Formation by Side Chain Incorporation

Various strategies has been used to synthesize macrocyclic lactones by ring enlargement. The reason for this development lies in the large number of different naturally occurring macrocyclic lactones. Many of these are of considerable clinical importance [61] [62] [63] [64] [65]. 

2-Nitrocycloalkanones have been successfully used for the preparation of many natural products. 

The ten-membered lactone (R)-(-)-phoracantholide I [(-)-VII/126] [66] was first isolated from the metasternal gland of the eucarypt longicorn Phoracantha synonyma Newman [67]. It is part of the beetle s defensive secretion. Several times in the past this compound has been synthesized several times using ring forming [68] [69] [70] [71] [72] [73], as well as ring enlargement reactions [3] [74] [75] [76] [77] [78] [79] [80] [81] [82], 

7) Optical active phoracantholide I (VII/126) was observed when ( )-2-nitro-2-(3 -oxobu-tan-4-yl)cyclohexanone was reduced with (S)- or (i )-Alpine-Hydride [85], 

The natural products [90], dihydrorecifeiolide (= 11-dodecanolide) [3] [91], 12-methyl-13-tridecanolide [92], and 12-tridecanolide [93] have been synthesized in high overall yields using this ring enlargement reaction as a key step. 

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VII.2. Ring Enlargement by Side Chain Incorporation with Lactam Formation... 

Structurally, plastomers straddle the property range between elastomers and plastics. Plastomers inherently contain some level of crystallinity due to the predominant monomer in a crystalline sequence within the polymer chains. The most common type of this residual crystallinity is ethylene (for ethylene-predominant plastomers or E-plastomers) or isotactic propylene in meso (or m) sequences (for propylene-predominant plastomers or P-plastomers). Uninterrupted sequences of these monomers crystallize into periodic strucmres, which form crystalline lamellae. Plastomers contain in addition at least one monomer, which interrupts this sequencing of crystalline mers. This may be a monomer too large to fit into the crystal lattice. An example is the incorporation of 1-octene into a polyethylene chain. The residual hexyl side chain provides a site for the dislocation of the periodic structure required for crystals to be formed. Another example would be the incorporation of a stereo error in the insertion of propylene. Thus, a propylene insertion with an r dyad leads similarly to a dislocation in the periodic structure required for the formation of an iPP crystal. In uniformly back-mixed polymerization processes, with a single discrete polymerization catalyst, the incorporation of these intermptions is statistical and controlled by the kinetics of the polymerization process. These statistics are known as reactivity ratios. 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

The hrst step in the preparation of the antidepressant maprotiline (33-5) takes advantage of the acidity of anthrone protons for incorporation of the side chain. Thus treatment of (30-1) with ethyl acrylate and a relatively mild base leads to the Michael adduct saponihcation of the ester group gives the corresponding acid (33-1). The ketone group is then reduced by means of zinc and ammonium hydroxide. Dehydration of the hrst-formed alcohol under acidic conditions leads to the formation of fully aromatic anthracene (33-2). Diels-Alder addition of ethylene under high pressure leads to the addition across the 9,10 positions and the formation of the central 2,2,2-bicyclooctyl moiety (33-3). The hnal steps involve the construction of the typical antidepressant side chain. The acid in (33-3) is thus converted to an acid chloride and that function reacted with methylamine to form the amide (33-4). Reduction to a secondary amine completes the synthesis of (33-5) [33]. 

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