A-Enoyl derivatives

Asymmetric conjugate addition of lithium amides to alkenoates has been one of the most powerful methods for the synthesis of chiral 3-aminoalkanoates. High stereochemical controls have been achieved by using either chiral acceptors as A-enoyl derivatives of oxazolidinones (Scheme 4) 7 7a-8 chiral lithium amides (Schemes 5 and 6),9-12 or chiral catalysts.13,14... 

Preparation of Derivatives. A -Acyl- and A-enoylsul-tam derivatives are routinely prepared in good yields using either sodium hydride-acid chloride or trimethyl-aluminum-methyl ester single-step protocols. A variant of the former method employing in situ stabilization of labile enoyl chlorides with CuCl/Cu has also been reported. A two-step procedure via the A-TMS derivative (1) is useful when a nonaqueous work-up is desirable and for synthesis of the A-acryloyl derivative. A-Enoyl derivatives may also be prepared via the phosphonate derivative (2) by means of an Homer-Wadsworth-Emmons reaction (eq... 

Cadogan and coworkersi developed a fructose-derived l,3-oxazin-2-one chiral auxiliary which they applied in the Diels-Alder reactions of its A-enoyl derivatives 246 with cyclopentadiene using diethylaluminum chloride as the Lewis acid catalyst. The reactions afforded mixtures of endo 247 and exo 248 (equation 68). The catalyst binds to the chiral dienophile in a bidentate fashion (co-ordination to both carbonyl groups). As a consequence, the dienophile is constrained to a rigid confoimation which accounts for the almost complete diastereofacial selectivities observed. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted important interest thanks to there various applications in different synthetic transformations. These simple structures, directly related to the well-documented Evans oxazolidinones, have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations (7V-enoyl derivatives), but mainly in condensation of their 7V-acyl derivatives on aldehydes. Those have shown interesting characteristics in anti-selective aldol reactions or combined asymmetric addition. Normally, the use of chiral auxiliaries which can accomplish chirality transfer with a predictable stereochemistry on new generated stereogenic centers, are indispensable in asymmetric synthesis. The use of OZTs as chiral copula has proven efficient and especially useful for a large number of stereoselective reactions. In addition, OZT heterocycles are helpful synthons that can be specifically functionalized. 

Some use has the been made of the N-Grignard derivative of carbazole phenylacetyl (from the acid chloride), ethoxycarbonylcarbonyl, acetyl and 5-bromopent-4-enoyl, and various a-aminoacyl derivatives, (all... 

Although isoniazid has been in use for about 45 years, the enzyme that it inhibits has been recognized only recently. It is a specific NADH-depen-dent enoyl reductase involved in synthesis of mycolic acids.h/1 The isoniazid must be activated by action of a bacterial catalase-peroxidaseh This enzyme may convert the drug to a reactive radical that combines with a NADH-derived radical to form an adduct in the active site of the enzymes. One possible reaction sequence follows.11 However, the mechanisms are not clear. 

A-Aminophthalimide (118) can also be added to olefins in an asymmetric fashion. Thus, reaction of A -enoyl oxazolidinone 122 with 118 and lead tetraacetate in the presence of the camphor-derived chiral ligand 120 provides aziridine 123 in 83% yield and with 95% ee <020L1107>. Other useful chiral ligands include imine 121, derived from the condensation of 2,2 -diamino-6,6 -dimethylbiphenyl with 2,6-dichlorobenzaldehyde. The corresponding monometallic Cu(I) complex was found to be very efficient in chiral nitrogen transfer onto chromene derivative 124 using (Ar-(p-toluenesulfonyl)imino)phenyliodinane (PhI=NTs) to provide aziridine 125 in 87% yield and 99% ee <02JOC3450>. 

Cyclopropanation and Aziridination (Alkene Three-Membered Cycloadduct) - Cyclopropanation of various trans-N-enoyl derivatives using diazomethane with Pd(OAc)2 as catalyst affords cyclopropyl products with good C(a)-re -facial control (eq 8). Similarly, aziridination with N-aminophthalimide-lead tetraacetate affords N-phthalimidoaziridines with variable but generally good jr-face selectivity (33-95% de). ... 

Davies and coworkers , for example, used iV-enoyl derivatives of a cw-l-aminoindan-2-ol based L3-oxazolidin-2-one (222) as chiral dienophiles in the Diels-Alder reactions with isoprene (91a) and piperylene (91b) which give 223 (equation 62). Their results have been summarized in Table 6. The reactions proceeded with high endo/exo and regioselectivities. Bidentate co-ordination of the catalyst to both carbonyl groups kept the dienophile in a rigid conformation, which gave rise to the high de values observed. 

The loading module comprises three domains. The first (CL) shows homology to ATP-dependent carboxylic acid-CoA ligases, the second is a putative enoyl reductase (ER) and the third an ACP. The probable sequence of operations starts with the enoic acid 74 derived from shikimic acid which is reduced by the ER domain. The first domain will activate the carboxylic acid to an active acyl derivative ready for transfer to the thiol residue of the ACP. The final saturated product will end up attached to the ACP as a thioester derivative ready for transfer to the KS domain of the first chain extension module. The timing of the reduction in this sequence of operations cannot be predicted. 

Regarding the chemical behavior of (-)-emetine (1), the stereochemistry of asymmetric electroreductions of bromocyclopropanes at a mercury cathode in the presence of adsorbed 1 has been studied 95,96). Bertz et al. (97) have reported asymmetrie induction (with 70 30 R/S ratio, but in only 6% chemical yield) that occurred in the conjugate addition of an (-)-emetine-incorporating phenylamidocuprate to 2-cyclohexenone. Fraser-Reid s group 98,99) has reported that the NH group of 1 is readily protected as the A-pent-4-enoyl derivative, which can be rapidly... 

Two A, A -enoyl-CoA isomerases exist in rat mitochondria. One is mitochondrial A, A -enoyl-CoA isomerase that has been purified and its cDNA has been cloned [18]. The crystal structure revealed that this enzyme is a homotrimer with a subunit molecular mass of 30 kDa. In addition to converting the CoA derivatives of 3-c/5 -enoic acids and... 

Four rounds of [3 oxidation of a fatty acid with a trans-A ° double bond would yield a trans-A -enoyl CoA derivative. This compound is the natural intermediate formed by an acyl CoA dehydrogenase. It would be hydrated by enoyl CoA hydratase to form the L-3-hydroxyacyl CoA derivative. For the fatty acid with a cis-A double bond, four rounds of (3 oxidation would produce a ds-A double bond, which would not serve as a substrate for enoyl CoA hydratase. An isomerase would convert this bond into the trans-A configuration to allow subsequent metabolism. Since the double bond already exists in the fatty acids and does not arise from (3 oxidations, one less FADH2 would be formed. Consequently, approximately 1.5 fewer ATP would be produced for each pre-existing double bond. 

The most likely deficiency is a lack of 2,4-dienoyl CoA reductase, an enzyme that is essential for the degradation of unsaturated fatty acids with double bonds at even-numbered carbons. Such fatty acids include linoleate (9-ds,12-ds 18 2). Four rounds of oxidation of linoleoyl CoA generate a 10-carbon acyl CoA that contains a trans-A and a cis-A double bond. This intermediate is a substrate for the reductase, which converts the 2,4-dienoyl CoA to ds-A -enoyl CoA. A dehciency of 2,4-dienoyl reductase leads to an accumulation of trans-A, ds-A -decadienoyl CoA molecules in the mitochondrion. The observation that carnitine derivatives of the 2,4-dienoyl CoA are found in blood and urine provides evidence that these molecules accumulate in the mitochondrion and are then attached to carnitine. Formation of carnitine decadienoate allows the acyl molecules to be transported across the inner mitochondrial membrane into the cytosol, and then into the circulation. 

Coenzyme A thioesters can also promote nucleophilic attack at the j8-carbon in o(,j8-enoyl derivatives. In these cases an electrophilic centre is stabilized at the j8-carbon by resonance with the carbonyl system. This could be particularly favoured by hydrogen bonding or protonation of the carbonyl oxygen by an enzyme. An example is the enoyl coenzyme A hydratase reaction of fatty acid degradation. 

A silver-ion assisted halohydrin formation from a,p-unsaturated carboxylic acid derivatives was performed with chiral A-enoyl-2-oxazolidinones to form awri-o -halo- S-hydroxy carbonyls in good yields (90-94%, eq 2S). This alternate method of carboxyhalohydrin asymmetric-synthesis produced better diastereoselectivity (up to S,S RJi = 80 20) with AgOAc (or AgNOg) than with Ag2C03. The observed stereoselectivity required a nonnucleophilic (alkyl) substituent on the oxazolidi-none chiral auxiliary. 

NADPH. The elongation differs from the condensation inasmuch as (a) enoyl-CoA produced by dehydration of /3-hydroxyacyl-CoA is a cis compound in fatty acid synthesis via condensation, and a trans compound in microsomal synthesis (b) the intermediates formed by condensation remain protein bound and are not derived from CoA (Bressler and Wakil, 1961, 1962 Brodie et al., 1964) whereas these are released as CoA derivatives in the microsomal synthesis (c) in this case, an acid with the chain containing more than 10 carbons is elongated and (d) the elongation can proceed with the 18-carbon unsaturated acyl-CoA derivatives. 

Oppolzer W, Mills RJ, Pachinger W, Stevenson T. Preparation of enantiomerically pure p-silylcarboxyl derivatives by asymmetric 1,4-addition to A-enoyl-sultams. Preliminary communication. Helv. Chim. Acta 1986 69 1542-1545. 

FIGURE 24.15 The conversion of trans- and m-enoyl CoA derivatives to l- and d-/3-hydroxyacyl CoA, respectively. These reactions are catalyzed by enoyl-CoA hydratases (also called crotonases), enzymes that vary in their acyl-chain length specificity. A recently discovered enzyme converts ram-enoyl-CoA directly to D-/3-hydroxyacyl-CoA. 

Hydroxybutyric acid can also be directly incorporated [38], though some of it reacts with the corresponding enoyl-CoA. A more likely pathway proposed is via succinate semialdehyde, succinate, pyruvate, and acetyl-CoA, derived from 4-hydroxybutyrate, generally leading to a copolymer of 3-hydroxybutyryl and 4-hydroxybutyryl monomers from 4-hydroxybutyric acid [39]. 

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