Claisen rearrangement of allyl esters

Codeine 1 and morphine 2, the principal constituents of opium, continue to attract the attention of organic chemists thanks to both their biological activities and their unique structure.[1] Their complex pentacyclic skeleton, which includes a quaternary carbon center, has stimulated extensive efforts. To date there have been more than 20 total syntheses of codeine (1), morphine (2), and thebaine (3).[2] We were interested in the synthesis of codeine for two reasons: first, codeine was found to be an allosteric potentiating ligand of nicotinic receptors, [3] and second we have a general program underway in the laboratory in which we have shown that tricyclic spirocyclohexadienones are valuable intermediates for the synthesis of natural products in the Amaryllidacea galanthamine-type, maritidine-type, and Aspidosperma alkaloids. [4] In an effort to develop new allosteric potentiating ligands of nicotinic receptors with a codeine-type scaffold, we initiated our own studies of a total synthesis of codeine. Herein we disclose a total diastereoselective synthesis of (AE )-codeine (1), which involves a new construction of the morphinan skeleton. The present study provides an efficient method for the elaboration of the quaternary carbon at C-13 and for the highly diastereoselective introduction of the C-14 stereogenic center of the morphinan system.Our retrosynthetic analysis of (AE )-codeine (1) is shown in Scheme 1. Codeine could be obtained from amine intermediate 4 by using an intramolecular hydroamination reaction to form the D ring. Compound 4 could in turn be prepared from aldehyde 5. In our synthetic pathway, we planned to use for the first time a Claisen-type rearrangement to introduce the C-14 substituent. This type of rearrangement applied to compound 6 would provide a precursor of the aldehyde 5 and control the stereochemistry of the substituent at C-14 of 5. The tricyclic amine 6 would be obtained from the spirocyclohexadienone 7 by a lactone ring opening with an amine followed by a spontaneous intramolecular Michael

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“…Attempts to achieve a Claisen rearrangement on 12 under Kazmaiers, [12] Irelands, [13] or Johnsons [14] conditions failed.…”

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Diastereoselective Total Synthesis of (±)‐Codeine

Varin

Barré

Iorga

et al. 2008

Chemistry A European J

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“…The ensuing aldehyde was protected as dimethyl acetal 9 (method according to [10]) without previous purification. Application of a slight modification [11] of the original Ireland ± Claisen rearrangement procedure [12] furnished silyl ester 10, which was reduced in situ to the primary alcohol 11. This intermedidate, again obtained as a 1 : 1 mixture of two diastereoisomers, was transformed in straightforward fashion via aldehyde 12 into oxime 13, which was isolated as a 2 : 1 mixture of (E)-isomer 13A and a (Z)-isomer 13B.…”

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Enantioselective Synthesis of Key Intermediates in a Novel Approach towards the Iboga‐Alkaloid Family

Höck

Borschberg

2003

Helvetica Chimica Acta

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Dedicated to Professor Jack D. Dunitz on the occasion of his 80th birthday Significant improvements in the realm of a recently disclosed, novel synthetic concept towards the Iboga alkaloid family are presented. The key step for the construction of the bicyclic aliphatic core consists of an intramolecular nitroneÀolefin 1,3-dipolar cycloaddition reaction of a 1 : 1 mixture 15/16 yielding the two diastereoisomeric tricyclic isoxazolidine derivatives 17 and 18. The required nitrones were prepared from the readily available (S)-hydroxylactone 6 in twelve steps with an overall yield of 15% (average: 83.5% per step). The relative configuration of the minor isomer was deduced unambiguously by single-crystal X-ray analysis of the derived tricyclic carbamate 21. As four out of five asymmetric centers in the pair 17/18 have opposite configuration, destruction of the one possessing the same absolute configuration transforms the original set of diastereoisomers into a pair of enantiomers. We verified this contention by oxidizing the two alcohols 20 and 22 to yield the two antipodal forms of ketone 23. The absence of significant amounts of by-product and the high reproducibility of the crucial cycloaddition reaction represent marked improvements over our earlier attempts. In addition, the new route, which starts from l-glutamate, should provide access to both naturally occurring antipodal series of the targeted alkaloid class.

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“…The highly-ordered transition state guarantees the reliable chirality transfer from starting materials to products. One of the most successful implementations of the many variants of the Claisen rearrangement is that of Ireland [2] [3].…”

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Allylsilane‐Modified Amino Acids from the Claisen Rearrangement

Mohamed

Brook

2002

Helvetica Chimica Acta

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It is an honour to dedicate this paper to Dieter Seebach on the occasion of his 65th birthday. He has been an exceptionally important presence in my professional life, both through his example of how to be a successful scientist and by the many doors he has opened for me. I am very grateful to have had the opportunity to be one of −die Mitarbeiter×.The Claisen rearrangement of the N-protected, silylated allyl glycinates 11 and 12 led to the formation of allyl/silyl-functionalized amino acids 13 and 14 in yields up to 80%. The diastereoisomer ratio varied from 2 : 1 to 29 : 1 for 11mb, and from 2 : 1 to 46 : 1 (syn/anti) for 12mb, depending on reaction conditions, as shown by X-ray crystallographic analysis of 14mb. The relationship between the size of the alkyl groups on the chlorosilane reagent (Me 2 R''SiCl, R'' Cl, Me, t-Bu, Ph) used as an enolate trap and the observed stereoselectivity was investigated in the case of the Ireland ± Claisen variant. Me 3 SiCl gave the best results. However, the size of the alkyl groups on the silylated ester (Me 2 R''Si, R Me, t-Bu, Ph, i-Pr) did not exert a significant effect on the diastereoselectivity or yield of the rearrangement.

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Claisen rearrangement of allyl esters

Cited by 375 publications

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Diastereoselective Total Synthesis of (±)‐Codeine

Diastereoselective Total Synthesis of (±)‐Codeine

Enantioselective Synthesis of Key Intermediates in a Novel Approach towards the Iboga‐Alkaloid Family

Allylsilane‐Modified Amino Acids from the Claisen Rearrangement

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