C3-synthon

Despite the fact that transition metal complexes have found wide application in the synthesis of carbo- and heterocycles, [3+3] cyclisation reactions mediated or assisted by transition metals remain almost unexplored [3, 86]. However, a few examples involving Fischer carbene complexes have been reported. In all cases, this complex is a,/J-unsaturated in order to act as a C3-synthon and it reacts with different types of substrates acting as C3-synthons as well. 

All around this chapter, we have seen that a,/J-unsaturated Fischer carbene complexes may act as efficient C3-synthons. As has been previously mentioned, these complexes contain two electrophilic positions, the carbene carbon and the /J-carbon (Fig. 3), so they can react via these two positions with molecules which include two nucleophilic positions in their structure. On the other hand, alkenyl- and alkynylcarbene complexes are capable of undergoing [1,2]-migration of the metalpentacarbonyl allowing an electrophilic-to-nucleophilic polarity change of the carbene ligand /J-carbon (Fig. 3). These two modes of reaction along with other processes initiated by [2+2] cycloaddition reactions have been applied to [3+3] cyclisation processes and will be briefly discussed in the next few sections. 

The formal [3+2+1]-cycloaddition involves an a,ft-unsaturated carbene ligand (C3-synthon),an alkyne (C2-synthon) and a carbonyl ligand (Cl-synthon) and takes place within the coordination sphere of the chromium(O), which acts as a metal template (Scheme 2). 

Quinolizinium and other fused pyridinium salts are formed when a-methylheterocycles react with 2,4,6-triphenylpyrylium, which thus behaves as a C3-synthon <96MC99>. Pyrylium salts also feature in a stereocontroUed route to conjugated dienynes which has led to a synthesis of Carduusyne A, a marine metabolic fatty acid <96TL1913> and in the formation of pyridinium containing crown ethers <96LA9S9>. 

The stereochemistry of the first step was ascertained by an X-ray analysis [8] of an isolated oxazaphospholidine 3 (R = Ph). The overall sequence from oxi-rane to aziridine takes place with an excellent retention of chiral integrity. As the stereochemistry of the oxirane esters is determined by the chiral inductor during the Sharpless epoxidation, both enantiomers of aziridine esters can be readily obtained by choosing the desired antipodal tartrate inductor during the epoxidation reaction. It is relevant to note that the required starting allylic alcohols are conveniently prepared by chain elongation of propargyl alcohol as a C3 synthon followed by an appropriate reduction of the triple bond, e. g., with lithium aluminum hydride [6b]. 

An example of synthesis A is that of 5-methyl-1,2,4-triazolo[l,5-a] pyrimidin-7-on (MOT) (3) by Bulow and Haas (09CB4638) given in Scheme 1. This reaction is a pyrimidine synthesis The C3-synthon condenses with a N—C—N moiety, which is a part of an AT. Apparently the reaction passes through the nonisolable intermediate 2 (Section II,A,2). 

Table I illustrates this synthesis in schematic form. The first column lists all functions A and B of the 1,3-dicarbonyl compounds or their equivalents that are used to introduce certain substituents R and R" into positions 5 and 7 e.g., unsubstituted TP is formed by malondialdehyde, the 5,7-dione by diethyl malonate, and the 5,7-diamine by malonitrile. Unsymmetrical C3-synthons with different A and B moieties may form two isomeric TPs in which R and R" interchange their positions. The direction of attack depends on both synthon structure and reaction conditions.

Cleavage by amines and ammonia seldom occurs (a) in a reaction under Chichibabin conditions [68DIS(B) 1303] and (b) with substrates like6-nitro-TP (91ZOR1100). Here the inherent C3-synthon is scavenged as imine 50 (Scheme 24). 

Usually, the a-pyranic addition products (3) cannot be isolated because they isomerize immediately in a thermally allowed electrocyclic process affording acyclic dienones (4), which in many cases react further. Therefore, pyrylium salts 2A react with most nucleophiles as if they had the electronic structure 2B, and thus the pyrylium cation behaves as a useful synthon, namely the last vinylog in the series of acyl halides (Cj synthon) - p-halovinyl ketones (C3 synthon) - pyrylium (C5 synthon) [50, 51],... 

When we consider the synthesis of a quinoline, the obvious disconnections are, first, the C-N bond in the pyridine ring and, then, the C-C bond that joins the side chain to the benzene ring. We will need a three-carbon (C3) synthon, electrophilic at both ends, which will yield two double bonds after incorporation. The obvious choice is a 1,3-dicarbonyl compound. 0... 

Another illustration of isostructural synthons with reversed polarity comes from the allyl halide and allylsilane pair. Allyl halide, in reactions with standard nucleophiles, is an electrophile, equivalent to the synthon CH2=CH-CH/. Allylsilane is a nucleophile, equivalent to the synthon CH2 = CH-CHf (in Lewis acid mediated reactions with electrophilic reagents, examples in Scheme 2.41). The availability of both types of C3 synthon permits the introduction of an allyl group to either a nucleophilic or electrophilic site and to treat the respective synthetic options as viable alternatives. 

A remarkably short synthesis of the fused bicyclic system 288 was achieved through an ingenious exploitation of a bis-enolate alkylation. In general, this sequence corresponds to the coupling of two different 1,3-C3 synthons with the tetradentate 2,3-Cl synthon. 

This disconnection led to the C3 synthon 48 (and hence to its already familiar synthetic equivalent 44) and C9 amino dialdehyde 47. The Michael addition of malonic ester to acrolein was employed for the synthesis of the key starting material 49. The Claisen ester condensation of the latter followed by decarboxylation and reductive aminolysis led to the preparation of amino-bis-acetal 47a. The respective amino dialdehyde 47, generated in situ by a controlled hydrolysis of the acetal groups of 47a, reacted smoothly with acetonedicarboxylic diester and gave the required adduct 46 in a good yield and nearly complete stereoselectivity. 

The main research efforts in transition metal mediated [3 -1- 2] cycloaddition can be categorized into the development of three important types of C3 synthon dimethylenemethane, 2-oxyallyl, and trimethy-lenemethane. This review summarizes some recent achievements up to the first quarter of 1989, and centers around these three synthons. Emphasis will be placed on the chemo-, regio- and stereo-selectivity of these reactions, their preparative aspects, and their synthetic potential. 

The ready availability of starting materials, such as dienes and alkenes, has contributed to the popularity of the Diels-Alder reaction. Unfortunately, this is not true in [3 + 2] cycloadditions. While Ae C2 unit is well represented by simple unsaturated molecules as in the Diels-Alder reactions, the source of the odd-numbered 4ir fragment is less obvious because it is not a common stable entity. Hence, the success of using the [3 + 2] methodology in a synthetic sequence depends critically on the effective generation, reactivity and selectivity of this C3 synthon. 

To prepare 5-AI or 3-AI, hydroxylamine or /V-hydroxyurea may be used as synthetic equivalents of the NO-synthon and malonodinitriles, p-ketonitriles and cyanoacetylenes, as equivalents of the C3-synthon. The condensation of... 

R)-Isopropylideneglycerol is a useful C3-synthon in the synthesis of (S)-P-block-ers e.g. (S)-metoprolol. (R)-Isopropylideneglyceric acid can also be used as starting material for the synthesis of biologically active compounds. 

R) -1 sopropylideneglycerol is a useful C3-synthon in the synthesis of (S)-P-blockers, e. g. (S)-metoprolol. Also, (R)-isopropylideneglyceric acid may be used as the starting material for the synthesis of biologically active products. The resolution is carried out by selective microbial oxidation of the (S)-enantiomer (Fig. 19-9). The chemical synthesis of (R)-isopropylideneglycerol starts either from unnatural L-mannitol or from L-ascorbic acid (Fig. 19-10). In comparison to the biotransformation, here stoichiometric quantities of lead tetra acetate are needed. 

To obtain the highest yields in the synthesis of carotenoids, it is important to keep the synthetic routes as short as possible, especially when working with valuable labelled substances. It is therefore advantageous to use Cs-synthons rather than C2- and C3-synthons. 

Kdn). Dondoni s group have extended their earlier woik on the use of a diiazolyl phosphtnane as a masked C3 synthon for making 3-deoxy-2-ulosonic acids (Vol. 25, p. 187), and have now described this approach as applied to Dah, Kdn and A-epi- jAaM... 

Since the allyl cation is stabilized by resonance with the double bond, similar to the stabilization of the benzylic cation by an aromatic ring, the reactivity of the corresponding allyl halide l-bromobut-2-ene TM 2.12a is enhanced, resembling that of benzyl bromide. The anionic C3 synthon we already met in the former example will appear in many of the disconnections that follow. 

A surprising solution is offered by rcfro-Mannich type disconnection b where the acidic C-H group participates and the carbanion appears as an illogical synthon on the acyl C atom. We showed the transformation of the nitro to a carbonyl group already in Sect. 2.4. For the illogical C3 synthon, an unexpected reagent exists, 1-nitropropane, whose a-C-H atom has a of ca. 10. Taking into account this... 

This strategy was used to synthesize spirocyclopenteneoxindoles, as well as stereodefined cyclopentenes. Likewise, Hu reported a [3 -f 2] annulation reaction of 2-atylideneindane-l,3-diones with MBH carbonates that proceeded smoothly in the presence of a multifunctional thiourea-phosphine catalysts to produce the corresponding quaternary carbon centered spirocyclic cyclopentenes. A phosphine-triggered tandem [3 + 4] annulation reaction between MBH carbonates and 1,4-diheteroatom dinucleophiles was described, which provided access to saturated seven-membered 1,4-heterocycles. Analogously, MBH carbonates were used as C3 synthons in asymmetric [3 + 2] annulation reactions for the asymmetric synthesis of 3-spirocyclopentene-2-oxindoles. Another kind of annulation reaction for the construction of highly functionalized stereodefined cyclopentene skeletons involved a Rauhut-Currier Domino Reaction. Finally, an efficient asymmetric [3 + 2] cycloaddition reaction between MBH carbonates of isatins and... 

Croton aldehyde (2-butenal), like many other a,p-unsaturated aldehydes, is a good substrate for almond HNL [98,125]. The unsaturated cyanohydrin (/ , )-2-hydroxy-3-pen-tenenitrile can be used, after protection of the hydroxyl group, as a potential chiral C3-synthon in which the double bond serves as a masked oxygen functionality. 

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