Alkenes amino acid synthesis from

The key synthetic steps in the formation of the desired unnatural amino acids, 5-8, involved the preparation of appropriately substituted cyclobutanones followed by a Btlcherer-Strecker amino acid synthesis.12 The syntheses of the boron-containing amino acids were initiated utlizing alkenes 16 -19. Alkene 17 was prepared by a SN2 displacement of bromide from 4-bromobenzyl bromide (Scheme 3). In the syntheses of alkenes 18 and 19, a catalytic... 

Another amino acid synthesis is called the azlactone synthesis. Remember from before that an azlactone is an oxazolone (see 95). When glycine (52) is converted to its AT-benzoyl derivative (112 known as hippuric acid) by reaction with benzoyl chloride, treatment with acetic anhydride (AC2O) gives the azlactone 113. This is the reaction presented in the preceding section (see compormd 95). Compound 110 has the common name of hippuric acid azlactone. As with the thiohydantoin, the -CH2- unit in 113 is susceptible to an enolate anion condensation reaction with aldehydes (Chapter 22, Section 22.7.2), and reaction with 2-methylpropanal in the presence of pyridine gives azlactone 114. Catalytic hydrogenation of the alkene unit (Chapter 19, Section 19.3.2) and acid hydrolysis lead to the amino acid leucine (55). 

Finally, although not shown in the table, the material that is shown there can be combined with other reactions. The Slrecker amino acid synthesis, which is discussed again in Chapter 12, is among the most valuable, while the Shapiro Olefination and the related Bamford-Sfevens reaction have proved useful in producing alkenes from aldehydes and ketones. 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

In 1995, and regrettably missed in last year s review, Klotgen and Wiirthwein described the formation of the 4,5-dihydroazepine derivatives 2 by lithium induced cyclisation of the triene 1, followed by acylation <95TL7065>. This work has now been extended to the preparation of a number of l-acyl-2,3-dihydroazepines 4 from 3 <96T14801>. The formation of the intermediate anion and its subsequent cyclisation was followed by NMR spectroscopy and the stereochemistry of the final product elucidated by x-ray spectroscopy. The synthesis of optically active 2//-azepines 6 from amino acids has been described <96T10883>. The key step is the cyclisation of the amino acid derived alkene 5 with TFA. These azepines isomerise to the thermodynamically more stable 3//-azepines 7 in solution. 

Optically active aldehydes are available in abundance from amino and hydroxy acids or from carbohydrates, thereby providing a great variety of optically active nitrile oxides via the corresponding oximes. Unfortunately, sufficient 1,4- or 1,3-asymmetric induction in cycloaddition to 1-alkenes or 1,2-disubstituted alkenes has still not been achieved. This represents an interesting problem that will surely be tackled in the years to come. On the other hand, cycloadditions with achiral olefins lead to 1 1 mixtures of diastereoisomers, that on separation furnish pure enantiomers with two or more stereocenters. This process is, of course, related to the separation of racemic mixtures, also leading to both enantiomers with 50% maximum yield for each. There has been a number of applications of this principle in synthesis. Chiral nitrile oxides are stereochemicaUy neutral, and consequently 1,2-induction from achiral alkenes can fully be exploited (see Table 6.10). 

In a parallel study, Wipf and Fritch11041 have shown that also urethane-protected (Boc), and even amino acid segments, are tolerated as acyl compounds on the aziridine nitrogen. The best results were obtained with alkylcopper reagents derived from CuCN and an alkyl-lithium in the presence of boron trifluoride-diethyl ether complex. Some 6-alkylated compounds (11-15%) were isolated as well. This work was extended to a solid-phase procedure that resulted in resin-bound alkene isosteres that could immediately be used in further peptide synthesis.11051 For this purpose, the 2-nitrophenylsulfonyl (oNbs) group was used for nitrogen protection and aziridine activation. It could be readily cleaved with benzenethio-late, which was compatible with the acid-sensitive Wang linker used. 

Dondoni et al. prepared a 1-hydroxyethylene peptide using a thiazole-aldehyde synthesis starting from an amino acid.[38] The aldehyde is converted into an alkanoate by Wittig alkenation and reduction of the double bond (Scheme 18). Then, removal of the tert-bu-tyldimethylsilyl group gives the unsubstituted lactone. In the last step, the lactone is alkylated using the method reported by Kleinman and co-workers. 20 ... 

The method of Kim et al.[89-93] starts from the synthesis of the three-carbon phosphonium salt according to the modified method of Corey et alJ94,95] The Wittig reaction of the phosphonium salt with a Z-protected a-amino aldehyde using potassium hexamethyldisilazanide provides the ds-alkene without racemization. Efficient hydrolysis of the orthoester without double bond migration is achieved by acidolytic hydrolysis with aqueous hydrochloric acid in tert-butyl alcohol under reflux conditions. Then, an a-amino acid methyl ester is coupled. The desired epoxide product is obtained by treatment with 3-chloroperoxybenzoic acid. The epoxidation reaction is stereoselective and predominantly provides one isomer (R,S S,R = 4-10 1). The trans-epoxide can also be prepared using a trans-alkene-containing peptide. A representative synthetic procedure to obtain the ds-epoxide isostere is detailed below. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

A second application of the use of Lewis acid catalysis in the Julia coupling can be found in the synthesis of trans-Biiktnt isosteres of dipeptides (478 Scheme 62). Initially, attempts to couple aldehydes derived from amino acids (473) resulted in poor overall yield of the alkene. This difficulty was solved by reversing the substituents, and introducing the amino acid portion as the anion of sulfone (476) to the chiral aldehyde (477). The dianion of the sulfone was formed and to it were added 2 equiv. of aldehyde and 1 equiv. of diisobutylaluminum methoxide. The resulting p-hydroxy sulfone was t en on to the reductive elimination step to produce the desired ( )-alkene (478), in 74% overall yield. 

Topics of relevance to the content of this chapter which have been reviewed during the year include photoactive [2]rotaxanes and [2]catenanes, photochemical synthesis of macrocycles, phototransformations of phthalimido amino acids, photoaddition reactions of amines with aryl alkenes and arenes, photoreactions between arenenitriles and benzylic donors, photostability of drugs, polycyclic heterocycles from aryl- and heteroaryl-2-propenoic acids, photoreactions of pyrroles, photoamination reactions in heterocyclic synthesis, switching of chirality by light, photochromic diarylethenes for molecular photoionics and solid state bimolecular photoreactions. 

Enantioselection can be controlled much more effectively with the appropriate chiral copper, rhodium, and cobalt catalyst.The first major breakthrough in this area was achieved by copper complexes with chiral salicylaldimine ligands that were obtained from salicylaldehyde and amino alcohols derived from a-amino acids (Aratani catalysts ). With bulky diazo esters, both the diastereoselectivity (transicis ratio) and the enantioselectivity can be increased. These facts have been used, inter alia, for the diastereo- and enantioselective synthesis of chrysan-themic and permethrinic acids which are components of pyrethroid insecticides (Table 10). 0-Trimethylsilyl enols can also be cyclopropanated enantioselectively with alkyl diazoacetates in the presence of Aratani catalysts. In detailed studies,the influence of various parameters, such as metal ligands in the catalyst, catalyst concentration, solvent, and alkene structure, on the enantioselectivity has been recorded. Enantiomeric excesses of up to 88% were obtained with catalyst 7 (R = Bz = 2-MeOCgH4). 

This approach has been applied to the synthesis of peptide isosteres, compounds that have the same shape as peptides but lack the amide link. In this case 99 it is replaced by an E-alkene. The starting material 97 is made from the natural amino acid leucine and the Wittig-Still [2,3] shift on 98 rearranges this into an E-alkene flanked by two chiral centres 99. 

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