Amino acids, cyclopropane-containing

Recently, Charette et al. have also demonstrated this behavior in the stereoselective cyciopropanations of a number of enantiopure acyclic allylic ethers [47]. The high degree of acyclic stereocontrol in the Simmons-Smith cyclopropanation has been extended to synthesis several times, most notably in the synthesis of small biomolecules. Schollkopf et al. utilized this method in their syntheses of cyclopropane-containing amino acids [48 a, b]. The synthesis of a cyclopropane-containing nucleoside was also preformed using acyclic stereocontrol [48c]. 

This version of the Curtius rearrangement has been applied to the synthesis of amino acid analogs and structures containing amino acids. Several m-2-aminocyclopropane carboxylate esters were prepared by selective hydrolysis of cyclopropane-1,2-dicarboxylates, followed by reaction with DPPA.267... 

A similar, although less marked difference characterizes the cyclopropanation of olefins 41 and 42. In the presence of either copper or copper complexes whose chelating ligands contain an azomethine moiety derived from an a-amino acid, no stereoselectivity was observed with diene 41, whereas the cyclopropanes derived from 42 occur with cisjtrans ratios of 57 43 to 69 31, depending on the catalyst93). 

Applying only a few simple operations, the dibenzylaminocyclopropanes 133-R, prepared as described above from N,N-dibenzyl-a-benzyloxyacetamide in 33—48% yield (see Scheme 11.16 and Table 11.9), have been transformed into N-Boc-protected methyl esters of amino acids 138-R containing a cyclopropane moiety (Scheme 11.35) [109,110], Several such analogues of natural amino acids, also referred to as methanoamino acids, exhibit important biological activities [128],... 

As a potential approach towards enantiomerically pure amino acids containing a cyclopropane ring, Michael additions of enantiomerically pure chiral ammonia equivalents 95-100 have been examined (Fig. 5). 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

The products of cyclopropanation have been further elaborated to cyclopropane-containing amino acids (42) and Boc-protected amino esters (43) (see Scheme 10.23) [79]. A single recrystallization either before or after deprotection afforded enantiomerically pure material. As the acrylate precursors are made in one step, this sequence provides an efficient route to this important class of conformation-ally locked amino acids. 

Intermolecular cyclopropanation reactions with ethyl diazoacetate have been employed for the construction of the cyclopropane-containing amino acid 7 (equation 25) Thus, rhodium(II) acetate catalysed decomposition of ethyl diazoacetate in the presence of d-cbz-vinylglycine methyl ester 5 afforded cyclopropyl ester 6 in 85% yield. Removal of the protecting group completed the synthesis of 7. Another example illustrating intermolecular cyclopropanation can be found in Piers and Moss synthesis of ( )-quadrone 8" (equation 26). Intermolecular cyclopropanation of enamide or vinyl ether functions using ethyl diazoacetate has also been used in the synthesis of eburnamonine 9", pentalenolactone E ester 10" and ( )-dicranenone A11" (equations 27-29). 

Various amino acids containing a cyclopropyl residue have been found in members of the Sapindaceae, Hippocastanaceae and Aceraceae. The same plants often contain a range of Q- and Cz-amino acids, with a non-cyclic branched carbon skeleton. The position of branching suggests possible bio-genetic relationships to cyclopropane-containing amino acids. Variation of the basic structures mentioned in Fig. 3.22 is achieved by different chain lengths and by the introduction of double and triple bonds (Fowden, 1981). 

In contrast to the restricted occurrence of the secondary metabolites mentioned previously, all plants contain 1-amino-cyclopropane-l-carboxylic acid. This amino acid is the precursor of ethylene. In the course of the bios)mthesis of this gaseous phytohormone, 1-aminocyclopropane-l-carboxylic acid is oxidized and decomposed to yield ethylene, HCN, CO2 and water (John, 1997). 

Most of the compounds cited in this introductory section are produced in metabolic processes where the cyclopropane-containing metabolite appears to be the stable end product or secondary product with as yet unobvious metabolic function. However, this is not the case in at least two types of systems, in which cyclopropyl species are key and necessary intermediate structures in high flux metabolic pathways. The first example is the squalene (76) and phytoene (88) biosynthesis where presqualene pyrophosphate (77) and prephytoene pyrophosphate (89) are obligate cyclopropanoid intermediates in the net head-to-head condensations of two farnesyl pyrophosphate (73) or two geranylgeranyl pyrophosphate (66) molecules respectively. The second example is in plant hormone metabolism where C(3) and C(4) of the amino acid methionine are excised as the simple hormone ethylene via intermediacy of 1-aminocyclopropane-l-carboxylic acid (9). Both examples will be discussed in detail in the Section II. 

This addition sequence can be used to prepare non-natural a- and /3-amino acids 11, 13 and 14 containing cyclopropane groups. It is also possible to prepare organic compounds... 

Neoefrapeptins, neoefrapeptin A Ac-Pip-Aib- Pip- Iva-Aib- Leu-/3 -Ala-Gly-Acc-Aib-Pip-Gly-Leu-Iva-aX, a group of peptides with insecticidal activity isolated from the fungus Geotrichum candidum. AU 12 neoefrapeptins (A-I, L-N) contain the very rare amino acid 1-amino-cyclopropane-carboxylic acid (Acc), and some of them (F, I, L, M) also contain (2S,3S)-3-methyl-proline instead of pipecolic acid (Pip) in position 11. Further unusual building blocks are isovaline (Iva) and the C-terminal amide moiety X = 2,3,4,6,7,8-hexahydro-l-pyrrolo [ 1,2-a]pyrimidine. Neoefrapeptins show a close sequence similarity to the efrapeptins [A. Fredenhagen et al., J. Antibiot. 2006, 59, 2006]. 

Cyclopropanes containing alpha amino acids are important intermediates in medicinal chemistry. The racemic syn ethyl-substituted cyclopropane amino ester was prepared via Curtius rearrangement to generate the Teoc derivative followed by fluoride-induced deprotection (eq 31). ... 

In the presence of diazo compounds 9, enynes 10 containing a fluorinated amino acid moiety could be transformed into fluorinated alkenyl bicyclo[4.1.0]heptane amino acid derivatives 11 using Cp (Cl)Ru(COD) as the precatalyst (Scheme 5.5) [12], In this process, the in situ-generated catalyst from ruthenium complex and diazo compound completely inhibits RCM of enyne to the profit of cascade alkenyl-ation/cyclopropanation. The Cp (Cl)Ru moiety in ruthenacyclobutane is believed to favor reductive elimination versus expected alkene metathesis. 

Because 1 mole of cyanide is produced for each mole of ethylene generated from ACC (1-amino-cyclopropane-1-carboxylic acid) see Chapter 13), all plants must contain small amounts of cyanide (Peiser et al., 1984). However, due to a concomitant increase in the amount of (3-cyanoalanine synthase, the ability to detoxify cyanide in the tissues is much higher (Manning, 1988). 

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