Isoleucine scheme

The enol of glycine (4) has been generated by neutralization with trimethy-lamine of the corresponding cation-radical (4+ ) prepared by dissociative ionization of isoleucine (Scheme 3) [71]. The +NR+ mass spectrum of 4+ showed a substantial survivor ion attesting to the stability of isolated 4. In contrast, the survivor ion from glycine (5) is much less stable and appears as a very minor peak in the +NR+ mass spectrum of 5, in spite of the fact that neutral 5 is thermodynamically more stable than 4. 

This is obtained in three phases first the C j -C 4 unit is generated from (S)-malic acid (90) (Scheme 8) the C45-C24 unit is obtained from D-glucose (Scheme 9) and finally the C44-C28 unit is build up starting from L-isoleucine (%) (Scheme 10). 

Similar findings were reported for the acidic part in the PA strigosine [69] and for angeloylic and tigloylic acid [70]. In the case of the acidic part in the PA monocrotaline, it was shown that not acetate, mevalonate, orglutarate (as reported earlier) are involved but it is only formed via isoleucine [71], Stereospecific aspects were also studied in the case of senecic and isatinecic acid [72, 73]. The biosynthesis of trichodesmic acid was studied and it was shown that one part of the Cio acid was formed by (25)-isoleucine or its biosynthetic precursor (25)-threonine and the other C5 unit from (25)-leucine or (25)-valine [74]. The complete labeling pattern of senecic acid (the acidic part in the PAs rosmarinine and senecionine) was studied by NMR experiments and it was stated that the biosynthesis of this acid is processed via two molecules of isoleucine (Scheme 13.2) [75]. 

Compounds 296-299 inhibit acetohydroxy acid synthase (AHAS), formerly known as acetolactate synthase. Its activity is not present in animals, but it has been found in all plants where measurements have been attempted. Acetohydroxy acid synthase catalyses the first step in production of branched amino acids (leucine, valine and isoleucine) (Scheme 73), which are obviously needed for the protein synthesis and cell growth. The compounds 296-299 seem to bind within the substrate-access channel of the enzyme, thus blocking a-ketocarboxylate access to the active site. While these herbicides are undoubtedly highly successful, resistance developed due to mutations within AHAS is becoming a serious problem [274, 275]. 

It has been confirmed that isoleucine but not 3-hydroxy-2-methylbutanoic acid is a precursor for the tiglic acid which is the esterifying acid in some tropane alkaloids [e.g., meteloidine (77) (735)]. In the biosynthesis of meteloidine (77) from 3a-hydroxytropane (1), the hydroxyl groups at C-6 and C-7 are most probably introduced after esterification at C-3 (5) (Scheme 23). In this connection we would point out that scopolamine (89) is a well-known 2,3) metabolite of hyoscyamine (27) and that the reaction proceeds via 6-hydroxyhyoscyamine [(—)-anisodamine (63)] and 6,7-dehydrohyoscyamine (211) (Scheme 26). 

Earlier in this chapter, it was mentioned that many of the nonprotein amino acids are components of nonribosomal peptides. During such a biosynthesis, the peptide is attached to a carrier protein through a thioester bond, until chain termination occurs and the final product is released. The carrier protein is posttranslationally modified by the attachment of a phosphopantetheinyl group from coenzyme A. This step gives rise to the active carrier protein with a phosphopantetheine arm upon which amino acids are added to during NRPS. As an example, loading of isoleucine onto the carrier protein is depicted below (Scheme 5). Further details about nonribosomal peptide syntheses and enzymatic reactions can be found in Chapter 5.19. 

Scheme 5 Loading of isoleucine onto the phosphopantetheine arm of a carrier protein domain.

With the use of gene clusters of the natural products coronatine and kutznerides, the biosynthetic pathway of coronamic acid has also been elucidated by Walsh and coworkers. From the biosynthetic analyses, a nonheme Fe -dependent halogenase was identified as the chlorinating enzyme that converts L- //a-isoleucine to 7-chloroisoleucine. A second enzyme carries out a dehydrochlorination reaction to yield coronamic acid. The general biosynthetic pathway is shown below (Scheme 7). 

D-Allo-isoleucine and L-isoleucine derivatives have been prepared from the corresponding mixture of stereoisomers via a diastereoselective hydrolysis reaction catalyzed by the enzyme alcalase (Scheme 2.6). Initially, enantiomerically and diastereomerically pure derivatives of L-isoleucine 10 were submitted to chemical epimerization to yield a 1 1 mixture of stereoisomers at the a-position. Thereafter,... 

Scheme 2.6 Preparation of D-allo-isoleucine 13 from L-isoleucine.

By the same series of reactions which Fischer and Schmitz employed in the preparation of leucine, F. Ehrlich synthesised isoleucine in 1908 from malonic ester and secondary butyliodide, /., according to the following scheme —... 

The two epimeric 7-turn mimetics 162 and 163 were synthesized from the respective isomer of leucine 154 and 155 (Scheme 34). The two chiral reagents 156 and 159 were synthesized from (.S )-HOC isoleucine and (/5-lcucinc. respectively <1997TL6961>. 

While enantiomerically pure a-substituted isocyanoacetates have been used in Passerini condensation without significant racemization [4-6], the same class of compounds is believed to be configurationally unstable under the conditions of U-4CRs [7]. However, one notable exception is the reaction shown in Scheme 1.1, where L-isoleucine-derived isocyanide 2 has been condensed without such problems with pyrroline 1 [8]. The bulkiness of this isocyanide or the use of a preformed cyclic imine, thus avoiding the presence of free amine in solution, may be the reasons for the absence of racemization. 

Pyrrolizidine Alkaloids.—The necic acid component of senecionine (8) derives from two molecules of isoleucine, radioactivity from precursor amino-acid being equally incorporated into both halves of the necic acid fragment, as shown in Scheme 2 (c/. Vol. 9, p. 4). It has now been shown that biotransformation of isoleucine into the necic acid involves loss of half of a tritium label from C-4 in each of the two amino-acid fragments.6 Removal of a proton is, therefore, stereospecific, and oxidation at C-4 does not proceed beyond the two-electron level i.e., a higher intermediate oxidation level, corresponding to a ketone, is excluded. Further results indicate that for each molecule of isoleucine it is the 4-pro-S proton [see (14)] which is lost. 

These differences in the control of the product stereochemistry have recently been investigated by molecular modeling techniques [60,154], From these studies, the relevance of the side-chain of isoleucine 476 (PDCS.c.) (Table 2) for the stereo-control during the formation of aromatic a-hydroxy ketones became obvious, since this side-chain may protect one site of the ot-carbanion/enamine 6 (Scheme 3) against the bulky aromatic cosubstrate. Nevertheless, the smaller methyl group of acetaldehyde can bind to both sites of the a-carbanion/en-amine. The preference for one of the two acetoin enantiomers has been interpre-tated in terms of different Boltzmann distributions between the two binding modes of the bound acetaldehyde [155],... 

In contrast, the Hoveyda and Snapper groups reported the efficient catalysis of silver acetate complexes of imine 204.86 These authors first established the superior performance of IV-ort/zo-methoxyaniline-substituted imines in the reaction with Danishefsky diene 195. Because of the modular nature of ligand 206, optimization of its structure could be achieved by surveying a combinatorial library of amino acid derivatives. The /-isoleucine para-methoxyaniline conjugate 206 proved the best. This ligand facilitated full conversion within 2-3 h with high yield and enantioselectivity (Scheme 2.53). 

Scheme 5.15 No Irish type II fragmentation and Yang cyclization of isoleucine derivatives, illustrating the influence of conformational equilibria.

The reaction scheme in Fig. 9-17 depicts isoleucine (E) synthesis from aspartate (A) by the bacterium Rhodopseudomonas spheroides. The control is called sequential feedback control. Describe the operation of this metabolic control system. 

Several V- IJ<>c-A-MOM-a-am ino acid derivatives undergo a-methylation in 78% to nearly 93% ee with retention of the configuration upon treatment with KHMDS followed by methyl iodide at —78°C. The substituents of the nitrogen are essential for control of the stereochemistry. How much is the stereochemical course of the reaction affected by an additional chiral center at C(3) of substrates a-Alkylation of A -lioc-A-MOM-L-isoleucine derivative 61 and its C(2)-epimer, D-a/fo-isoleucine derivative 62, were investigated (Scheme 3.16). If the chirality at C(2) is completely lost with formation of the enolate, a-methylation of either 61 or 62 should give a mixture of 63 and 64 with an identical diastereomeric composition via common enolate intermediate K. On the other hand, if the chirality of C(2) is memorized in enolate intermediates, 61 and 62 should give products with independent diastereomeric compositions via diastereomeric enolate intermediates. 

Linear capsiacinoids with a C9/C12 chain are only trace constituents of capsicum oleoresin, which mainly contains branched capsaicinoids. The acyl moiety of these compounds is produced by the branched chain fatty acids pathway (Scheme 4.1) [30[. Depending on the nature of the amino acid that acts as the acyl starter precursor, different capsaicinoids are formed. Thus, capsaicinoids of the iso series such as CPS and homocapsaicin I are derived from valine and leucine via isobutyrylCoA and isovalerylCoA, respectively, while those from the anteiso series such as homocapsaicin II originate from isoleucine via 2-methylbutyrylCoA (Scheme 4.1) [31[. The polymethylene moiety of norcapsaicin has one less carbon than capsaicin. The... 

However, in the cases examined so far, the molar solubility in DMF has not increased significantly. The 1-adamantyloxycarbonyl (1-Adoc) group could potentially improve the solubility of amino acids and peptides protected by 1-Adoc in organic solvents due to its strong hydrophobicity.P Lys(l-Adoc) was successfully employed in the synthesis of peptide histidine isoleucine (PHI) (Scheme 9)P9 and in the synthesis of a peptide fragment of a lysozyme.P l... 

The synthesis of the flexible Isoleucine-isobutyl compound (9, Scheme 2) was lengthier, mainly as a consequence of the fact that the compound contains a butyl-carboxamide group capable of picking up binding interactions on the ST side of the protein. Synthesis of the key isobutyl-sllyl-methylamine compound 10 was achieved over 8 steps. The amine was then coupled in standard fashion with the P2 portion of the molecule and the prime-side side chain was modified to the desired amide 11. Deprotection of the diphenyl-silane using TFA, as described above, provided the target diol 9. 

This activation was successfully used in the preparation of unusual Y-amino-p-hydroxy esters such as the protected derivative of (354R5S)- Isostatine from D-allo-isoleucine as shown in scheme 212 (Ref. 262). 

The benzyl imine 260 of aldehyde 250 is an excellent building block for the synthesis of enantiomerically pure trifluoromethylated isoleucine 264 and valine 265 (see Scheme 9.56). The In-mediated alkylation of imine 260 with 4,4,4-trifluorocrotyl bromide in DMF proceeds with excellent diastereoselectivity (>95% de), affording 261. In contrast, poor diastereoselectivity (20% de) is obtained in the same In-mediated aldol reaction of aldehyde 250. The transition state structure 263 is proposed to explain the exclusive stereocontrol [84]. 

Highlighting the synthetic utility of this methodology, the group of Du Bois reported a three step synthesis of the amino acid (K) ( > isoleucine starting from the chiral sulfamate ester 11. Oxidative cyclization with retention of stereochemistry and a simple Cbz protection hydrolysis oxidation sequence provided the amino acid (Scheme 12.11) [17]. 

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