Natural product synthesis amination reactions

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The significance of chiral unnatural amino acids to drug and natural product synthesis is shown in the example of the antihypertensive dmg omapatrilat (Vanlev ), which is composed of no less than three amino acid derived intermediates [144-147]. Diverse biocatalytical approaches to L-6-oxonorleucine were made (Fig. 21). Two different enzymes were applied in reductive amination reactions to produce derivatives of the desired intermediate. 

This reaction has been utilized in the context of natural product synthesis. A recent example is the synthesis of colletodiol by Keck, shown in equation (45). In this example, no problems were encountoed with epimerization or ester cleavage. The desireid ( )-ester (182) was synttesized in 80% yield. Two examples are outlined (in equations 46 and 47) in which epimerization was a substantial problem with sodium or potassium salts, while the LiCl/amine method effectively suppressed this side reaction. When the phosphonate was allowed to react with the cyclohexanal derivative (183), the sodium salt gave epi-merized material. Use of LiCl and diisopropylethylamine gave an 88% yield of alkene (184), free of epimer (equation 46). In the synthesis of norsecurinine, Heathcock found that the phosphonate anion... 

Radical reactions are widely used for carbon-carbon bond formations. This has led to highly efficient novel synthetic methods that can be used in natural product synthesis as well as preparation of fine chemicals. Many of these processes involve a reductive final step (see for instance Volume 1, Chapter 1.3). Alternative methods that allow functionalization of carbon-centered radicals are highly desired. In this chapter, we will focus on oxygenation and amination reactions. 

New development of photoinduced electron transfer reaction and total synthesis of natural products, cyclic amines and 0-macrohetero-cycles 05YZ16. 

Except for the construction of isoprenyl aromatic natural products, the Claisen rearrangement of allyl phenyl ethers has been relatively little exploited in natural product synthesis. The potential value of the reaction, however, has now been demonstrated in a synthesis of (+)-latifine (128). Thus, the allyl phenol ether (125) was found to re-arrange smoothly in refluxing N,N-dimethylaniline to give (125) in 75% yield, which was then elaborated to the natural product via the amine (12 ) in a further seven steps. 

Another class of reaction for which chiral tertiary amines are privileged catalysts is the Morita-Baylis-Hillman type (477, 478). One of the first applications of Cinchona alkaloids to mediate an asymmetric Morita-Baylis-Hillman reaction in a natural product synthesis was reported by Hatakeyama et al. in 2001 (479). Using a stoichiometric amount of (3-isocupreidine (568), a stereoselective addition of hexafluoroisopropyl acrylate (569) to aldehyde 570 could be carried out in good yield and with excellent selectivity (99% ee) (Scheme 119). The chiral p-hydroxy ester 571 was converted further into the epoxide 572, a known intermediate in the synthesis of epopromycin B (573). Epopromycin B (573) is a plant cell wall... 

Nncleophilic attack by carbanions on Pd rr-complexes provides an excellent method for carbon-carbon bond formation. The first example of natural product synthesis by the reaction of Pd rr-complex with carbon nucleophiles appears to be Holton s synthesis of prostanoids via treatment of an allylic amine with the stoichiometric amount of lithinm tetrachloropalladate and sodium diethyl malonate, followed by addition of diisopropy-lethylamine, which led to the formation of an isomerically pure bicyclic Pd-amine complex in 92% yield " (Scheme 18). The carbon nucleophile ends up a and trans to the dimethylamino group. Both regio- and stereochemistries must be controlled by the Me2N group. The amino diester intermediate was further transformed into Corey lactone diol, which had previously been converted to PGp2a in two steps and 80% overall yield. 

A pioneering application of C-H activation to natural-product synthesis is in a synthesis of ibogamine 3.24 (Scheme 3.11). ° An asymmetric Diels-Alder reaction set up the chirality. The chirality was controlled by the use of a chiral auxiliary on the diene 3.18. Reductive amination then connected the Diels-Alder product 3.19 to an indole moiety. Palladium-catalysed cyclization then generated the bicyclic alkene 3.23. In this reaction. 

Treatment of ketone (69) with excess amounts of t-BuMe2SiOTf and bis[(k)-l-phenylethyl]amine ((i )-BPEA) gives tricyclic silyl aldolate (70) with moderate enantioselectivity [104]. The formation of (70) can be explained by the enol silylation to (71) followed by a tandem Michael-aldol reaction. The asymmetric induction by the chiral amine occurs in the enol silylation (Scheme 9.40). The combined use of silyl triflates and amines has been applied to an intramolecular aldol reaction for natural product synthesis [105]. 

Amine-catalyzed cascade reactions in natural product synthesis... 

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