Homoproline

Biochemistry and chemistry takes place mostly in solution or in the presence of large quantities of solvent, as in enzymes. As the necessary super-computing becomes available, molecular dynamics must surely be the method of choice for modeling structure and for interpreting biological interactions. Several attempts have been made to test the capability of molecular dynamics to predict the known water structure in crystalline hydrates. In one of these, three amino acid hydrates were used serine monohydrate, arginine dihydrate and homoproline monohydrate. The first two analyses were by neutron diffraction, and in the latter X-ray analysis was chosen because there were four molecules and four waters in the asymmetric unit. The results were partially successful, but the final comments of the authors were "this may imply that methods used currently to extract potential function parameters are insufficient to allow us to handle the molecular-level subtleties that are found in aqueous solutions" (39). 

Figure 7.10 Analogy between acetone enamines from cytisine and D-homoproline.

Dianions of A -monoprotected glutamic acid esters are very useful intermediates for y-monoalkylation leading to y-monosubstituted glutamic acids (such as 52, 53 Scheme 19).[94] Among them, y-allyl-substituted glutamic acid 52 (R1 = CH2CH=CH2) can be derivatized into y-substituted homoproline 56 (Scheme 20). 

Scheme 20 Synthesis of a y-Carboxy-Substituted Homoproline Derivative 94 ...

The chemistry of pipecolic acid (piperidine-2-carboxylic acid, homoproline, 6) and thus the protecting groups and coupling methods closely resemble those of proline, although steric hindrance due to the larger ring size makes its use in standard peptide chemistry more difficult. 

The conjugate addition of tetrahydrothiopyran-4-one to l-nitro-2-(3-nitrophenyl)ethene is promoted by the enantiomers of 5-pyrrolidin-2-yl-17/-tetrazole and gives the adducts in acceptable yields and with ca. 70% ee as determined by chiral HPLC (Equation 27) <20050BC84>. An enantiomeric excess of 90% was achieved using a homoproline tetrazole catalyst (Equation 28) <2005SL611>. 

Monte-Carlo simulations have been made of the known water structure in crystalline serine monohydrate, arginine dihydrate homoproline tetrahydrate [331], deoxycytidylyl-3, 5 -guanosine-proflavine hydrate [358] and the spine of hydration in the minor groove of a 5-type oligodeoxynucleotide duplex [359]. They resulted in partial agreement and demonstrated the sensitivity of the method to the pair potentials used. 

S. Abele, K. Vbgtli, D. Seebach, Oligomers of p - and of P -Homoproline What are the Secondary Structures of P-Peptides Lacking H-Bonds , Helv. Chim. Acta 1999, 82, 1539 -1558. 

The 3-amino acid homoproline can be synthesized via an Amdt-Eistert reaction from (S)-proline. ... 

A facile synthesis of (3R,5R)-dihydroxy-L-homoproline, an idulonic acid mimic, was realized using L-threonine aldolase-catalyzed reaction of glycine with an aldehyde derived from L-malic acid [96]. 

Under analogous reaction conditions, tricyclic isoxazolidines 85c afforded the p-homoprolines 87, probably by ring opening and A-acylation of the primary carbapenam intermediates 86c <04EJ02205>. The chemistry of spirocyclopropane isoxazolidines 85 as versatile precursors of different azaheterocycles has been reviewed <04M649>. 

Plpecolic Acid. 2-Piperidinecarboxylic acid pipe-colinic acid hexahydropicolinic acid homoproline dihydro-baikiaine. CtH,N02 mol wt 129.16. C 55.79%, H 8.58%, N 10.85%, O 24,78%. The /-form occurs in plants Phillips, Chem. A Ind. (London) 1953, 127. Prepn A. Ladenburg, Ber. 24, 640 (1891) Stevens, Ellman, J. Biol. Chem. 182, 75 (1950) V. Asher et ai, Tetrahedron Letters 22, 141 (1981). Synthesis of E-pipecolic acid from l-lysine Fujii, Miyoshi, Bull. Chem. Soc. Japan 48, 1341 (1975). 

These peptides contain a number of unusual aminoacids including 3,4-dimethylglutamine, [5-methoxytyrosine, 3-methoxyalanine, 2,3-diaminobutanoic acid or 2-amino-2-butenoic acid residues. Papuamides are also the first natural marine-derived peptides reported to contain the 3-hydroxyleucine and homoproline residues, as well as an unprecedented acid moiety N-linked to the terminal glycine residue. Papuamide A (56) was cytotoxic against a panel of human cancer cell lines with a mean IC50 value of 75 ng/ml papuamide A (56) and B (57) inhibited the infection of human lymphoblastoid cells by HIV-1 in vitro with an EC50 of 4 ng/ml. 

Homo-DNA, 344-345 Homoenolate synthons, 14-15, 70, 76 L-Homoproline FK 506 synthon, 324, 326—327 Homer olefinatlon 28-30... 

L-PfpecoHc add [(5)-2-piperidinecarboxylic acid, (5)-hexahydropicolinic acid, L-homoproline]. 

Scheme 2.15 Enantioselective Michael addition of aldehydes with functionalized nitroalkenes and an application to the total synthesis of densely functionalized homoprolines and natural product (-)-botryodipIodin.

Ley and coworkers also used tetrazole 5a to catalyse the asymmetric Michael addition of a ketone to an aromatic nitro-olefin in a 1 1 mixture of ethanol and isopropanol. The products obtained had moderate to good diastereoselectivities (up to >19 1 dr) and moderate enantioselectivities (up to 73% ee). Further, a homoproline tetrazole derivative (5b) was prepared and used for asymmetric Michael reaction. Catalysts 5a and 5b gave similar diastereoselectivities however, the catalyst 5b produced products with higher enantioselectivities in the Michael addition of ketones to aromatic nitro-olefins (Scheme 9.34). Ley and coworkers explained that the side chain of the homotetrazole was responsible for the increased enantioselectivity. 

Methylprolines, A27.3, A27.4 Pipecolic acid, A10.7, A"6 Nipecotinic acid, A30.13 2-Aminohex-4-enoic acid, A10.12 Hygrinic acid. All. 14 Homoproline, A"21.6 Coronamic acid, A"35.6... 

Triethylamine and sec-butyl chloroformate added dropwise at -15° to a stirred ethereal soln. of N-benzyloxycarbonyl-L-proline, the resulting triethylamine hydrochloride removed by filtration, ethereal diazomethane added dropwise, stirred 4 hrs. at 0°, and allowed to stand overnight in a refrigerator a-diazoketone (Y 91%) dissolved in methanol, and refluxed 12 hrs. with AggO on a water bath -> methyl N-benzyloxycarbonyl- -L-homoprolinate (Y 95.1%). L. Balaspiri et al., Helv. 58, 969 (1975) / -lysine deriv. cf. T. Wakamiya et al.. Bull. Chem. Soc. Japan 48, 2401 (1975). 

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