hydrocyanation, epoxidation, hydroformylation, and alkene dihydroxylation reactions respectively. 

Synthesis of Alkaloids Containing a Quinolizidine Core by Means of Strategies Based on a Hydroformylation Reaction... 

Following her, in his thesis work, Thomas Spangenberg used these homo-allylamines as substrates for the hydroformylation reaction in order to synthesize alkaloids in a limited number of steps. He mainly focused on the... 

Airiau E, Girard N, Pizzeti M, Salvadori J, Taddei M, Mann A (2010) Hydroformylation of alkenylamines. Concise approaches toward piperidines, quinolizidines, and related alkaloids. J Org Chem 75 8670-8673... 

Radical addition of thiol or thiol-modified support to the vinyl group gives the respective thioether linkage 34 and represents one of the most convenient ways to immobilize Cinchona alkaloids [163, 172]. There are also few examples of platinum-catalyzed hydrosilylation of Cinchona alkaloids toward 11-silyl-substituted derivatives 35 with the use of monomeric silanes or polysiloxane polymers [173-175]. De Vries reported rhodium-catalyzed hydroformylation of the four main members of Cinchona alkaloids carried out on a hundred gram scale. Under optimized condition, linear aldehydes 36 were selectively obtained with the yield over 80% [176]. 

Hydroformylation can be highly tolerant of functional groups. An azide, normally highly reactive towards transition metals, can survive. This property has been exploited in a synthesis of the pyridine alkaloids anaba-sine 4.158 and nicotine 4.159 from the same hydroformylation reaction (Scheme 4.58). Another approach to both of these alkaloids can be found in Chapter 8, Schemes 8.76 and 8.77. Double hydroformylation of the azido diene 4.160 gave the bis-aldehyde 4.161 (Scheme 4.59). Tandem azide reduction and double reductive amination then gave the indolizidine alkaloid, lupinine 4.162. ... 

Chiou et (d. [81] investigated the hydroformylation-acetalization in the framework of the synthesis of pyrrolidinoindolines and tetrahydrofuranoin-dolines (Scheme 5.89). The hydroformylation occurred in the a-position of the aryl ring. Double cyclization constructed the fused pyrrolidine ring in a stereoselective maimer. Based on this protocol, a variety of pharmacologically important alkaloids were synthesized. By application of the corresponding allyl alcohol as starting material, the THF-based physovenine was prepared. 

In 2011, Bates et al. [105] showed that hydroformylation of (/ )-Af-tosylhept-1-enamine followed by intramolecular dehydration could serve as a key step in the synthesis of the hemlock Conium macidatum) alkaloid pseudoconhydrine... 

The naturally occurring cinchona alkaloids, cinchonidine, quinine, and quinidine, were hydroformylated selectively to the corresponding terminal aldehyde derivatives with 87, 71, and 85% isolated yields, respectively, using Rh(CO)2(acac)/tetrapho-sphite/5 catalyst system at 90 °C and 20bar CO H2 = 1 1 in toluene [15]. 

In contrast to the previous examples, the preferred formation of linear aldehydes was the main target in some syntheses to construct a cyclic derivative with an appropriate ring size in the next step or for simply elongating a carbon chain. The linear aldehydes are the proper intermediates for the synthesis of indolizidine alkaloids [11], the tricyclic marine alkaloid lepadiformine [12], ACE inhibitors such as MDL 27210 and its analogues [13,14], and bryostatin, a remarkably potent anticancer agent [15]. Rhodium complexes of bisphosphite ligands provide one of the best known classes of linear-selective hydroformylation catalysts for simple ot-olefins. Except for the lepadiformine intermediate, where hydroformylation was carried out in the presence of the Rh(acac)(CO)2/P(OPh)3 catalyst system, in other... 

Hydroformylation of substrates incorporating O- or N-nudeophilic moieties leads to cyclic hemiacetals, acetals, 0,N-acetals, or enamines depending on the reaction conditions and the functional groups of the substrates. In the total synthesis of the anticancer agent, natural product leucascandroUde A (24), three different carbonyla-tion steps were incorporated (Scheme 12.1). Alkene 20 underwent a cyclohydrocar-bonylation reaction under hydroformylation conditions, resulting in the formation of hemiacetal 21. The other two carbonylation steps involved formylation of 18 and intramolecular alkoxycarbonylation of alkene 22 [28]. Various tryptamine derivatives [29] and the framework of piperidine alkaloids [30] were also synthesized via cyclohydrocarbonylation starting from functionalized homoallylic amines or aniline derivatives, respectively. 

Cuny GD, Buchwald SL. Regioselective olefin hydroformylation as a route to indolizidine and pyrrolizidine alkaloids. Synlett 1995 519-522. 

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