Construction-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. 

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 ... 

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... 

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 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... 

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. 

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... 

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. 

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. 

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. 

On the methodological front of these broadly based endeavors, we have exploited pericyclic processes such as the dipolar cycloadditions of nitrile oxides together with the aldol reaction and related constructions as tactical devices for the formation of new carbon-carbon bonds with high levels of stereochemical control Another important focus of these explorations has been upon the development of techniques for the manipulation and refunctionalization of hydropyrans, since this structural subunit is not only common to a variety of natural substances, but it may also be effectively exploited as a conformationally-biased template for the stereoselective construction of various skeletal arrays present in numerous natural products. In this context, we have devised a novel and highly effective strategy for the asymmetric syntheses of oxygenated natural products. The fundamental approach features the intermediacy of the hydro-3-pyranones 12, which may be accessed from the chiral furfuryl carbinols 10 via the hydroxy enediones 11 by well-established oxidative techniques (Scheme 1). A critical element of this overall planll is that the hydro-3-pyranones 12 are admirably endowed with differentiated functionality that is suitable for further elaboration by reaction with selected nucleophiles... 

Construction Reactions. The important dichotomy in any structure between the skeleton and the functional groups has a paraUel dichotomy in reactions. Reactions may be divided between constructions, reactions which create the skeletal bonds, and refunctionalizations, which alter the functional groups without affecting the skeleton. Constructions, therefore, are defined as reactions which make carbon-carbon a-bonds. 

Reactions which have only one single exchange of bonds at each changing carbon (the 16 exchanges of Figure 3) are unit reactions. In our survey of reaction databases (8), some 80% of all reactions are simply unit reactions and most of the rest are just composites of two sequential unit reactions, as with ZH+ZH to describe reduction of carboxyl to primary alcohol. Some common and useful constructions, like the Wittig reaction, are composites of a construction and a refunctionalization. 

All of these reactions can be sharply defined with this system of description (9,10). In one class are the refunctionalizations with ZAa=0 the rest are skeletal alterations, cf., constructions with Aa=2. These classes can be subclassified by... 

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