Alkynes retrosynthesis

Since the targeted streptazolin-related natural products have a C2-unit at the C6-position, we first prepared the 2-oxazolone-alkyne derivative 82 with the simplest C2-unit, an ethyl group, at the triple bond terminus to not only identify suitable ring-closing conditions, but also to determine the level of stereoselectivity that could be expected in the intramolecular Pauson-Khand reaction. Thus, the 2-oxazolone-alkyne derivative 82, required for the intramolecular Pauson-Khand reaction in our retrosynthesis, was easily prepared from the known alcohol 78 by conventional means, as shown in Scheme 18. Oxidation of 78 was... 

If the carbon atom in 3 is electrophilic, then the carbon in 2 must be nucleophilic. This assumption is based on simple bond polarization and it makes it possible to correlate the imaginary 3 with a carbonyl compound that has an electrophilic carbon with a polarized C-0 bond. Nucleophilic acyl addition to a ketone is a known reaction, so 3 correlates with a real molecule—acetone. If 3 correlates with an electrophilic center, then 2 must be a nucleophilic center and an alkyne anion is a reasonable choice. It is known that an alkyne anion will react with a ketone via acyl addition (see Chapter 18, Section 18.3.2). The correlation of 2 with an alkyne simply requires adding a hydrogen atom to the red carbon to give terminal alkyne, 7. Conversion of alkyne 7 to the anion, followed by acyl addition to acetone, should lead to 1. Disconnection of 1 generates acetone and 7, and the reaction of 7 and acetone leads to 1. Recognizing the forward and reverse relationships is essential for correlating the disconnection (retrosynthesis) with the reactions that make the bond (synthesis). 

The readily available 1-propyne reacts with HBr to obtain 29. Disconnection of the bond adjacent to the carbonyl in 27 (the functional group) leads to 30 and 31. Because 30 is the one-carbon fragment, it becomes the acceptor and the synthetic equivalent is iodomethane. This makes 31 the donor, and a reasonable synthetic equivalent is the enolate anion of acetaldehyde, 32 (see Chapter 22, Section 22.9, for alkylation of enolate anions). This leads to the overall synthesis shown, based on the retrosynthesis (see Figure 25.11). The ability to see the relationship between an alkene and an alkyne allowed identification of a logical disconnection and a reasonable synthesis. 

The retrosynthesis of an alkyne involves a disconnection on either side of the C-C triple bond, with the less hindered electrophile (alkyl halide) being preferred as the faster Sn2. 

At first, this transformation might seem challenging, since no reaction exists that adds an alkynyl group to an alkene. However, a systematic approach to these problems always begins with the ending a retrosynthesis of the desired product. Once the alkyne TM is disconnected to give an acetylide nucleophile and a five-carbon electrophile (1-bromopentane), the solution becomes clear. 

The retrosynthesis of an alkane TM generally begins with an FGI that adds a functional group of your choice (an alkyl halide, alkene, alkyne, aldehyde, or ketone), and continues with a disconnection consistent with that functional group. Addition of the functional group at a branch point will likely lead to a good disconnection, but its precise location is not critical since it will ultimately be removed. 

Among the syntheses which cannot be deduced from classical retrosynthesis is the ring transformation [22] of oxazoles to furans by a Diels-Alder reaction with activated alkynes. For example, 4-methyloxazole 68 reacts with dimethyl acetylenedicarboxylate to provide furan-3,4-dicarboxylic ester 70 via a nonisolable cycloadduct 69 ... 

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