Transition state Claisen-Ireland rearrangements

Structure B corresponds to the most stable transition state of the Claisen-Ireland rearrangement of Figure 11.44. In this transition state, the substituent at the allyllic stereocenter is in a quasi-equatorial orientation with respect to the chair-shaped skeleton. This is the same preferred geometry as in the case of the most stable transition state B of the Claisen rearrangement of Figure 11.43. The reason for this preference is as before that is, an allylic substituent that is oriented in this way experiences the smallest possible interaction with the chair skeleton. The obvious similarity of the preferred transition state structures of the Claisen-Ireland rearrangements of Figures 11.44 and 11.43 causes the same fnms-selectivity. 

The same stereoselectivity due to a boat-hke transition state has been observed by Lallemand [16] during an approach in the synthesis of antifeedent compound clerodine. Interestingly, a chemical correlation has been done with the products resulting from a Claisen-Ireland rearrangement in the open chain series. Accordingly, the E-ester enolate obtained after deprotonation and silylation of ester 64 [17] afforded, via a chair-like transition state, a compound which was correlated via 63 with the cyclic orthoester product 62 which resulted from a necessarily Z-ketene acetal. Consistently the E-ester enolate gave rise to a diastereomer 65 after the same sequence of reactions (Scheme 6.8). 

A highly successful route to stereoisomers of substituted 3-cyclohexene-l-carboxylates runs via Ireland-Claisen rearrangements of silyl enolates of oj-vinyl lactones. The rearrangement proceeds stereospeaifically through the only possible boat-like transition state, in which the connecting carbon atoms come close enough (S. Danishefsky, 1980 see also section 4.8.3, M. Nakatsuka, 1990). 

Only limited precedent exists for the stereoselective enolization and subsequent condensation of a-heteroatom-substituted esters 48a and 48b (eq. [29]). Ireland has examined the enolization process for a-amino ester derivatives where the Claisen rearrangement (chair-preferred transition states) was employed to ascertain enolate geometry (Scheme 10) (43). These results imply that 48a [X = N(CH2Ph)2 ] exhibits only modest selectivity for ( )-enoIate formation under the... 

Sigmatropic rearrangements proceed via closed transition states in the Claisen-Ireland variation a silyl-enol ester, 27 or 28, is used, which may be selectively generated in (Z) or (E) configuration12 (Section A. 1.6.3.1.). As shown in the transition states 32 and 29, this results in the formation of 30/31 and 33/34. 

Although a chairlike transition state is favored for the Claisen rearrangement reactions of acyclic substrates, this is not always the case with cyclic systems. For example, Bartlett and Ireland independently studied the rearrangement reactions of cyclohexenyl silylketeneacetals and found that there was competition between the chairlike and boatlike transition states11 (Scheme l.VII). Clearly, the -isomer IE gives 8a via a chairlike transition state, whereas the Z-isomer 7Z affords the same product (8a) via a boatlike transition state. 

For the reaction of 7 (OMe), chairlike transition state A is favored over boatlike transition state B12 (Scheme l.IX). These computational results provide a solid theoretical rationalization of the original proposal by Bartlett and Ireland that the boatlike transition state is favored for the Claisen rearrangement of 7Z, and the chairlike transition state is preferred for IE. 

Danishefsky and coworkers have demonstrated the conversion of lactones to carbocycles by the 3,3-sigmatropic shift of silylketene acetals. Jq the total synthesis of the Fusarium toxin equisetin, for example, keto lactone (138) was converted to its bissilyl derivative (139) by reaction with 2 equiv. of LDA and an excess of TMS-Cl. In situ thermolysis of ketene acetal (1 ) led to a very smooth transformation into ester (140), which was carried on to equisetin (Scheme 26). This methodology was also applied by Schreiber and Smith in the preparation of the cyclohexyl moiety of the immunosuppressive agent FK-506. Ireland-Claisen rearrangement of silylketene acetal (142), prepared by treatment with TBDMS-OTf and triethylamine at low temperature, provided, after hydrolysis of the silyl ester, the carboxylic acid (143) in 71% overall yield (Scheme 27). The strict translation of configuration via a boatlike transition state is typical for this permutation. 

In cyclic systems, however, conformational constraints can override the inherent preference for chairlike transition states in Cope as well as Claisen rearrangements and lead to a partial involvement if not a dominance of boat-like TS structures. In the Ireland rearrangement of lactones of type (247), for example, chair-like transition state (249) is accessible only when the diaxial bridging methylene chain becomes sufficient in length (n = 7, Scheme 44). The preference of boat-like transition state (250) over (251) is due to a serious A - -type interaction between the endocyclic oxygen atom and pseudoaxial substituent R in (251). 

Ireland, R. E., Wipf, P., Xiang, J. N. Stereochemical control in the ester enolate Claisen rearrangement. 2. Chairlike vs boatlike transition-state selection. J. Org. Chem. 1991, 56, 3572-3582. 

This result in particular should warn you that the choice between a chair- and boat-like transition state is narrow. In general open-chain compounds prefer the chair and cyclic compounds the boat but do not rely on it In spite of this apparent disadvantage the Ireland version of the Claisen rearrangement is one of the most widely used ways to set up complicated molecules. Ireland himself has used it to make a catalogue of polyether antibiotics with the monensin synthesis being perhaps the most remarkable. These syntheses are beyond the scope of this book but are worth reading.36... 

Protection of the primary and acylation of the secondary alcohol prepares the way for an Ireland-Claisen rearrangement. The E-enolate is produced and the [3,3] sigmatropic rearrangement transmits the chirality across the alkene to set up two new centres. The mechanism of the Ireland-Claisen rearrangement is described above 94 and occurs suprafacially across the backbone of the molecule through a chair-like transition state. We hope you agree both with the relative stereochemistry of the new centres and the E stereochemistry of the new alkene. 

Corey and Lee [696] have recently proposed a variant of the Ireland-Claisen rearrangement that uses boron enolates of allylic esters derived from 2.62. The E-crotyi (Re = Me) or E-cinnamyl (Rz = Ph) derivatives could be selectively transformed into the Z- or E-boron enolates 10.46 at low temperature (Figure 10.16). The rearrangements take place at about 0°C, and the Z-enolates lead vay selectively to anti acids 10.47 with an excellent enantiomeric excess while the E-enolates lead to syn acids 10.48, with an interesting selectivity if R = Me or Et (Figure 10.16). In most cases, the enantiomeric excesses are excellent however, when the reaction is conducted with ally] esters (R = H), the ee s are a little bit lower (74 - 84%). These results are interpreted via a chair transition state that minimizes steric interactions [696],... 

Hydroxyethylene dipeptidc isosteres 35, which are of interest as transition state analogs, e.g., in renin inhibitors where they replace the scissile dipeptide unit (Leu-Val) of angiotensinogen, the natural substrate of renin, can be obtained from optically active acid 32 via iodolactoniza-tion in several steps. The synthesis of 32 is achieved using an Ireland - Claisen rearrangement as the key step which allows complete control of the three stereogenic centers44. For a stereocontrolled synthesis of peptide bond isosteres via Claisen rearrangements see also ref 448. 

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