[3,3]-Sigmatropic rearrangements

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1 1 [3,3]-Sigmatropic rearrangements heat R 1 R 3 R 1 R 3 R 1 R 3 A class of pericyclic reactions whose stereochemical outcome is governed by the geometric requirements of the cyclic transition state Reactions generally proceed via a chair-like transition state in which 1,3-diaxial interactions are minimised Many similarities to the aldol reaction Absolute stereochemistry - controlled by existing stereocentre (destroyed in rct) Relative stereochemistry - controlled by alkene / enolate geometry a b c R d d c a b R d c a b R a b R c d rganic Chemistry

2 2 Cope rearrangement 91% 1,3-diaxial interactions disfavoured 9% A very simple example of a substrate controlled [3,3]-sigmatropic rearrangement is the Cope rearrangement To minimise 1,3-diaxial interactions phenyl group is pseudo-equatorial ote: the original stereocentre is destroyed as the new centre is formed This process is often called chirality transfer rganic Chemistry

3 3 Claisen rearrangements Claisen rearrangement Et g + heat + Johnson-Claisen rearrangement + + heat Eschenmoser-Claisen rearrangement heat 2 2 Ireland-Claisen rearrangement + Et 3 R 3 SiCl base heat SiR 3 SiR 3 ne of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it s variants rganic Chemistry

4 4 Enantioconvergent synthesis SET reduction gives most stable alkene a i-pr 2 i-pr 2 i-pr 2 i-pr 2 2 same configuration 2 Lindlar cat. heterogeneous hydrogenation leads to syn addition of 2 2 Both enantiomers of initial alcohol can be converted into the same enantiomer of product This process (Eschenmoser-Claisen) shows the importance of alkene geometry rganic Chemistry

5 5 Ireland-Claisen reaction 1. LDA, TF 2. R 3 SiCl SiR 3 SiR 3 SiR 3 SiR 3 1. LDA, TF/MPA 2. R 3 SiCl SiR 3 SiR 3 SiR 3 SiR 3 Enolate geometry controls relative stereochemistry Therefore, the enolisation step controls the stereochemistry of the final product As we saw earlier it is relatively easy to control enolate geometry rganic Chemistry

6 6 Substrate control in Ireland-Claisen rearrangement methyl group is pseudo-equatorial 91% ee 1. LMDS 2. TMSCl TMS TMS TMS TMS 2 C TMS 98% syn 91% ee In a similar fashion to the Cope rearrangement we saw earlier, the Ireland-Claisen rearrangement occurs with chirality transfer Initial stereogenic centre governs the conformation of the chair-like transition state Largest substituent will adopt the pseudo-equatorial position nce again, the relative stereochemistry is governed by the geometry of the enolate rganic Chemistry

7 7 Auxiliary controlled rearrangement in total synthesis LiTMP Li LiAl 4 ( ) 7 ( )-malyngolide ( )-Malyngolide is an antibiotic isolated from the blue-green marine algae Lyngbya majuscula This synthesis utilises Enders' RAMP hydrazone as a chiral auxiliary to set up the quarternary centre Dieter Enders & Monika Knopp Tetrahedron 1996, 52, rganic Chemistry

8 8 Chiral reagent control in the Ireland-Claisen rearrangement i-pr 2 Et C 2 Cl 2 78 C R* 2 B warm + Ar 2 S B S 2 Ar Br Et 3 Tol / hexane 78 C R* 2 B warm >97% ee 96% ee Funnily enough, it is possible to carry the reaction out under reagent control Although, it could be argued that this is just a form of temporary auxiliary control! Enolate formation (enolate geometry) governs relative stereochemistry rganic Chemistry

9 9 The use of a chiral reagent in total synthesis 2 S B S 2 F 3 C Br CF 3 F 3 C (i-pr) 2 i-pr (i-pr) 2 CF 3 86% >98%ee C 2 dolabellatrienone Dolabellatrienone is a marine diterpenoid isolated from gorgonian octocorals such as Eunicea calyculata and other marine organisms This synthesis of dolabellatrienone relies on boron enolate chemistry to establish the stereochemistry of the final molecule E. J. Corey & Robert S. Kania, J. Am. Chem. Soc. 1996, 118, rganic Chemistry

10 10 Chiral catalyst control in the Ireland-Claisen rearrangement Si Al(R*) 2 Si 3 Si 3 Si 2 t-bu Al(R*) 2 = Al Si 2 t-bu It is also possible to perform the reactions under chiral catalyst control Presumably, the Lewis acid coordinates to the oxygen & influences the reactive conformation thus controlling enantioselectivity rganic Chemistry

11 11 2,3-Wittig rearrangement Z Base Z Z Z Useful rearrangement allowing good 'chirality transfer' Requires method for formation of anion - either acidic proton (Z=electron withdrawing group) or metal-functional group exchange Driving force is stability of alkoxide (although other elements can be used...) Transition state debatable but useful model is the 'envelope' based on chair BuLi 85 C 98%de Largest substituents adopt pseudo-equatorial position BuLi 85 C 98%de 98%ee rganic Chemistry

12 12 Enantioselectivity in the 2,3-Wittig rearrangement 2 S C 2 + B Br S 2 Et 3 B Reagent control utilising boron reagent seen in both aldol & Claisen reactions Chiral catalysis is far less developed in this area ne example is given below: S 2 B 2 S C 2 66%de 96%ee (C 2 ) 2 Ar cat (20mol%), rt, 5d 75% 60%ee (dr 2:1) 2*R R Ar (C 2 ) 2 Ar rganic Chemistry

13 13 [2,3]-aza-Wittig reaction in total synthesis C 5 11 C 2 t-bu LDA 97% Li C 5 11 t-bu C 5 11 C 2 t-bu C 5 11 indolizidine 209B Aza-Wittig reaction is less common as normally no driving force ere relief of ring-strain accelerates reaction Utilised in the synthesis of indolizidine 209B from Dendrobates pumilio or the strawberry poison dart frog by Jens Åhman & Peter Somfai, Tetrahedron, 1995, 51, rganic Chemistry