Two-carbon elongation

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Cross-metathesis of terminal alkyne 142 and cyclopentene gives cyclic compound 143 having a diene moiety [Eq. (6.114)]. ° Terminal ruthenium carbene generated from an alkyne and methylidene ruthenium carbene complex reacts with cyclopentene to afford two-carbon elongated cycloheptadiene 143 ... 

D-(-)-Tartaric acid, the unnatural enantiomer, was converted to the known ditosylate A. Two-carbon elongation of A with sodium cyanide was problematic. When the required amount (2 moles) of sodium cyanide was added in one portion to a DMSO solution of A, crystalline (2 ,4 )-2,4-hexadienedinitrile... 

Although less active than the microsomal system, mitochondrial chain elongation has been extensively investigated, particularly in liver and brain. The two-carbon elongation donor in mitochondria is acetyl-CoA. Generally, a monounsaturated fatty acyl-CoA substrate is more active than saturated CoA and both support higher activity than PUFA, particularly in brain. 

A total synthesis of squalene and lower terpenes" using the functionalized isoprene 2-hydroxymethyl-4-phenylthio-l-butene (21) has been recently reported. The starting material (21) has three functionalities an allylic alcohol allowing two-carbon elongation by Claisen rearrangement a homoallyl phenyl... 

Both of these pathways require two desaturation steps and a single two-carbon elongation reaction. The results of several different types of studies, during the past 40 years have supported, but not conclusively proven that the endoplasmic reticulum contains position-specific A6- and A5-desaturases. First, when liver microsomes were incubated with mixtures of PUFA, with their first double bond at different positions, the composition of the products was consistent with the presence of position-specific desaturases (7). For example, the desaturation of 9,12-18 2 decreased when 9,12,15-18 3 was included in the incubation suggesting that a single A6 desaturase accepted both substrates. Second, when mixtures of different PUFA were fed to rats, the composition of esterified PUFA also suggested the presence of different desaturases (8). Third, several cell lines were able to introduce a double bond at position-5, but not at position-6, when appropriate PUFA were used as substrates (9,10), thus suggesting the presence of position-specific A6 and A5 desaturases. 

Another method for two-carbon elongation via acetylene was studied by Horton and co-workers [21]. Scheme 5 presents their synthesis. Addition of acetylene magnesium bromide to the known aldehyde 10 gave a mixture of alcohols, from which epimer 27 was isolated. Tosylation followed by oxidation afforded ketone 28. The Sn2 substitution of the 6-tosylate by an azide anion, and then reduction, gave amino alcohol 30. 

Striking are the differences between the components necessary for acyl-CoA elongation according to the organelle in mitochondria acetyl-CoA is the immediate precursor of the two carbon elongation unit and both NADH and NADPH are necessary for synthesis of saturated fatty acids. On the contrary, microsomal enzymes require... 

Figure 11.60 Preparation of multiply labeled complex compounds containing mutiple stereogenic centers from N-protected amino aldehydes by a two-carbon elongation...

As seen already, palmitate is the primary product of the fatty acid synthase. Cells synthesize many other fatty acids. Shorter chains are easily made if the chain is released before reaching 16 carbons in length. Longer chains are made through special elongation reactions, which occur both in the mitochondria and at the surface of the endoplasmic reticulum. The ER reactions are actually quite similar to those we have just discussed addition of two-carbon units... 

FIGURE 25.12 Elongation of fatty acids in mitochondria is initiated by the thiolase reaction. The /3-ketoacyl intermediate thus formed undergoes the same three reactions (in reverse order) that are the basis of /3-oxidation of fatty acids. Reduction of the /3-keto group is followed by dehydration to form a double bond. Reduction of the double bond yields a fatty acyl-CoA that is elongated by two carbons. Note that the reducing coenzyme for the second step is NADH, whereas the reductant for the fourth step is NADPH. 

This pathway (the microsomal system ) elongates saturated and unsaturated fatty acyl-CoAs (from Cjg upward) by two carbons, using malonyl-CoA as acetyl donor and NADPH as reductant, and is catalyzed by the microsomal fatty acid elongase system of enzymes (Figure 21-5). Elongation of stearyl-CoA in brain increases rapidly during myehnation in order to provide C22 and C24 fatty acids for sphingoEpids. 

Reactions of imidazolides with the magnesium enolates of malonates (Mg2+/malo-nate, ratio 1 1) are used for the elongation of carboxylic acids by two carbon atoms to give jS-ketoesters (Tables 14—3 and 14-4). 

Acetogenins. Acetogenins are produced upon chain elongation with activated acetate units (or malonate followed by loss of carbon dioxide). A simplified sketch of this sequence is given in Fig. 1. During the first steps, a Claisen-type condensation of two acyl precursors yields a (3-ketoacyl intermediate A. Upon reduction to B and dehydration to C, followed by hydrogenation to D and hydrolysis, the chain elongated fatty acid E is produced. The next cycle will add another two carbons to the chain. Similarly, a reversed sequence leads to chain... 

The first step is carboxylation of acetyl CoA to malonyl CoA. This reaction is catalyzed by acetyl-CoA carboxylase [5], which is the key enzyme in fatty acid biosynthesis. Synthesis into fatty acids is carried out by fatty acid synthase [6]. This multifunctional enzyme (see p. 168) starts with one molecule of ace-tyl-CoA and elongates it by adding malonyl groups in seven reaction cycles until palmi-tate is reached. One CO2 molecule is released in each reaction cycle. The fatty acid therefore grows by two carbon units each time. NADPH+H is used as the reducing agent and is derived either from the pentose phosphate pathway (see p. 152) or from isocitrate dehydrogenase and malic enzyme reactions. 

The next phase focused on the goal of elaboration of the side chain in the desired sense. The primary alcohol function at C7 was unveiled by hydrogenolysis (Pd(OH)2/EtOAc-MeOH). Oxidation of the resultant compound 13 with chromic oxide pyridine afforded aldehyde 14, which was now to be elongated through some variation of a Homer-Emmons type of reaction. Shortly before tiiese investigations were launched. Still had demonstrated the use of phosphonate 15 as a device to achieve the two-carbon extension of an aldehyde to a Z-enoate (12). Happily, application of the Still method to compound 14 afforded the desired 16, mp 120-121° C, in 80% yield as a 20 1 mixture of Z E enoates. 

Thus, the (R)-glycidol (R)-897 was transformed to ethyl (S)-6-benzyloxy-3-methyl-4(E)-hexenoate (S)-899 via addition of acetylide followed by spontaneous isomerization, stereoselective reduction, and Claisen-Johnson rearrangement. The chiral ester (S)-899 was converted to (R)-4-methyl-6-phenylthiohexanol (R)-902. The primary alcohol (R)-902 was then transformed to the terminal acetylene (R)-904, a common intermediate for the synthesis of carbazoquinocins A (272) and D (275). Chain elongation of (R)-904 by two carbon atoms led to (R)-905, the chiral precursor for carbazoquinocin D (275) (639) (Scheme 5.116). 

The crystal structure of this compound shows a slightly elongated C=C bond of the alkyne and the usual deviation from linearity at the two carbon atoms of the triple bond.18,19... 

In non-ruminants, the malonyl CoA is combined with an acyl carrier protein (ACP) which is part of a six-enzyme complex (molecular weight c. 500 kDa) located in the cytoplasm. All subsequent steps in fatty acid synthesis occur attached to this complex through a series of steps and repeated cycles, the fatty acid is elongated by two carbon units per cycle (Figure 3.8, see also Lehninger, Nelson and Cox, 1993). 

Although palmitate, a 16-carbon, fully saturated LCFA (16 0), is to primary end-product of fatty acid synthase activity, it can be further I elongated by the addition of two-carbon units in the endoplasmic] reticulum (ER) and the mitochondria. These organelles use separate enzymic processes. The brain has additional elongation capabilities, allowing it to produce the very-long-chain fatty acids (up to 24 car bons) that are required for synthesis of brain lipids. 

It is of interest to compare two chain elongation processes by which two-carbon units are combined. 

Enzyme complexes occur in the endoplasmic reticulum of animal cells that desaturate at A5 if there is a double bond at the A8 position, or at A6 if there is a double bond at the A9 position. These enzymes are different from each other and from the A9-desaturase discussed in the previous section, but the A5 and A6 desaturases do appear to utilize the same cytochrome b5 reductase and cytochrome b5 mentioned previously. Also present in the endoplasmic reticulum are enzymes that elongate saturated and unsaturated fatty acids by two carbons. As in the biosynthesis of palmitic acid, the fatty acid elongation system uses malonyl-CoA as a donor of the two-carbon unit. A combination of the desaturation and elongation enzymes allows for the biosynthesis of arachidonic acid and docosahexaenoic acid in the mammalian liver. As an example, the pathway by which linoleic acid is converted to arachidonic acid is shown in figure 18.17. Interestingly, cats are unable to synthesize arachidonic acid from linoleic acid. This may be why cats are carnivores and depend on other animals to make arachidonic acid for them. Also note that the elongation system in the endoplasmic reticulum is important for the conversion of palmitoyl-CoA to stearoyl-CoA. 

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