1 [3,3]-Sigmatropic rearrangements

R2 R2 R2 heat X X X

R1 R3 R1 R3 R1 R3

• 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

R c c R a a X d d X X R X R c a a b R2 b b R2 2 2 b d R H R H c d

123.702 Organic Chemistry 2 Cope rearrangement

H Ph Me Me Ph

Ph Me H Me 91% Me

Me H Me Ph Me Me

Ph Me H 9% 1,3-diaxial interactions disfavoured

• 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 • Note: the original stereocentre is destroyed as the new centre is formed • This process is often called ‘chirality transfer’

123.702 Organic Chemistry 3 Claisen rearrangements Claisen rearrangement

OEt Hg+ O heat O OH + H

Johnson-Claisen rearrangement

MeO OMe H+ O heat O OH + Me OMe OMe OMe

Eschenmoser-Claisen rearrangement

MeO OMe H+ O heat O OH + Me NMe 2 NMe2 NMe2

Ireland-Claisen rearrangement

R SiCl O O 3 Et N O base O heat O OH + 3

Me O Me Me O OSiR3 OSiR3

• One of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it’s variants 123.702 Organic Chemistry 4 ‘Enantioconvergent’ synthesis

SET reduction gives most stable alkene NMe NMe MeO OMe 2 2 OH Na OH NH3 Me NMe2 O O Me Me H Me Me Me Me Me Me Me Me Me Me ≡

H NMe H NMe 2 2 O O Me O H H i-Pr H i-Pr H i-Pr O i-Pr O Me Me2N Me2N NMe2 H Me H Me Me Me Me ≡ same configuration

NMe2 NMe2 H2 MeO OMe OH Lindlar OH Me cat. Me NMe2 O O Me Me Me Me Me Me Me Me Me H Me Me heterogeneous hydrogenation leads to syn addition of H2 • Both enantiomers of initial alcohol can be converted into the same enantiomer of product • This process (Eschenmoser-Claisen) shows the importance of alkene geometry 123.702 Organic Chemistry 5 Ireland-Claisen reaction

H H 1. LDA, THF O OSiR3 OSiR3 O 2. R SiCl 3 Me Me H H Me OSiR MeMe O O 3 OSiR3 Me O Me Me

Me O 1. LDA, H H Me THF/HMPA O OSiR3 OSiR3 O 2. R3SiCl Me Me Me Me Me OSiR3 O O Me OSiR3 Me Me H H

• 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...

123.702 Organic Chemistry 6 Substrate control in Ireland-Claisen rearrangement

methyl group is pseudo-equatorial

Me Me Me Me H H OTMS 1. LHMDS O O 2. TMSCl O Me Me Me OH HO2C H H OTMS OTMS Me O OTMS OTMS 91% ee 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 • Once again, the relative stereochemistry is governed by the geometry of the enolate

123.702 Organic Chemistry 7

Auxiliary controlled rearrangement in total synthesis

OMe OMe OMe O N N Li Me LiTMP N O LiAlH4 N O N O N OH ( )7 O O Me OH (–)-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, 5805 123.702 Organic Chemistry 8

Chiral reagent control in the Ireland-Claisen rearrangement

i-Pr2NEt R*2B OH CH Cl O 2 2 warm –78°C Me Me O O Ph Ph O Me Me Me >97% ee O + N N ArO2S SO2Ar B R*2B O OH Me Br warm Me O O Et3N Me Tol / hexane –78°C Me Me 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

123.702 Organic Chemistry 9

The use of a chiral reagent in total synthesis

Ph Ph

O S N N SO 2 B 2 Br Me Me Me Me F3C CF3 Me O CF3 F3C O Me Me Me Me (i-Pr)2N Ni-Pr CO2H Me H H O Me N(i-Pr) 2 86% dolabellatrienone >98%ee

• 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, 1229 123.702 Organic Chemistry 10

Chiral catalyst control in the Ireland-Claisen rearrangement

Ph Ph Ph

MeAl(OR*)2 O Me O Si H Me SiMe O SiMe3 Me 3

SiMe2t-Bu

O MeAl(OR*)2 = Al Me O

SiMe2t-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

123.702 Organic Chemistry 11 2,3-Wittig rearrangement

1 1 O 2 Z Base O Z O Z HO 2 Z 1 H 1

2 3 2 3

• 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

Me H Me H H H BuLi H H –85°C O HO HO O H Me ≡ H Me H H 98%de

• Largest substituents adopt pseudo-equatorial position

H H Me Me H Me H Me Me BuLi –85°C O Me O HO HO H H H H ≡ Me Me 98%de 98%ee 123.702 Organic Chemistry 12 Enantioselectivity in the 2,3-Wittig rearrangement

Me

O SO2 CO Me Me Ph Me 2 N Ph + Et N MeO O 3 Me B Ph Ph O ≡ HO N R2B O Ph CO Me O OMe Ph 2 N N O2S PhO2S B SO2Ph 66%de Br 96%ee • Reagent control utilising boron reagent seen in both aldol & Claisen reactions • Chiral catalysis is far less developed in this area • One example is given below:

cat (20mol%) O O Ar O MeOH, rt, 5d

O Ar Ar Ph(CH2)2 Ph(CH2)2 75% 60%ee (dr 2:1) 2*RN R OH

N H N

123.702 Organic Chemistry 13 [2,3]-aza-Wittig reaction in total synthesis

H C5H11 Me Me LDA N H Me N 97% C H N CO t-Bu LiO H 5 11 2 CO t-Bu H C5H11 2 Ot-Bu

Me

C5H11 N

indolizidine 209B

• Aza-Wittig reaction is less common as normally no driving force • Here 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, 9741 123.702 Organic Chemistry