Retro-Wittig reaction

This accounts for the considerable discrepancy between the alkene Z/E ratio found on work-up and the initial oxaphosphetan ais/trans ratio. By approaching the problem from the starting point of the diastereomeric phosphonium salts (19) and (20), deprotonation studies and crossover experiments showed that the retro-Wittig reaction was only detectable with the erythreo isomer (19) via the cis-oxaphosphetan (17). Furthermore, it was shown that under lithium-salt-free conditions, mixtures of (19) and (20) exhibited stereochemical drift because of a synergistic effect (of undefined mechanism) between the oxaphosphetans (17) and (18) during their decomposition to alkenes. 

The retrosynthesis involves the following transformations i) isomerisation of the endocyclic doble bond to the exo position ii) substitution of the terminal methylene group by a more stable carbonyl group (retro-Wittig reaction) iii) nucleophilic retro-Michael addition iv) reductive allylic rearrangement v) dealkylation of tertiary alcohol vi) homolytic cleavage and functionalisation vii) dehydroiodination viii) conversion of ethynyl ketone to carboxylic acid derivative ix) homolytic cleavage and functionalisation x) 3-bromo-debutylation xi) conversion of vinyl trimethylstannane to methyl 2-oxocyclopentanecarboxylate (67). 

Despite the obvious possibilities for disengaging the allylic methyl group of 7 by retro-S reaction, Kim preferred to disjoin this molecule by a (Z)-selective Wittig reaction to obtain aldehyde 9 and ylide 8. Since further analysis of 9 also indicated that it could potentially be reached from the readily available 5-deoxy-D-xylose derivative 10, this was the strategy eventually settled upon. 

Schemes 2.3a-c outline the retro-synthetic production of BTX B (1). The final approach to PbTx-2 involved separate assembly of the ABCDEFG and UK ring systems 4 and 5, their coupling, and final elaboration to the end. The didehydrooxocane ring in BTX B (ring H) was thus designated as the final ring to be constructed. Retro-synthetic cleavage of the indicated C-0 bond in 1 and removal of the terminal electrophilic groupings reveal hydroxy dithioketal 3 as a plausible precursor. Tricyclic aldehyde 4 and heptacyclic phosphonium salt 5 can thus be defined as potential precursors to 3. The reliable and usually stereoselective Wittig reaction would be employed to accomplish the union of compounds 4 and 5 (Scheme 2.3a). Tricyclic aldehyde 4 was traced retro-synthetically to D-mannose 10.

The retro-Wittig reaction (i) (Scheme 2.39), with disconnection across the double bond, seems to be an obvious candidate for models containing disubstituted double bonds. In these cases, the steric outcome of the reaction can be easily controlled. An alternative route of disconnection at the vinyl bonds (ii) corresponds to a retro-carbometallation reaction. This disconnection is generally applicable to double bonds with any substitution pattern and is especially useful owing to the high stereoselectivity of the carbometallation step. Route (iii) involves a retrosynthetic dehydrogenation leading to the immediate acetylenic precursor, which can be conventionally disassembled into a parent acetylide and a pair of electrophiles as shown. 

In the total synthesis of antitumor antibiotic (+)-phloeodictine A1 by B.B. Snider and co-workers, the key step was an aza-Wittig reaction followed by a retro-Dlels-Alder reaction to afford the desired bicyclic amidine. The polystyrene-supported PPhs made it easy to separate the product from by-products with a simple filtration. 

The second kind of thermally allowed [2 + 2] cycloaddition occurs when one of the atoms involved is a second-row or heavier element, as in the Wittig reaction. Whether the first step of the Wittig reaction actually proceeds in a concerted fashion is a matter of debate, but the point here is that a concerted mechanism is a reasonable possibility. Moreover, there is no controversy over whether the second step of the mechanism is a concerted [2 + 2] retro-cycloaddition. 

Why aren t the [2 + 2] cycloaddition and retro-cycloaddition of the Wittig reaction disallowed The Woodward-Hoffmann rules state that when the symmetries of the MOs of the reactants are mismatched in ways that we have discussed, the TS for the reaction is raised very high in energy, and the reaction is therefore disallowed. In principle, even a disallowed reaction can proceed at sufficiently high temperatures the reason this approach usually doesn t work is that other reactions usually take place at temperatures far below those required for the disal-... 

The presumed mechanism of action of the Tebbe reagent is very simple after dissociation of Me2AlCl, [2 + 2] cycloaddition of Cp2Ti=CH2 and R2C=0 is followed by [2 + 2] retro-cycloaddition to give the product. Unlike the conventional Wittig reaction, the Tebbe reaction works well with esters. 

When coupled with living radical systems, living ringopening metathesis polymerization (ROMP) also permits the synthesis of other types of block copolymers (Figure 23) such as B-102 to B-108.67,396,397 A molybdenum carbene or ROMP intermediate is converted into a benzyl bromide-type terminal by quenching the ROMP with /> (b r omo me thy 1) b en z al d e hy d e by a retro-Wittig reaction.396 The macroinitiator thus obtained induced living radical polymerizations of styrene and MA with copper catalysts to afford B-102 to B-105. 

Our retrosynthetic analysis is shown in Scheme 18. Retro-Wittig reaction leads to aldehyde 105 which is generated from alcohol 106 by Swem oxidation. This tetrahy-drofuran system might be generated by ring closure of epoxy alcohol 107 although this would involve an SN2 type attack of the hydroxyl function at the more hindered position of the epoxide. The diol unit in 107 was to be created by osmylation of an allylic alcohol as represented by precursor 108 (8). 

The [2 -I- 2] cycloadditions of the Wittig reaction are allowed by the Woodward-Hoffmann rules because the ylide (Ph3P=CH2) has a tt bond that is made up of a P(d) orbital and a C(p) orbital, and therefore the termini of the HOMO are antisymmetric, not symmetric as they would be if the tt bond were made up of two p orbitals. The ylide s antisymmetric HOMO allows there to be bonding interactions between the termini of the ylide HOMO and the ketone LUMO in the TS for the [2 -I- 2] cycloaddition. The [2 + 2] retro-cycloaddition that completes the Wittig reaction is allowed for the same reason. Metal alkylidenes (M=CR2), which similarly have tt bonds made up of a M(d) orbital and a C(p) orbital, also undergo thermally allowed [2 + 2] cycloadditions with alkenes during olefin metathesis (see Chapter 6) and other reactions. 

There are some additional potential complications with the control experiments. Loss of stereochemistry in method D can be due to product equilibration induced by the phosphine additive as already mentioned. Furthermore, equilibration in method A or E can occur because of competing (reversible) (x-deprotonation to give the oxido ylide 38 or the derived hydroxy ylide 39 (21c). The latter problem can usually 1% avoided by lowering the temperature or by using a weaker base for the deprotonation of the )5-hydroxyphosphonium salt 27 or 28 (21c). Nevertheless, positive equilibration results cannot be attributed to retro-Wittig reaction unless (1) crossover is also demonstrated or (2) labeling results can rule out the intervention of 38 or 39. 

Aromatic and sterically restricting aliphatic aldehydes in marginal cases lead to retro-oxaphosphetane ring opening [53]. Reversibility has also been excluded as a significant process for semi-stable and stable ylides [43,54]. Therefore, the stereochemistry of the salt-free Wittig reaction would be established in virtually all cases by the formation of cis- or rraw5-oxaphosphetanes under kinetic control. 

Reviews have appeared on the use of the Wittig reaction in industrial practice, the Claisen rearrangement, synthetic applications of the retro-Diels-Alder reaction, organo-palladium intermediates for the alkylation and arylation of olefins, the Prins reaction to give 1,3-dienes, and intramolecular [4 + 2] (Diels-Alder) and [3 + 2] cycloadditions.An interesting discussion of the regiospecificity of the Diels-Alder reaction in terms of frontier orbital overlap favours the Woodward-Katz concept. Useful alkyne and polyene coupling reactions are described in reviews on the chemistry of vitamin the synthesis of insect sex... 

Abstract A problem-solving approach to retrosynthesis is introduced. Basic principles for good disconnections are postulated. Examples of interconversion and disconnection of carbinols, alkenes, ketones and nitro compounds are discussed. Concepts of retro-Diels-Alder and re/ro-Wittig disconnections are presented and the mechanisms of reactions explained. Application of the Wittig reaction on the industrial scale is exemphfied by the synthesis of the analog of bombykol, the principal of pear odor and anti-appelizer chlorphentermine. 

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