Enolates rearrangements

Scheme 2.45 Aza-[3,3]-Claisen enolate rearrangements of 1 -acyl-2-vi nylazi rid i nes.

In 1997, Lindstrom and Somfai reported aza-[3,3]-Claisen enolate rearrangements of vinylaziridines (Scheme 2.45) [70]. Treatment of l-acyl-2-vinylaziridines 179 with LHMDS resulted in the stereoselective formation of seven-membered lactams 181, presumably through a boat-like transition state 180. 

If the alkene is an alkyne instead, we are dealing with a propargylic alcohol and now the thermodynamics are more favourable and the product is an enone. Commercial application is found in the production of citral from dehydrolinalool via vanadium-catalysed isomerisation (Figure 5.9). Note that the last step involves a transfer of hydrogen as well when the enol rearranges to the aldehyde ... 

As with other ester enolate rearrangements, the presence of chiral ligands can render the reaction enantioselective. Use of quinine or quinidine with the chelating metal leads to enantioselectivity (see entry 21 in Scheme 6.12). 

Previously, Ireland-Claisen ester-enolate rearrangement of the corresponding a-propionyloxy-allylsilane led to model system 5.44 Therefore, elaboration to 4 via rearrangement of 15 was pursued. To complete our retrosynthetic analysis, a plausible route to 15 was devised, involving straightforward homologation of 2P,3a-disubstituted cyclohexanone 17 to cyclohexene-carboxaldehyde 16, which in turn undergoes silylanion addition and subsequent acylation (Eq. 8). 

Figure 1. Potential transition states in the Claisen ester-enolate rearrangement of diastereomers 30 and 31.

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

Danishefsky, S. J. Simoneau, B. Total synthesis of ML-236A and compactin by combining the lactonic (silyl) enolate rearrangement and aldehyde-diene cyclocondensation technologies./. Am. Chem. Soc. 1989, 111, 2599-2604. 

The conjugate addition of lithium peroxides on enones is a non-classical route to epoxidation. The original lithium enolate rearranges immediately in situU3. Note that a catalytic asymmetric version of this reaction was also developed (Scheme 41)184. 

The Johnson Ortho Ester Rearrangement 7.22.8 The Ireland Silyl Ester Enolate Rearrangement 722.9 Charge-accelerated Claisen Rearrangements 7.22.10 Cat ysis of Claisen Rearrangements 722.11 Competitive Rearrangements... 

It is important to note, however, that an observed erosion of diastereoselectivity in the Ireland silyl ester enolate rearrangement can be attributed either to the geometric integrity of the silylketene acetals or the selectivity of the chair-like vs. boat-like transition states, and interpretation and improvement of experimental stereoselectivities must take into account both of these factors. 

In the total synthesis of the esterase inhibitor ( )-ebelactone A, Paterson and Hulme applied an aldol-Claisen strategy for a relay of 1,2-syn into 1,5-syn relative stereochemistry (Scheme 25). - i3,ii4 critical Ireland ester enolate rearrangement could be performed without protecting the C9 ketone to give ester (137) in 74% overall yield. ... 

A related problem is elimination in ester enolates with leaving groups in the -position. Knight and coworkers observed virtually no a-allyl- -amino acid product in the Ireland silyl ester enolate rearrangement of phthalate (213 Scheme 41). Rearrangement of the -methoxycarbonyl analog (214), however, provided methyl ester (215) in a 79 21 mixture of stereoisomers after treatment with etheral diazomethane. 

For an aromatic version of the silyl ester enolate rearrangement, see H. Nemoto, E. Shitara and K. Fukumoto, Heterocycles, 1985, 23, 549. 

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