Carbon nucleophiles natural products synthesis

Nogano and co-workers [3] reported similar examples of asymmetric induction for natural product synthesis using protected sugars and a variety of R MgX, where X = C1, Br, or 1. In Table 2, entries 3 and 4, the tetralose carbonyl can also contain in the Ri position an ether, ester, urethane, alkyl, or aryl group [13]. The authors reported the diastereometer ratio from the R substrate and the labeled carbon-2 varied from 80 20 to 10 90 (2S/2R). The variability was controlled by the nature of the nucleophile, the solvent, and the temperature. The authors rationalized the product distribution based on chelation of the metal and steric bulk of the reactants, favoring the R-isom.er. 

Nucleophilic attack on Pd-bound ligands, be they a, tt, or (t-tt, provides an assortment of excellent methods for the formation of carbon-carbon and carbon-heteroatom bonds, as represented by general transformations shown in Scheme 1. In particular, these processes have provided three major methods for the formation of the carbon-heteroatom bonds, and they have extensively been applied to the synthesis of natural products. More recently, the Pd-catalyzed cross-coupling has also been developed so as to be applicable to the formation of C— N, C—O, and other carbon-heteroatom bonds, as discussed in Sect. III.3, even though the current scope of their application to natural product synthesis is still rather limited. 

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. 

C-Glycosides have been of interest as building units in natural product synthesis, and unsaturated sugars have proved to be Important precursors (see also Chapter 12). Glycals and hydroxy-glycals react with several nucleophilic carbon reagents to give 2,3-... 

The Bernet-Vasella reductive ring opening has found many applications in carbohydrate chemistry and is a key step in several natural product synthesis [25,26]. However, the instability of the liberated aldehyde can be a problem, leading to side reactions and decomposition [27,28]. To overcome this limitation, the aldehyde has been trapped in situ by nitrogen or carbon nucleophiles. As a result, a series of domino reactions based on the Bernet-Vasella reaction has been described and applied to the total synthesis of chemically and biologically relevant products. 

M-Acyliminium cyclizations of optically active mono- and di-oxygenated hydroxylactam derivatives have been used in the synthesis of a number of natural products. In case of a five-membered lactam the oxygen function adjacent to the iminium carbon directs attack of the internal nucleophile from the least hindered side, opposite to the substituent. In the examples given the size of the newly formed ring is determined by the electronic bias of the alkene substituent. 

The reactivity of alkynylstannanes toward electrophiles is one element in the oxygen-to-carbon rearrangement of alkynylstannane derivatives of furanyl and pyranyl lactols (e.g., Equation (85)). The cleavage of the anomeric C-O bond is assisted by the Lewis acid to give an oxonium ion, which is trapped in situ by the nucleophilic stannylalkyne. The utility of this process has been demonstrated in the synthesis of the natural product muricatetrocin C, and the drug substance CMI-977.246... 

Many new sugar based products present the advantage of being non-toxic and biodegradable. The products resulting from the telomerization of 1 with appropriate nucleophiles such as alcohols, amines, water, or carbon dioxide serve generally as useful intermediates in the synthesis of various natural products and fine chemicals [60-63], as precursors for plasticizer alcohols [56, 64], components of diesel fuels [65], surfactants [11, 66], corrosions inhibitors, and non-volatile herbicides [67]. 

Carbonyl ylides can be viewed as an adduct between a carbonyl group and a carbene and, in fact, some ylides have been prepared this way (see above). The application of carbonyl ylides to the synthesis of complex natural products has been greatly advanced by the finding that stabilized carbenoids can be generated by the decomposition of ot-diazocarbonyl compounds with copper and rhodium complexes. The metallocarbenoids formed by this method are highly electrophilic on carbon and readily add nucleophiles such as the oxygen of many carbonyl derivatives to form carbonyl ylides. This type of reaction is in fact quite old with the first report being the addition of diazomalonate and benzaldehyde (33,34). 

A formal asymmetric nucleophilic addition to carbonyl compounds is achieved by Trost and his co-workers in the allylic alkylation of acylals of alkenals. An excellent enantioselectivity is observed in this alkylation. The starting acylals are easily prepared by the Lewis-acid catalyzed addition of acid anhydrides to aldehydes, by use of Trost s ligand 118 (Scheme 13), where various carbon-centered nucleophiles are available (Scheme l4),101,101a-10lc Asymmetric synthesis of some natural products is achieved according to this procedure. 

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