Cycloaddition ketene

The cyclobutanone is the important aspect. We shall want to make it by ketene cycloaddition (the key reaction) (Chapter T 33) and this we can do after an aldol disconnection. 

Ketenes are especially reactive in [2 + 2] cycloadditions and an important reason is that they offer a low degree of steric interaction in the TS. Another reason is the electrophilic character of the ketene LUMO. As discussed in Section 10.4 of Part A, there is a large net charge transfer from the alkene to the ketene, with bond formation at the ketene sp carbon mnning ahead of that at the sp2 carbon. The stereoselectivity of ketene cycloadditions is the result of steric effects in the TS. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis, which is the stereochemistry usually observed in these reactions. 

Intramolecular ketene cycloadditions are possible if the ketene and alkene functionalities can achieve an appropriate orientation.170... 

Some trends in relative reactivity for intramolecular ketene cycloadditions have been examined by internal competitions.172 For example, 12 gives exclusively 13, pointing to a preference for five-membered rings over six-membered ones. 

Although an intramolecular thermal [2 + 2] allene-ketene cycloaddition reaction was reported, the regioselectivity was moderate [55]. 

Katsuki-S harpless epoxidation, 48, 1 Ketene cycloadditions, 45, 2 Ketenes and ketene dimers, synthesis of, 3, 3 45, 2... 

Cycloadditions of ketenes and alkenes have been shown to have synthetic utility for the preparation of cyclobutanones.101 The stereoselectivity of ketene-alkene cycloaddition can be analyzed in terms of the Woodward-Hoffmann rules.102 To be an allowed process, the [2n + 2n] cycloaddition must be suprafacial in one component and antarafacial in the other. An alternative description of the transition state is a [2ns + (2ns + 2ns)] addition.103 Figure 6.6 illustrates these transition states. The ketene, utilizing its low-lying LUMO, is the antarafacial component and interacts with the HOMO of the alkene. The stereoselectivity of ketene cycloadditions can be rationalized in terms of steric effects in this transition state. Minimization of interaction between the substituents R and R leads to a cyclobutanone in which these substituents are cis. This is the... 

The observation of stereoselectivity in these cycloadditions (e.g., formation of 9) compares favorably with that of ketene cycloadditions. 

Allene ketene cycloadditions are of greater synthetic utility than cither mixed allene dimerization or mixed ketene dimerization. In this class of reaction the ketene is the more reactive species and homodimerization of ketene can be minimized by use of excess allene. Such cycloadditions always result in 2-alkylidenecyclobutanones with the sp carbons of both moieties forming the initial bond. In substituted allenes and ketenes, mixtures of stereoisomers of 2-alkylidenecyclobutanones are obtained with very little stereoselectivity, the stereoisomers arise from cisUrcins isomerism in the cyclobutane ring and EjZ isomerism of the exocyclic double bond. In unsymmetrically substituted allenes some regiochemical preference for ketene cycloaddition is observed. Examples of dimethylketene allene cycloadditions are summarized in Table 1,2... 

The regiochemistry of ketene cycloadditions is one in which the electrophilic carbonyl carbon of the ketene is bonded to the less substituted or more nucleophilic carbon of the alkene. This can be seen in the examples of5,15 18 6,14- 16 7,16 8,14,16 9,17 and 10.19... 

The stereochemistry with respect to the ketene iminium salt in cases of monosubstituted or unsymmetrically disubstituted derivatives in cycloadditions to alkenes show differences from the ketene counterpart. In contrast to ketene cycloadditions of monosubstituted ketenes with alkenes where the substituent in the bicyclic derivative ends up in the endo position, the cycloaddition of two monosubstituted ketene iminium salts with cyclopentene and cyclohexenc gives the e.wp-substituted derivatives 4.6... 

The regiochemistry of ketene iminium salt cycloadditions can also differ from ketene cycloadditions. Whereas reaction of styrene with a series of ketene iminium salts gave 3-phenyI-cyclobutanones7 (60-70% yield) similar to the regiochemistry of ketene cycloadditions, reaction with a series of acrylates and a,/J-unsaturated ketones gave cyclobutanones 5 with regiochemistry opposite to what would be expected from electrostatic considerations of ketene cycloadditions.s... 

It is interesting to note that the dimethyl-substituted derivative with the identical chiral auxiliary gives the opposite configuration in the cycloadduct compared to that obtained for the parent derivative. This has been ascribed to the nature of the [2 + 2] transition state in these cycloadditions. The enantioselectivities of these reactions exceed that for a ketene cycloaddition with a chiral auxiliary group (menthyloxy) attached to the a-carbon of the ketene in which a 45-50% ee was reported.12... 

Heterocyclic derivatives can be prepared by this route when one of the tether atoms is a nitrogen or an oxygen. Again this route is more efficient than the corresponding intramolecular ketene cycloaddition method for monosubstituted ketenes. Examples are the formation of 17,17 18,18 19 and 20,19 21,19 and 22.19... 

The advantage of using the photocycloaddition of pentacarbonylcarbenechromium complexes over the ketene cycloaddition method is the absence of ketene dimerization and the avoidance of use of excess alkene in the former method. Also, the mild reaction conditions associated with the use of chromium carbene complexes avoids epimerization and thermodynamic equilibration of 2-monosubstituted cyclobutanones. 

On the other hand, stereospecificity is not always complete, and many ketene cycloadditions take place only when there is a strong donor substituent on the alkene. An ionic stepwise pathway by way of an intermediate zwitterion 3.34 is therefore entirely reasonable in accounting for many ketene cycloadditions. It seems likely that some of these reactions are pericyclic and some not, with the possibility of there,being a rather blurred borderline between the two mechanisms, with one bond forming so far ahead of the other that any symmetry in the orbitals is essentially lost. But when it is pericyclic, how does it overcome the symmetry-imposed barrier ... 

Between the above two methods for the synthesis of (3-lactam derivatives, the venerable Staudinger [2+2] imine-ketene cycloaddition [36] is by far the most versatile and simplest entry to the lactam fragment. Application of Staudinger... 

The stereochemistry of ketene cycloadditions is remarkable,50 as exemplified in the following reaction ... 

The Nazarov Cyclization Katl L. Habermas, Scott E. Den-mark, Todd K. Jonas Ketene Cycloadditions John Hyatt, Peter W. Reynolds 0-47103101-0 390.00... 

Related to ketene cycloadditions are the group of cycloadditions with vinyl cation intermediates. The reaction between 2-butyne 6.120 and chlorine giving the dichlorocyclobutene 6.122 is the Smirnov-Zamkow reaction, and there is a similar reaction between allene 6.123 and hydrogen chloride giving the... 

Ketene Cycloadditions. As we saw earlier [see (Section 6.3.2.8) pages 211 and 212], ketenes undergo cycloadditions to double bonds 6.118 (repeated below) to give cyclobutanones. In practice, the reaction is faster and cleaner when the ketene has electron-withdrawing groups on it, as in dichloroketene, and when the alkene is relatively electron-rich, as in cyclopentadiene. The product from this pair of reagents is the cyclobutanone 6.249. 

Figure 3. Carbon-carbon bonds introduced from synthetic building blocks by Nicolaou et al. (A) and Danishefsky et al. (B, C2-C9 broken after ketene cycloaddition). In the putative biosynthesis of the diterpenoid 4,7-oxaeunicellanes from cembranoid precursors, only one additional carbon-carbon bond (Cl-CIO) would have to be formed (C). (1 R1 = (E)-N(6 )-methyluroca-nyl, R2 = beta-D-0(2)-acetylarabinopyranosyl stereochemistry has been omitted for clarity).

The requisite a-diazo thiol esters are conveniently prepared by using the "detrifluoroacetylative" diazo transfer strategy previously developed in our laboratory. Cycloadditions are best carried out by using as little as 0.006 equiv of rhodium(II) acetate to promote the thia-Wolff rearrangement. Reactions involving the more nucleophilic ketenophiles proceed smoothly in refluxing dichloromethane (40°C), while cycloadditions with less reactive partners are best accomplished in 1,2-dichloroethane (83°C). As is standard for ketene cycloadditions, the optimal protocol involves slowly adding a solution of the diazo thiol ester to a solution of the ketenophile and catalyst in order to minimize competitive ketene dimerization. 

In general, cyclobutanones are synthesized by either ketene cycloadditions or by ring expansions of cyclopropyl precursors. For the synthesis of simple a-substituted monocyclic cyclobutanones, the latter method is usually employed, and a variety of approaches have been used to prepare the required eyclopropyl intermediates. 

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