Refunctionalization

The ideal synthesis creates a complex skeleton... in a sequence only of successive construction reactions involving no intermediary refunctionalizations, and leading directly to the structure of the target, not only its skeleton but also its correctly placed functionality. Hendrickson JB (1975) J Am Chem Soc 97 5784... 

Attaching the functionality to already constructed dendrimer skeletons by suitably refunctionalizing the end groups or other moieties in the dendrimers 14 141... 

A further refunctionalization of the N,O-acetal 5-alkylhexahydropyrrolo[2,1-/>]oxazole allows for the elaboration of 2,5-dialkylated pyrrolidines by reaction with Grignard reagents74. 

The dithiane derivative 60 (Scheme 14) is such a compound, it being made from 2,3 5,6-di-0-isopropylidene-D-mannose by treatment with 2-lithio-l,3-dithiane to give a heptose dithioacetal that was refunctionalized at C-2-C-3 by way of the C-l anion and then converted to the 6,7-epoxide following selective acid-catalyzed cleavage of the 6,7-acetal ring. Treated with n-butyllithium it gives, in 70% yield, the cyclized 61, which is efficiently convertible into validatol 62, a component of validamycin A, by desulfurization with Raney nickel and de-O-protection by use of boron tribromide in dichloromethane [31]. 

Copper halide transmetallation of a fluorovinylzinc reagent and refunctionalization of the copper reagent preparation of (Z)-1,1,2,5,5,5-hexafluoro-4-iodo-3-trifluoro methylpenta-1,3-diene15-16... 

In the case of 3.25 and the difunctionalized derivative 3.30, Richert, et al. have performed various functional group interconversion. This has afforded a number of differentially substituted porphycenes." For instance, it was found that when the porphycene tetraether 3.25 was treated with 0.74 equivalents of BBry, the mono-refunctionalized derivative 3.96 could be isolated in 18% yield (Scheme 3.1.18). However, the selectivity in this reaction was low. In fact, it afforded, in addition to 3.96, a 50-60% return of educt 3.25 along with the three possible isomeric dialcohols 3.97-3.99 (10-12% combined yield) and the trialcohol 3.100 in 4% yield. Fortunately, with the exception of the dialcohol isomers 3.97-3.99, these products could be readily separated by standard chromatographic means. These types of isomer problems were not encountered in the case of diether 3.30. Here, treatment... 

A procedure has been reported for the removal of the aminoadipoyl side-chain of cephamycin C (96c) [202] (utilizable for cephalosporin C as well), thereby enabling the easy refunctionalization of the 7-amino group to yield semisynthetic cephamycins (98). 

The isomerization of olefinic bonds can lead to a refunctionalization of the molecule if it contains the appropriate substituents. In this fashion, allyl alcohol is not isomerized to methylvinyl alcohol but to propionalde-hyde ... 

In addition to the functionalization protocols of Schemes 13 and 14, vinylic substitution reactions involving metalation and palladium-mediated carbon-carbon bond formation have been formulated," which further broaden the variety of structural types available from the Patemo-BUchi reaction. For example, deprotection and stannylation of photoaldol (133), followed by refunctionalization of the a-enol ether position of vinylstannane (134), gave the substituted oxetane (135) in good overall yield. Similar functionalization of bicyclic oxetane (136) via exo-face dihydroxylation and acid-catalyzed reorganization of the acetal to the protected 3-deoxy-( )-streptose (137) has been reported, which illustrates the synthetic utility of such processes in the synthesis of polyoxygenated materials. 

Finally, a program is also described which proceeds from all starting materials in a forward direction to synthesize close analogs of a target using refunctionalization reactions as well as constructions. 

When this procedure is applied, using the nine possible pairs of three nucleophilic and three electrophilic half-reactions (Figure 4), the results obtained show many viable sequences but reveal two shortcomings. First, some common one-step constructions do not appear and, second, many of the generated reactions are chemically non-viable. The constructions which do not appear are those in which the actual "one-step" reaction is in fact two successive unit reactions, a construction and a refunctionalization. Thus the Wittig reaction is a construction followed by an elimination, while the common Grignard half-reaction consists of a prior reduction of RfX to RfMgBr followed by construction. 

We discerned three kinds of refunctionalization unit reactions which can usefully couple with a construction in a nonstop, or one-step, procedure prior reduction to carbanion nucleophiles, elimination following construction, or various tautomerizations before or after construction. The overall net structural changes for these composite constructions were then added to our list of construction half-reactions and, after some further subdivision of common types into chemically recognizable subheadings, we had expanded the list from the six of Figure 4 to 24 half-reactions ... 

In our initial examination of the current literature file from REACCS there are 29,700 reactions (in 23,100 entries) and 16,500 are constructions, the rest being refunctionalizations (or a few more complex multiple constructions). To date we have found 5600 construction matches, i.e., about 34%. The rest are written in ways that require more translation and as this proceeds, the proportion matched will rise, but there are still many which are too specific, or involve hidden refunctionalization steps, to be useful general precedents (also a nontrivial number are incorrectly entered). Even so, the literature base available to the SYNGEN user is already substantial, and our search procedure makes this readily available. 

One of the strictest constraints placed on the SYNGEN protocol is that requiring an "ideal synthesis, i.e., a direct sequence of constructions only with no refunctionalization reactions to "repair" functional groups. Certainly in real life such syntheses are very rare, though for SYNGEN they constitute a desirable goal since they should be the shortest sequences possible. An overview... 

This synthesis can be compared with another one [40] in Scheme 7.26 which follows the same bond set [41]. This means that the same skeletal bonds are made in both syntheses. Any differences between these two syntheses therefore arise from differences in the refunctionalization and protecting group steps. 

The structures of most natural NCCs, such as of //v-NCC-1 (2) or of C/ -NCC-1 (23), indicate further refunctionalization reactions, most of which are likely to be enzyme-catalyzed. A remarkable peripheral hydroxylation at the terminal position of the ethyl side chain at ring B is systematically indicated by the published structures of NCCs (such as, e.g. Hv-NCC-1, 2) (1, 2, 10). This peripheral hydroxylation, for which an enzyme-catalyzed reaction appears to be required, may serve the purpose of increasing the polarity of the catabolites and of providing an anchor point for further, secondary refunctionalization with hydrophilic groups (4). A uniform picture concerning the timing and the spatial localization in the leaf cell of the enzymatic activities for hydroxylation of the ethyl group at carbon 8 and for oxidation (with di-hydroxylation) of the vinyl side chain at carbon 3 is not yet apparent. Possibly, even the discrimination between FCCs or NCCs as enzyme substrates by some of... 

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