Vinylogous carbamate

Treatment of methyl bromozincacetate with VV-(Boc)pyrrolidine-2-thione affords good yield of vinylogous carbamate (Scheme 35).74... 

The reduced electrophUicity of indole-3-carboxylic esters (they are vinylogous carbamates) means that they are much more versatile directors of lateral lithiation than the comparable benzoates, as illustrated by the synthesis of 564 (Scheme 221... 

When a,/3-unsaturated esters are the target molecules, the use of a thioaldehyde or thioketone is advisable for the easy elimination of H2S from the intermediate thiol adduct. This strategy has been applied to thiolactams 94a and to thionolactones 94b, opening a route to vinylogous carbamates 95a143 and carbonates 95b144(equation 57). 

An alternative method for cleaving carbamates is exhaustive reduction with LiAlFLt to yield methylamines (Entry 3, Table 3.22). Entry 9 in Table 3.22 is an example of the nucleophilic cleavage of a carbamate with sodium methoxide. The mild reaction conditions required in the case are attributable to the structure of the amine (a vinylogous amide) these conditions are unlikely to lead to the cleavage of simple A-alkyl- or A, A-dialkylcarbamates, although A-arylcarbamates are also susceptible to nucleophilic cleavage (Entry 6, Table 3.26). 

Reduction of vinylogous carbamate 36 with sodium cyanoborohydride in acidic methanol gave exclusively the equatorial aminoester 38. Eschenmoser and co-workers (181 have explained this result by invoking a stereoelectroni-cally controlled anti peri planar addition of hydride ion on the iminium ion 37. 

A different sequential DreM pathway involving O-carbamate ring switch-vinylogous tolyl amide cydization, 170 —> 171 —> 172 (Scheme 44), a formal bridging of a 2,2 -methyl diaryl dicarbanion with a carbonyl dication equivalent (173) has been affirmed in a model study (174 —> 175, Scheme 45) [73] and applied in natural product total synthesis [73, 74]. 

The same is true when an electron-withdrawing group is present in beta to the amino group and great numbers of vinylogous amides, carbamates and ureas have been transformed to their ethynylogs 29 for which the term push-pull acetylenes is used (49) 90,91 A Their chemistry has been thoroughly studied and they represent the best known class of ynamines. 

Several of the older and more common herbicides have been shown to interfere with one or more steps of photosynthesis. A number of these are powerful inhibitors at or near photosystem II (PS II) ( 1). Beginning in 1981, J. N. Phillips and J. L. Huppatz and their group at CSIRO (Australia) have shown that a series of cyanoacrylate (vinylogous carbamate) herbicides are potent inhibitors of PS II (2-6). 

As work progressed, we desired an acid intermediate that would allow us a broader spectrum of structural variants on the amide nitrogen. We found that the desired vinylogous carbamic acid could be prepared directly from cyanoacetic acid (Figure 5). When R equals (substituted)benzyl, an approximate 1 1 ratio of desired products and decarboxylated products was obtained. When R equals (substituted)phenyl, only the desired carboxylic acid intermediates were obtained. The impure vinylogous carbamic acids could easily be purified by base extraction. These acids were converted to vinylogous ureas via their stable acid chlorides. 

Figure 5. Preparation of Vinylogous Ureas Via Vinylogous Carbamic Acid...

Since the ureas, carbamates and vinylogous carbamates are all PS II inhibitors (Figure 1), it is not surprising that these compounds are also powerful PS II inhibitors. The more active compounds (Table I) were considerably more active than atrazine (Table II) in the Hill reaction assay. The Hill reaction assay frequently does not correlate with whole plant (greenhouse) activity ( 1 and 2 and references cited therein). However, vinylogous ureas do correlate fairly well (Table III). Other assays including the carotinoid biosynthesis and acetolactate synthesis (ALS) assays showed little or no activity for these compounds. 

The Knoevenagel condensation is the method of choice for the preparation of a,p-unsaturated dicarbonyl compounds and related compounds and only a few alternative methods have been developed. However, with the traditional Knoevenagel condensation there are problems with the reactivity of ketones, with the competitive Michael addition occuring in the reaction of some active methylene compounds. There is also a problem with steieocontrol in the synthesis of Knoevenagel products from unsymmetrical 1,3-dicarbonyl compounds. An alternative method is the addition of Grignard reagents to vinylogous carbamates (see Section 11.2.6). Another possibility is the reaction of a metal ketimate with malonodini-trile to yield ylidenemalonodinitriles (see Section 11.3.1.7). ... 

A third application of the Eschenmoser reaction in the synthesis of racemic perhydrogephyrotoxin (76) is based on an extension of the chemistry developed during the pumiliotoxin C synthesis. - Beginning with the bicyclic thiolactam (73), the sulfide-contraction reaction was used to append to the decahydro-isoquinoline a functionalized five-carbon side chain that would later be cyclized and become the a-hy-droxyethylpyrrolidine portion of the molecule. Alkylation of the thiolactam (73) with methyl 5-bromolevulinate followed by treatment with the Eschenmoser dual base-thiophile reagent (28) produced the vinylogous carbamate (74) in 81% yield from the starting thiolactam (73 Scheme 17). Reduction of the vinylogous amide (74), followed by equilibration of the amino ketones in the presence of... 

The first total synthesis of racemic histrionicotoxin (58), the parent structure in a family of related spirocyclic alkaloids isolated from the skins of Dendrobates histrionicus, utilized the Eschenmoser reaction to generate the anchor of what would become the enyne group extending from the a-position of the piperidine nucleus. The spirothiolactam intemiediate (77) was condensed with ethyl 2-bromoace-toacetate in the presence of sodium bicarbonate to produce (78) in good yield (Scheme 18). Prior to further reaction on the vinylogous carbamate, the pendent allylic acetate was elalx>rated to the enyne (79). Subsequent deacylation and enyne protection yielded spirobicycle (80), which gave a 1 1 mixture of isomers upon reduction. The desired diastereomer (81) was isolated and subsequently converted to racemic histrionicotoxin (58). 

The Eschenmoser reaction was applied a second time as one of the methods to introduce the -butyl appendage. The alkylated a-amino ester (97) was oxidized to the monosubstituted thiolactam (98), and introduction of the butyl side chain, via sulfide contraction as described above, yielded a mixture of vinylogous carbamates (99). Treatment of the carbamates (99) under transfer hydrogenolysis conditions yielded the optically pure dialkylpyrroline (100), another component of the ant trail pheromone. Subsequent reduction of the pyrroline with platinum afforded the optically pure ds-2,5-dialkyl-substituted pyrrolidine (101). Other pyrrolidine-containing alkaloids have been prepared by similar approaches involving the Eschenmoser reaction. ... 

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