Cyclopropyl amino acid

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... 

Vaillancourt, F.H., Yeh, E., Vosburg, D.A. et al. (2005) Cryptic chlorination by a non-haem iron enzyme during cyclopropyl amino acid biosynthesis. Nature, 436, 1191-1194. 

Much was unknown about the halogenation for unreactive substrates until very recently, when the biosynthesis of the cyclopropyl amino acid side-chain of coro-... 

C.H. Stammer, Dehydro and cyclopropyl amino acids and peptides, NIDA Res. Monogr. 69, 148 (1986). 

Vaillancourt FH, Yeh E, Vosburg DA, O Connor SE, Walsh CT (2005) Cryptic Chlorination by a Non-Haem Iron Enzyme During Cyclopropyl Amino Acid Biosynthesis. Nature 436 1191... 

Jain and Vederas utilized the reaction to synthesize protected cyclopropyl amino acids 136-140 (Scheme 2.33) [64]. The decarboxylation of the corresponding cyclopropyl precursors 131-135 gave the products in 52-58% yield. These authors also explored the diastereoselectivities of the reaction in their synthesis of two compounds... 

Cryptic chlorination by a non-haem iron enzyme during cyclopropyl amino acid biosynthesis. Nature 2005 436 1191-1194. 

For the synthesis of cyclopropyl amino acids, Williams has used an oxazinone auxiliary (cf. Scheme 3.12) as an electrophilic component in a sulfur ylide cyclopropanation using Johnson s sulfoximines, as illustrated in Scheme 6.41 [148]. Surprisingly, the sulfur ylide approaches from the P face the authors speculate that there may be some sort of 7t-stacking between the phenyls on the oxazinone ring and the phenyl in the sulfoximine to account for this [149]. With Corey s [147] dimethylsulfonium methylide, the diastereoselectivity was only about 75%, but with Johnson s sulfoximines (used in racemic form), only one diastereomer could be detected for most substrates studied (with the exception of R = H, [149]). Dissolving metal reduction afforded moderate yields of the cyclopropyl amino acids. 

Scheme 6.41. Williams asymmetric synthesis of cyclopropyl amino acids [149].

Aminocyclopropane-1-carboxylic acids. These cyclopropyl amino acids can be obtained in high chemical and optical yield by reaction of this ylide with the a, /3-dehydro lactones (3) prepared from (5S,6R)-4-/-butoxycarbonyl-5,6-diphenyl-2,3,5,6-tctrahydro-4W-l,4-oxazin-2-one (2, 14,58-59). The reaction of 3 with the ylide derived from... 

Good ees are also obtained using cycKc and acyclic vinyl diazoacetates, such as (9.31), and the product (9.32) is converted into the cyclopropyl amino acid (9.33). The same product (9.32) has also been converted into the antidepressant Sertraline by Corey and Gant. 

Dioxines (157) reacted with the 5oc-protected phosphonoglycine (158) via a multistep cascade reaction to give p-cyclopropyl amino acid... 

Wakamiya, T., Oda, Y., Fujita, H., and Shiba, T. (1986) Synthesis and stereochemistry of camosadine, a new cyclopropyl amino acid from red alga Grateloupia camosa. Tetrahedron Lett., 27, 2143-2144. 

It is worth mentioning here that the spirocyclopropyl-substituted oxazoline-5-car-boxylates 2-172, as well as the corresponding thiazoline-4-carboxylates, can be transformed into cyclopropyl-substituted amino acids, which might act as potential enzyme inhibitors [93] and interesting building blocks for peptidomimetics [94]. 

During the biosynthesis of nonribosomal peptides, there are two ways to incorporate the nonprotein amino acids. They can be incorporated either as a single unit or as an L-a-amino acid, which then undergoes structural modifications, while attached to the carrier protein. In the case of coronamic acid, L-rr//o-isoleucine is loaded onto the carrier protein and a unique biosynthetic pathway produces a cyclopropyl group containing a nonprotein amino acid. Specific examples of the biosynthesis of nonprotein amino acids will be discussed in the following sections. 

This section focuses on the nonprotein amino acids containing alkyl or haloalkyl groups as side chains. There are number of examples containing linear and branched alkyl chains, such as ethyl, propyl, and t-butyl. Some amino acids contain the cyclopropyl group as side chains (coronamic acid derivatives and BZR-cotoxin 11). Furthermore, dysamides, a class of diketopiperazines, contain nonprotein amino acids with chlorinated alkyl side chains. ... 

In fact, the cyclopropyl group of 26 is strongly electrophilic and reacts readily with amino acids, nucleosides and nucleotides under mild conditions [25 d]. Thus dienone 26 forms covalent adducts with DNA and causes DNA strand breaks DNA is the principal biological target of ptaquiloside 25 [26]. 

Fig. 10. Different types of cyclopropyl-group containing amino acids prepared from chloro-cyclopropylideneacetates 1,2...

Besides the large number of a-amino acids found in nature, )3-amino acids are gaining an ever increasing attention [100]. Amino acids are e.g. found in the side chain of the cancerostatic taxol [101] as well as the new antibiotics sperabillin and TAN 1057 A/B [102]. The simple deprotection of 2 -substituted cyclopropylacetic acid derivatives 196-R by hydrogenolysis (and hydrolysis for the methyl esters 196b,i,j,m-Me) yielded enantiomerically pure 2-(r-amino-cyclopropyl)acetic acids (Scheme 59) [10]. 

On the other hand, the reaction of 119 with carbon disulfide followed by iodomethane gave dithioester 122 in high yield (equation 32). Methanolysis of the dithioester 122 in methanol with excess Hg(OCOCF3)2 gave the cyclopropyl a-amino acid derivative 123 in high yield. 

Hydride reduction of imine chelates such as (92) offers a synthetic route to a-amino acids, as demonstrated for cyclopropyl glycine and proline (Scheme 44).214... 

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