Unnatural enantiomer

Aziridine lactone 235 (Scheme 3.87) underwent ring-opening with allyl alcohol to give a 53% yield of a-amino lactone 236, which was successfully transformed to the unnatural enantiomer of polyoxamic acid (—)-237 [32],... 

Deslongchamps and coworkers [26] used a combination of a transannular Diels-Alder cycloaddition and an intramolecular aldol reaction in the synthesis of the unnatural enantiomer of a derivative of the (+)-aphidicolin (4-74), which is a diterpe-noic tetraol isolated from the fungus Cephalosporium aphidicolia. This compound is an inhibitor of DNA polymerase, and is also known to act against the herpes simplex type I virus. In addition, it slows down eukaryotic cell proliferation, which makes it an interesting target as an anticancer agent... 

In one final improvement to the synthesis of the racemate, after it had been shown that even the unnatural enantiomer of the pheromone attracted bugs, the Z-isomer of diene ester 139 was used in the ester-enolate Claisen rearrangement, resulting in a slightly higher yield, and avoiding the use of HMPA as a solvent in that step [113]. 

Natural (-)-cocaine (7.57, Fig. 7.8), which has the (2/ ,3S)-configuration, is a relatively poor substrate for hepatic carboxylesterases and plasma cholinesterase (EC 3.1.1.8), and also a potent competitive inhibitor of the latter enzyme [116][121], In contrast, the unnatural enantiomer, (+)-(2S,3/ )-cocaine, is a good substrate for carboxylesterases and cholinesterase. Because hydrolysis is a route of detoxification for cocaine and its stereoisomers, such metabolic differences have a major import on their monooxygenase-catalyzed toxification, a reaction of particular effectiveness for (-)-cocaine. 

Lamivudine (also known as Epivir and 3TC) is a potent antiviral drug used in the treatment of HIV and hepatitis B virus (HBV) infections. Although both enantiomers are equipotent antiviral agents, the unnatural enantiomer (with respect to natural nucleosides) is far less cytotoxic, and so a method of selectively accessing the single enantiomer was required. 

Lycorine is the most abundant alkaloid in plants of the Amaryllidaceae. Several syntheses of racemic lycorine had been reported prior to our initiation of studies directed at an asymmetric synthesis of the unnatural enantiomer 64. 2 a common theme in all of the syntheses of ( )-lycorine has been the utilization of either an intermolecular or intramolecular Diels-Alder construction of the key C-ring of the alkaloid. This six-membered ring presents a rather formidable synthetic challenge because of the four contiguous stereogenic centers, the trans 1,2-diol moiety, and the juxtaposition of the aromatic substituent and the carbon-carbon double bond. 

An enantioselective synthesis of the natural venom pumiliotoxin C 98 and its unnatural enantiomer was achieved from (/ )-norvaline in a multistep... 

In a study which was conducted simultaneously to the work in the Mehta group and which also aimed to prove the absolute configuration of natural kelsoene (1), Schulz et al. used a stereoselective approach starting from the enantiomerically pure chiral pool material (i )-pulegone 17 [9, 10] (see above). The final steps of their synthesis of the unnatural enantiomer of kelsoene (ent-l) were similar to the above-described first total synthesis of natural kelsoene (1) (Scheme 8). Taking into account the steric limitations of the system as communicated by Srinivas and Mehta, diquinane enone ent-6... 

Another impressive example is the synthesis of ( + )-anisomycin, the unnatural enantiomer, in 88-90% ee and 22% overall yield, the key step being an asymmetric alkylation of 2,5-dihydro-1//-pyrrole44. ... 

Remarkably, there is very little difference between the natural and unnatural enantiomer of epibatidine with respect to their antinociceptive potency in various animal models (Sullivan et al., 1994 Bai et al., 1997). 

Baxendale, I.R., Ley, S.V. and Piutti, C., Total Synthesis of the Amaryllidaceae Alkaloid (+)-plicamine and its unnatural enantiomer by using solid-supported reagents and scavengers in a multistep sequence of reactions, Angew. Chem., Int. Ed. Engl., 2002, 41, 2194. 

The noteworthy advantages of this method are that the pure acid can be prepared, on a hundred gram scale, and that even the unnatural enantiomer, (S)-acid, can be obtained simply by use of (S,S)-tartaric acid for the modification of the Raney-Ni catalyst (7). 

The unnatural enantiomers (—)-hyacinthacine A2 (natural enantiomer is (+)-hyacinthacine A2), 7-deoxy-2-ep -alexine (enantiomer of 3-ep -hyacinthacine A2), enf-7-deoxyalexine (enantiomer of 7-deoxy-alexine) and 2-epi-hyacinthacine A2 were synthesised [150]. Interestingly, (—)-hyacinthacine A2 exhibited an a-D-glucosidase inhibitory effect which was not observed for the naturally occurring (+) enantiomer. This fact clearly indicates the urgent need for additional syntheses of non-natural enantiomers in the natural products field. 

In Scheme 1.2 one possible retrosynthetic analysis of the unnatural enantiomer of shikimic acid, a major biosynthetic precursor of aromatic a-amino acids, is sketched. Because cis dihydroxylations can be performed with high diastereoselectiv-ity and yield, this step might be placed at the end of a synthesis, what leads to a cyclohexadienoic acid derivative as an intermediate. Chemoselective dihydroxylation of this compound should be possible, because the double bond to be oxidized is less strongly deactivated than the double bond directly bound to the (electron-withdrawing) carboxyl group. 

In several growth inhibition assays the unnatural ( -enantiomer was as active as (+)-ABA. However, (-)-ABA was much less active than (+)-ABA in closing stomata of detached barley leaves (see 3). When assayed in darkness (to avoid photoisomerization) t-ABA was completely inactive (2). 

Inoue, M., Lee, N., Kasuya, S., Sato, T., Hirama, M., Moriyama, M., and Fukuyama, Y. (2007) Total synthesis and bioactivity of an unnatural enantiomer of merrilactone a development of an enantioselective desymmetrization strategy. Journal of Organic Chemistry, 72, 3065-3075. 

Riley et aK (157) identified S-(+)-4-methyl-3-heptanone as the alarm pheromone of Atta texana and reported that it was 100X more active as an alarm releaser than the unnatural (-)-enantiomer. Similarly, Benthuysen and Blum (158) demonstrated that workers of Pogonomyrmexbadius were more sensitive to the S(+) enantiomer than to the R-(-) enantiomer of this compound, which is the primary alarm pheromone of this species. 

Naturally occurring amino acids can be obtained by hydrolyzing proteins and separating the amino acid mixture. Even so, it is often less expensive to synthesize the pure amino acid. In some cases, an unusual amino acid or an unnatural enantiomer is needed, and it must be synthesized. In this chapter, we consider four methods for making amino acids. All these methods are extensions of reactions we have already studied. 

Figure 2.3 Dextromethorphan 6, the unnatural enantiomer of a narcotic morphine analog, is an antitussive drug. The antidiarrhea drug loperamide 7 and the neuroleptic drug haloperidol 8 also resulted from structural modification of morphine. The morphine antagonist nalorphine 9 differs from the opioid agonist morphine 3 (Figure 2.2) only by having an N-allyl group instead of the N-methyl group.

This chemistry was applied in a synthesis of (-)-goniofufuron (35), the unnatural enantiomer of a cytotoxic compound isolated from the bark of... 

Xia and Kozikowski developed a palladium-catalyzed bicycloannulation route (Scheme 4-4) to racemic HA from 2a in 40% overall yield. The three-carbon bridge was more efficiently introduced by Pd-catalyzed alkylation of 2a with 2-methylenepropane-l,3-diyl diacetate on both sides of the ketone carbonyl. Compared with (—)-HA (IC50 for AChE inhibition 0.047 pM), the racemate exhibited an IC50 of 0.073 pM, which is, within error, as expected if the unnatural enantiomer is inactive. 

Enzymes from Gluconobacter roseus organisms proved somewhat less venatile, but did allow a simple enantioselective synthesis, of the unnatural enantiomer of mevalonolactone (35 Scheme 13) in reasonable optical purity. ... 

During a second-generation synthesis this problem was solved by application of a different reaction sequence. Even the introduction of additional hydroxyl functionalities could be accomplished, thus guiding the development from a naturally occurring terpene to the unnatural enantiomer of taxusin (104). This first synthesis of (-)-taxusin is presented in Scheme 32. 

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