Refunctionalization reactions

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. 

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... 

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... 

Refunctionalization. Reaction changing functionality but creating no carbon-carbon (T-bond, i.e., not affecting the skeleton. 

Self-consistent Sequence. A sequence of construction half-reactions on one synthon which requires no intermediate refunctionalization reactions. The functionality left by one construction is consistent with that required for the next. 

The full sequence of steps in a synthesis will be not only the central constructions of the bondset, but also the refunctionalization reactions which are used to prepare the functional groups (a) for their role in construction and (b) for final conversion to the target structure after the last construction. In an average published synthesis there are actually twice as many refiinctionaUzation steps as construction steps. 

There are a handful of examples where amino acids with ring sizes of seven members and larger have been prepared using the carboxyl refunctionalization reaction just shown. Reaction of anhydride 7.29H with ammonia, for example, gave amide-acid 7.30. Hofmann rearrangementl of the amide led to cfs-2-aminocyclo-heptane-1-carboxylic acid, 731. An alternative synthesis conjugate addition of ammonia to cycloheptenecarboxylic acid, 7.32. This reaction gave rra/is-2-amino-cycloheptane-1-carboxylic acid, 7.33. 

Lactams are cyclic molecules that can be used as synthetic precursors to cyclic amino acids, usually by refunctionalization reactions. One example is the conversion of the alkene moiety in bicyclic lactam 7.75 (2-azabicyclo[2.2.1]hepl-5-en-3-... 

The distinction is made between refunctionalization reactions and skeletal alteration reactions, the former in almost all cases having no more that four carbons in the reaction center, the latter (constructions and fragmentations) having no more than three in each joining or cleaving half of the molecule, i.e., half-reactions . Hence most reactions can be accontunodated on four- or six-cycle schemes. 

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... 

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. 

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... 

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. 

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. 

Such successive half-reactions are not properly self-consistent, and a tally of such combinations could be made and used mechanically to discard certain sequences from a derived set if a criterion of true self-consistency is desired 5>. On the other hand many of the refunctionalization steps in the actual s mtheses surveyed 24,31) are of exactly this kind, i.e., derivatization of alcohols to mesylates, acetates, etc., ketone-ketal protective interconversions, ester-acid interconversions, etc. Thus, although the self-consistency criterion was applied for reasons of efficiency and does strongly reduce the tree, the fact that the original definition of Z is broad allows a generous amount of implicit refunctionalization in practice. Furthermore, it should be possible to tabulate which of the pairs of successive half-reactions require it and which do not so that its exclusion can be a matter of choice. 

In any case, if the protocol aims for discovery of all sequences within the defined criteria, any published synthesis from this bondset should turn up, and indeed one combination here has been successfully executed by Corey and his group this synthesis is outlined at the bottom of Fig. 10 and is written directly as derived from the /-lists in the second matched sample above it. In the actual work, the C—9—Z was a nitro-carbanion (Bi), the C—13—Z was C —P03 for the B2 reaction of synthon III and implicit refunctionalization occurs in protection and release of the C—11 aldehyde as acetal before construction 3. The first matched sample shown is an afiy) pattern of otherwise very similar chemistry for comparison. 

The system as defined is also flexible with respect to future development in incorporating presently excluded options. Since all possible target /-lists are not produced by the self-consistent sequences of the lists, there must be occasions which demand refunctionalization. At present these are assumed to occur at the end of the route, following full skeletal construction, but it is equally efficient and more flexible to allow them en route as well. It is possible to systematize refunctionalization in the same format as constructions (cf.. Table 3), perhaps including the Z - Z reactions implicit in the present sequences With this added tool the self-consistency criterion could be made less inflexible by allowing certain specified refunctionalizations to intervene among constructions, with a view to exploring the expansion of options this will produce. 

The masterlist in Table 3 is a slightly altered presentation of Table 8 in Ref. i >. It incorporates also the variants on certain half-reactions discussed in the appendix of Ref. i ). These variants incorporate the net change of certain construction - - refunctionalization... 

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