Cyclopropanes amino acids

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

Keywords Diels-Alder reactions of chiral polyfunctional carbocyclic nucleosides and cyclopropane amino acids... 

Treatment of isoxazoline-fiised [60]fullerene 48 with NaOMe in the presence of MeOH gave the p-hydroxy nitrile derivative 49 in good yield <00SL361>. The synthesis of the enantiomerically pure cyclopropane amino acid 51 covalently attached to a fulleroisoxazoline has been achieved . 

Jimenez, J.M., Rife, J., and Ortuno, R.M. (1996) Enantioselective total syntheses of cyclopropane amino acids natural... 

The biosynthetic pathway of coronatine has been extensively studied. The coronafacic acid moiety is proposed to be constructed by bacterial modular type-I PKS via 5-oxocyclopentene carboxylic acid. A recent study clarified the detailed mechanism of the formation of highly unusual cyclopropane amino acid via D-3-chloroalloisoleucine (enzyme-bound form).307... 

In the series of cyclopropane amino acids, compounds 651,652 and 653 have also been studied. The cyclopropyl analogs 651 and 652 showed distinctly lower activity than the corresponding amino acids histidine and thyroxine Compounds 653 were tested for their behavior towards several hydroxylase, aminotransferase and decarboxylase enzyme systems The cis isomer had no inhibitory effect . 

Cyclopropane amino acids are extremely interesting compounds, which have been found in nature. They present tremendous interest because of their biological activity and potential use in conformationally restricted peptides (peptide mimics)... 

Fowden, L., A. Smith, D. S. Millington, and R. C. Sheppard Cyclopropane amino acids from Aesculus and Blighia. Phytochemistry 8, 437 (1969). 

Fig. 208. Formation of cyclopropane amino acids from threonine 1 Threonine dehydratase...

Burgess and co-workers have illustrated the use of reagent 1 in the total syntheses of all four stereoisomers of carnosadine, a cyclopropane amino acid based natural product isolated from red marine alga (eqs 4 and 5). These synthetic efforts ultimately led to preparations of a series of novel 2,3-methanologs of... 

Protected 2-substltuted cyclopropane amino acids could be prepared from the adducts formed from the reaction of a chiral 4-methyleneoxazolldlnone and EDSA (eq 9). ... 

Strecker amino acid synthesis starting with the cyclopropanone hemiacetal provides a enantioselective route to a cyclopropane amino acid (eq 16). ... 

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]. 

Amino-5-chlorobenzophenone Cyclopropane carboxylic acid chloride Phthalimidoacetyl chloride... 

Preparation of 2-Cyclopropylcarbony/amido-5-Chlorobenzophenone To 400.5 g (1.73 mols) of 2-amino-5-chlorobenzophenone dissolved in 220 g (2.18 mols) of triethylamine and 3.5 liters of tetrahydrofuran is added cautiously 181 g (1.73 mols) of cyclopropane-carboxylic acid chloride. The reaction is refluxed 2 /2 hours and allowed to cool to room temperature. The solvent is then removed under vacuum to obtain 2-cyclopropylcarbonyl-amido-5-chlorobenzophenone as a residue which is dissolved in 1 liter of methylene chloride, washed twice with 5% hydrochloric acid, and then twice with 10% potassium hydroxide. The methylene chloride solution is then dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. The residue is recrystallized from 1,500 ml of methanol, charcoal-treating the hot solution to give 356 g of 2-cyclopropylcarbonylamido-5-chlorobenzophenone, MP 105° to 105.5°C (69% yield). 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

Scheme 24 Titanium-mediated intramolecular reductive cyclopropanation of N-aUyl-a-amino acid dimethylamides...

In recent years, the variety of useful diazo substrates for asymmetric intramolecular cyclopropanation processes has really expanded. As another example, Charette and Wurz have reported the first example of an intramolecular cyclopropanation involving a-nitro-a-diazo carbonyl compounds.This reaction, catalysed by Rh2[(S)-DOSP]4, led to the formation of nine-membered nitrocyclopropyl lactones in good yields and enantioselectivities with extremely high diastereoselectivities (Scheme 6.17). This novel methodology constituted an efficient entry into chiral functionalised macrocyclic-fused cyclopropane oc-amino acids. 

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... 

Much was unknown for the halogenation for unreactive substrates until very recently, when the biosynthesis of the cyclopropyl amino acid side chain of coronatine was elucidated. This intriguing pathway, which involves /-chlorination of an enzyme-bound L-isoleucine followed by chloride displacement by the a-carbon, yields the cyclopropanated precursor... 

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). 

The ring-opening of the cyclopropane nitrosourea 233 with silver trifiate followed by stereospecific [4 + 2] cycloaddition yields 234 [129]. (Scheme 93) Oxovanadium(V) compounds, VO(OR)X2, are revealed to be Lewis acids with one-electron oxidation capability. These properties permit versatile oxidative transformations of carbonyl and organosilicon compounds as exemplified by ring-opening oxygenation of cyclic ketones [130], dehydrogenative aroma-tization of 2-eyclohexen-l-ones [131], allylic oxidation of oc,/ -unsaturated carbonyl compounds [132], decarboxylative oxidation of a-amino acids [133], oxidative desilylation of silyl enol ethers [134], allylic silanes, and benzylic silanes [135]. 

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],... 

---