1 The Diels-Alder reaction

Me Me Me δ– δ+ δ– CO2Me Δ CO Me + 2 + δ+ δ– δ+ CO2Me major minor δ δ Me + – δ– CHO Me Me CHO + Δ + δ– δ+ δ+ CHO toluene, 120°C, no catalyst 59 : 41 Lewis acid benzene, 25°C, SnCl4 96 : 4 improves selectivity • Diels-Alder (DA) reaction is incredibly valuable method for the synthesis of 6-rings • Normally DA is highly regioselective (as seen above) • It is controlled by the ‘relative sizes’ of the p orbitals in the LUMO & HOMO involved • More accurately referred to as the orbital coefficients • In the presence of a Lewis acid dienophile is polarised giving higher regioselectivity and a faster reaction

NMe2 NMe2 NMe2 δ– δ+ δ– CO2Me CO Me 2 CO Me + 2 δ+ δ– δ+

HOMO LUMO regioselectivity often follows simple electronic argument (consider which C is δ+ve123.702 or δ–ve) Organic Chemistry 2 Endo vs. exo selectivity

secondary A orbital overlap H A A H C endo favoured C H ≡ B B A C H D D D C B endo A H A D A H C B exo C ≡ B C B H D D H D B exo

• Endo transition state & adduct is more sterically congested thus thermodynamically less stable • But it is normally the predominant product • The reason is endo transition state is stabilised by π orbital overlap of the group on C or D with the diene HOMO; an effect called ‘secondary orbital overlap’ • The reaction is suprafacial and we observe that the geometry of the diene & dienophile is preserved

123.702 Organic Chemistry 3 Diels-Alder reaction

A A A A A A H H H H C H H ≡ D C C H C C H B B B B B H D D H D D H B H draw a add the add dienophile remember other do reaction should be able to see cube diene (endo product has substituents (make new relative stereochemistry substituents directly present bonds) under diene)

• The ‘cube’ method is a nice way to visualise the relative stereochemistry • Finally, remember that the dienophile invariably reacts from the less hindered face • If you are a little rusty on the Diels-Alder reaction either re-read your lecture notes or any standard organic text book

H H MeO MeO OMe + H H NO2 O2N NO2

123.702 Organic Chemistry 4 Chiral auxiliaries on the dienophile

O O BnOH + + Cl OBn O OBn O OBn achiral + achiral 1 : 1 mixture of enantiomers dienophile diene

• One diastereoisomer is formed - the endo product • But mixture of enantiomers • If we add a chiral auxiliary then there are two possible endo diastereoisomers • But one predominates - thus we can prepare a single enantiomer

O

R Cl O O O R O R N O Et2AlCl BnOH + O N O R HN O Me O OBn Me Me Me Me Me chiral dienophile achiral single(ish) single diene diastereoisomer enantiomer (S)-valine R = H 86% de derivative R = Me 90% de >98% endo 123.702 Organic Chemistry 5 Explanation of diastereoselectivity

s-cis favoured

Et2 O Al O H N O Et2AlCl2 Et Et O Me O Al Et2 Me O O O Al O N O H N O N O Me Et Me 2 Me Me O Al O Me H Me N O

Me s-trans lower face disfavoured Me blocked

• Coordination to the Lewis acid activates dienophile • The rigid chelate governs reactive conformation (s-cis) as s-trans disfavoured • iso-Propyl group blocks bottom face • Diene’s approach maximises secondary orbital overlap and favours endo product

123.702 Organic Chemistry 6 Camphor-derived auxiliary

Me Me R O TiCl4 H –78°C N R +

S O O N O O2S Me Me R = H 99% de R = Me >97% de >98% endo

Me Me R Me Me R N S O N

O O Ti SO2 O Ln

• A range of auxiliaries can be utilised • Most give good diastereoselectivities

123.702 Organic Chemistry 7 Chiral auxiliaries II

phenyl group blocks lower face Me O Me H H O Me O Me Me BnO AlCl3

+ OBn ≡ O ≡ H BnO Me Me O Me CO2R diene approaches from the top O BnO Me

• It is possible to attach the chiral auxiliary to the diene as well

O O O OH MeO OMe O O OH O H B(OAc)3 H Ph H Ph +

O H O >95% de endo 123.702 Organic Chemistry 8 Chiral auxiliary controlled DA in total synthesis

S S O Me S S H O H Me2AlCl H H Me PMBO O H N PMBO O H Me N O NR * 2 (–)-stenine Ph O

• Use of a chiral auxiliary in an intramolecular Diels-Alder reaction (IMDA) • Note how it sets up 4 stereocentres and the central ring of (–)-stenine • (–)-Stenine is isolated from Stemona family of subshrubs is a constituent of a variety of Eastern folk medicines • This synthesis is by Morimoto Y, Iwahashi M, Nishida K, Hayashi Y, Shirahama H, Angew. Chem. Int. Ed. Engl., 1996, 35, 904 123.702 Organic Chemistry 9 Chiral catalysis and the Diels-Alder reaction

O Me H O Me MeO MeO cat. + N Br N Br

O H O >97% ee

Me Me

Me Me

N N F3CO2S Al SO2CF3 Me

• The fact the Diels-Alder reaction is mediated or catalysed by Lewis acids means enantioselective variants are readily carried out • The aluminium catalyst above has been utilised in enolate chemistry (aldol) reaction and is very effective in this Diels-Alder reaction

123.702 Organic Chemistry 10 Bis(oxazoline)-based catalysts & the DA reaction Diels-Alder reaction

Me Me O O O Me Me H O O N N O O R2N Cu H Me Me TfO OTf Me N 2+ N O N Me Cu same as Me Me Me Me O O + Me Me cat 5-10mol% Me Me OMe N Me Me Me 92% H 97%ee O H O N O

Hetero-Diels-Alder reaction (HDA)

OH O i. KOH H cat 2-5mol% O ii. HCl + OEt H H O 72% O O 97%ee CO2Et H

• Bis(oxazoline) ligands (Box) are amongst the most versatile & well used ligands known • Simply prepared from amino alcohols (& hence amino acids) • Here used in both DA and the equally useful HDA 123.702 Organic Chemistry 11

Catalytic enantioselective HDA in total synthesis

Me

Me

N O OBn Cr O Cl O + H N O neat, 25°C Cr OBn 64% TBSO TBDPSO 97%ee O O

TBDPSO H TBSO

Et OBn Et O ent-cat Me Me neat, 25°C O + O H 64% TESO TESO OTBS 97%ee TBSO OTBS OTBDPS

• From the synthesis of (+)-ambruticin by Ping Liu and Eric N. Jacobsen, J. Am. Chem. Soc. 2001, 123, 10772 123.702 Organic Chemistry 12

Catalytic enantioselective HDA in total synthesis

OH OH Me

O O Et CO2H Me Me Me (+)-ambruticin

• (+)-Ambruticin is an antifungal agent extracted from the myxobacterium Polyangium cellulsoum • It has shown activity against Coccidioides immitis the cause of coccidioimycosis...

123.702 Organic Chemistry 13 Organocatalysis and the Diels-Alder reaction

OMe cat. (20%) COEt O HClO + 4 Et OMe 96% ee endo / exo >200 : 1 Me O N

Ph N O O Me H Me N O Ar N Me N N OMe O Et Et Me

• Organic secondary amines can catalyse certain Diels-Alder reactions • The reaction proceeds via the formation of an iminium species • This charged species lowers the energy of the LUMO thus catalysing the reaction • In addition one face of dienophile is blocked thus allowing the high selectivity

123.702 Organic Chemistry 14 Organocatalysis and total synthesis

O Me N O O Bn N t-Bu Me H CHO Me O H CHO cat 20mol% H OMe 71% H Me >20:1 dr H 90%ee H

solanapyrone D

• The marine metabolite solanapyrone D is a phytotoxic polyketide isolated from the fungus Altenaria solani

123.702 Organic Chemistry 15 Organocatalysis and the Diels-Alder reaction

OMe O 1. cat. (10%) O 2. TFA + Ph Ph H O TBSO O Ph Ph O 87% ee Tf N N Tf H H TFA

Ph H Me Ph O Tf N N Tf O MeO H O O H TBS Ph O Ph H O TBSO

• This is an example of a hetero-Diels-Alder reaction • The aldehyde is the dienophile • We have to use a very electron rich diene • The amine catalyst acts as a Lewis acid via two hydrogen bonds

123.702 Organic Chemistry 16 Organocatalysis

TBSO 1. cat. (10%) O Ph H Ph 2. AcCl + O O N >98% ee Me Me Ph Ph O Me OH Me OH O AcCl Ph Ph

H TBSO Ph O O H O O O O H H Ph H N Me Me

• Another hetero-Diels-Alder reaction • It looks very similar to the previous reaction but... • It is believed that only one hydrogen bond activates the aldehyde • The other is used to form a rigid chiral environment for the reaction

123.702 Organic Chemistry