Octanoate synthesis

Synthesis of PHAMCL from fatty acids such as octanoic acid or from the corresponding alkanes such as octane was first detected in P. oleovorans [119]. The alkanes are oxidized to the fatty acids the latter are activated by thiokinases and then degraded via the fatty acid /1-oxidation pathway. Obviously intermediates of this pathway accumulate under conditions favorable for the synthesis of PHA and are subsequently converted into substrates for the PHA synthase. Many reactions for the conversion of an intermediate of the -oxidation cycle into R-(-)-3-hydroxyacyl-CoA were considered. These were ... 

There is considerable interest in synthesizing copolymers. This is actually possible if organisms are confronted with mixtures of so-called related and unrelated substrates. Copolymers can also be synthesized from unrelated substrates, e.g., from glucose and gluconate. The 3-hydroxydecanoate involved in the polyester is formed by diversion of intermediates from de novo fatty-acid synthesis [41,42]. Related , in this context, refers to substrates for which the monomer in the polymer is always of equal carbon chain length to that of the substrate offered. Starting from related substrates, the synthesis pathway is closely connected to the fatty-acid /1-oxidation cycle [43]. In Pseudomonas oleovor-ans, for example, cultivated on octane, octanol, or octanoic acid, the synthesized medium chain length polyester consists of a major fraction of 3-hydroxyoc-tanoic acid and a minor fraction of 3-hydroxyhexanoic acid. If P. oleovorans is cultivated on nonane, nonanol, or nonanoic acid, the accumulated polyester comprises mainly of 3-hydroxynonanoate [44]. 

Fatty acids have also been converted to difunctional monomers for polyanhydride synthesis by dimerizing the unsaturated erucic or oleic acid to form branched monomers. These monomers are collectively referred to as fatty acid dimers and the polymers are referred to as poly(fatty acid dimer) (PFAD). PFAD (erucic acid dimer) was synthesized by Domb and Maniar (1993) via melt polycondensation and was a liquid at room temperature. Desiring to increase the hydrophobicity of aliphatic polyanhydrides such as PSA without adding aromaticity to the monomers (and thereby increasing the melting point), Teomim and Domb (1999) and Krasko et al. (2002) have synthesized fatty acid terminated PSA. Octanoic, lauric, myristic, stearic, ricinoleic, oleic, linoleic, and lithocholic acid acetate anhydrides were added to the melt polycondensation reactions to obtain the desired terminations. As desired, a dramatic reduction in the erosion rate was obtained (Krasko et al., 2002 Teomim and Domb, 1999). 

The one-pot dynamic kinetic resolution (DKR) of ( )-l-phenylethanol lipase esterification in the presence of zeolite beta followed by saponification leads to (R)-l phenylethanol in 70 % isolated yield at a multi-gram scale. The DKR consists of two parallel reactions kinetic resolution by transesterification with an immobilized biocatalyst (lipase B from Candida antarctica) and in situ racemization over a zeolite beta (Si/Al = 150). With vinyl octanoate as the acyl donor, the desired ester of (R)-l-phenylethanol was obtained with a yield of 80 % and an ee of 98 %. The chiral secondary alcohol can be regenerated from the ester without loss of optical purity. The advantages of this method are that it uses a single liquid phase and both catalysts are solids which can be easily removed by filtration. This makes the method suitable for scale-up. The examples given here describe the multi-gram synthesis of (R)-l-phenylethyl octanoate and the hydrolysis of the ester to obtain pure (R)-l-phenylethanol. 

Vinyl octanoate was obtained from TCI (Tokyo, Japan). All other chemicals with the exception of the zeolite beta are available from Sigma Aldrich. The synthesis of a particularly active modification of low-alumina zeolite beta has been described by us. Commercial material, available as samples from, for example, Zeolyst or Siidchemie can be used, but because of excessive acidity may result in up to 15 % of styrene formation. 

The conventional synthesis of aliphatic polyesters based on adipic acid and a range of diols, such as 1,4-butanediol or 1,6-hexanediol, involves a high-temperature esterification reaction typically at 240-260 °C and an organometallic catalyst such as stannous octano-ate. The use of enzyme catalysis results in a much lower reaction temperature, but also the possibility of removing the esterification catalyst, giving the polyester significantly improved hydrolysis resistance. 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

In 1988, an improved synthesis of orlistat (1) was reported by the Hoffmann-La Roche discovery chemistry. The scheme involved a pivotal P-lactone 14. In the approach, an aldol condensation of aldehyde 7 with the dianion generated from octanoic acid and two equivalents of LDA. After tosylic acid-facilitated lactonization and Jones oxidation, the resultant lactone 14/14 was hydrogenated to establish two additional chiral centers. A battery of somewhat tedious protections and deprotections transformed 15 to P-lactone 19 via the intermediacy of 16,17, and 18. Six additional steps then converted P-lactone 19 to orlistat (1). This route may provide better overall yield in comparison to the previous scheme. However, too many protections and deprotections render this approach less elegant and not very practical for large-scale process. 

An alternative route for the synthesis of TV-methyl amino acids without racemization is shown in Scheme 8.[98 This method includes the use of TBPB in the presence of copper(I) octanoate. The proposed mechanism of this free radical reaction is given in Scheme 8. Electron transfer from copper(I) to TBPB affords the copper(II), benzoate, and tBuO radical 4, which undergoes (3-scission to acetone and methyl radical 5. In turn, electron transfer from the urethane to the copper(II) ion, followed by proton transfer, affords the corresponding urethane radical 6, which reacts with the methyl radical 5 to give the desired product in overall yields of 54% (Z derivative) or 57% (Boc derivative), respectively. 

Stannous octanoate has also been studied as a catalyst for the synthesis of polydimethyl-and poly(methylphenyl)siloxanes via polycondensation. 

In the Sepracor synthesis of chiral cetirizine dihydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-... 

Bhagwat, S. S., Gude, C., Cohen, D. S., Dotson, R., Mathis, J., Lee, W., Furness, P. Thromboxane receptor antagonism combined with thromboxane synthase inhibition. 5. Synthesis and evaluation of enantiomers of 8- [(4-chlorophenyl)sulfonyl]amino -4-(3-pyridinylalkyl)octanoic acid. J. Med. Chem. 1993, 36, 205—210. 

The same year, Gerlach described a synthesis of optically active 1 from (/ )- ,3-butanediol (7) (Scheme 1.2). The diastereomeric esters produced from (-) camphorsulfonyl chloride and racemic 1,3-butanediol were fractionally recrystallized and then hydrolized to afford enantiomerically pure 7. Tosylation of the primary alcohol, displacement with sodium iodide, and conversion to the phosphonium salt 8 proceeded in 58% yield. Methyl-8-oxo-octanoate (10), the ozonolysis product of the enol ether of cyclooctanone (9), was subjected to Wittig condensation with the dilithio anion of 8 to give 11 as a mixture of olefin isomers in 32% yield. The ratio, initially 68 32 (E-.Z), was easily enriched further to 83 17 (E Z) by photolysis in the presence of diphenyl disulfide. The synthesis was then completed by hydrolysis of the ester to the seco acid, conversion to the 2-thiopyridyl ester, and silver-mediated ring closure to afford 1 (70%). Gerlach s synthesis, while producing the optically active natural product, still did not address the problem posed by the olefin geometry. 

If the removal of a protecting group by chemical methods fails in a lengthy synthesis, this can be quite costly and therefore the availability of biocatalysts on the shelf is very useful. The removal of the acetoxy-group in (S)-2-acetoxy octanoic... 

Fig. 4. Rate of cholesterol synthesis along the length of the intestine in 4 species. Cholesterol synthesis was determined in vitro in small intestinal slices obtained from segments 1 (proximal duodenum) through 10 (terminal ileum) using [ C]octanoate (panels A and B) or [ CJacetate (panels C and D). The data represent the flux of acetyl-CoA units to cholesterol from the two substrates in nmoles/h/g wet weight and are uncorrected for dilution by endogenous acetyl-CoA. Thus, the absolute numbers are not strictly comparable between the different species and substrates. The columns and bars represent the means 1 S.E.M.

Rhodium(II) octanoate catalyzed decomposition of vinyldiazomethane 174 in the presence of pyrrole 177 has been applied in the synthesis of naturally occurring ferruginine899. 

Oxoglutarate can also serve as a starter piece for elongation by the oxoacid pathway. Extension by three carbon atoms yields 2-oxosuberate (Eq. 21-1). This dicarboxylate is converted by reactions shown in Eq. 24-39 into biotin and in archaebacteria into the coenzyme 7-mercaptoheptanoylthreonine phosphate (HTP), Eq. 21-1. Lipoic acid is also synthesized from a fatty acid, the eight-carbon octanoate. A fatty acid synthase system that utilizes a mitochondrial ACP may have as its primary fimction the synthesis of ocfanoate for lipoic acid formation. The mechanism of insertion of the two sulfur atoms to form lipoate (Chapter 15) is imcerfain. If requires an iron-sulfur protein jg probably similar to the corresponding process in the synthesis of biotin (Eq. 24-39)9 93a formation of HTP (Eq. 21-1). One component of the archaebacterial cofactor methano-furan (Chapter 15) is a tetracarboxylic acid that is formed from 2-oxoglufarafe by successive condensations with two malonic acid imits as in fatty acid synthesis. ... 

---