Diels-Alder Reactions
(and Some Other Cycloadditions) The Diels-Alder reaction the parent or “neutral” reaction (not very good):
net addition (cycloaddition)
diene ene (dienophile) cyclohexene
a classical Diels-Alder reaction: Otto Diels and Kurt Alder
Otto Diels (1876-1954) Kurt Alder (1902-1958)
The 1950 Nobel Prize in Chemistry The nomenclature of cycloadditions counting the atoms in the perimeter (round brackets):
COOMe COOMe (4 + 2) COOMe (3 + 2) COOMe + Bn N + Bn N COOMe COOMe COOMe COOMe
counting the pi-electrons [square brackets]:
COOMe COOMe [4 + 2] COOMe [4 + 2] COOMe + Bn N + Bn N COOMe COOMe COOMe COOMe
adding the facial selectivitysubscript:
COOMe [π4s + π2s] COOMe + MeOOC COOMe
s = suprafacial (from the same side); a = antarafacial (from the opposite side); IUPAC Definition Thermodynamics of Diels-Alder reactions
3 + 1 σ-bonds 6 σ-bonds 2 + 1 π-bonds 1 π-bond
⇒ 2 new σ-bonds are made at the expense of 2 π-bonds.
(2 x – 80) kcal/mol – (2 x – 66) kcal/mol = –28 kcal/mol (exothermic)
Therefore: ΔH is usually strongly negative.
But: ΔS is negative as well.
And: ΔV is negative
Remember: ΔG = ΔH – T ΔS (Gibbs-Helmholtz equation) The retro Diels-Alder reaction is more favorable at higher temperatures
200 °C
biscyclopentadiene 2 cyclopentadiene
ΔH > 0 (sigma bonds are broken)
ΔS > 0 (two molecules out of one)
–TΔS << 0 (at high temperatures)
therefore: ΔG = ΔH – T ΔS < 0 (in the forward direction shown) The Diels-Alder reaction is more favorable at higher pressures
Furan Diels-Alder reactions are enthalpically not particularly favorable because they break aromaticity:
O O O 15 kbar O O + S O DV < 0 O O S
Diastereoselectivties, which depend on DDG ‡ and DDV‡ , also improve at high pressures.
Me OTBS H 10 kbar OTBS COOMe + N OTBS N COOMe O Bz O TBSO O OTBS Ph TBSO
[Reference] Thermodynamics of Diels-Alder reactions
ΔG ∂ΔG ΔG ∂ΔG = –ΔS = ΔV ∂T ∂P endergonic endergonic
0 0 exergonic exergonic
T P
ΔG = ΔH – T ΔS The Diels-Alder reaction is concerted
In the transition state both σ-bonds are formed.
–28 kcal/mol (exothermic) The diene needs to reside in an s-cis conformation
The s-cis conformation is required. As a consequence, cyclic dienes generally react faster than acyclic ones: The Diels-Alder reaction is concerted
The classical Diels-Alder reaction is concerted, i.e. there is only one transition state. The two bonds are more or less formed simultaneously.
The Diels-Alder reaction is suprafacial with respect to both components. Six electrons are involved and 0 antarafacial components. As such, it abides to the Woodward-Hoffmann rules.
COOMe [π4s + π2s] COOMe + COOMe COOMe The Woodward-Hoffmann rules in a nutshell
A pericyclic process involving 4n+2 electrons is thermally allowed if the number of antarafacial components involved is even. note: 0 is an even number
‡
+ ≡
[π4s + π2s]
A pericyclic process involving 4n electrons is thermally allowed if the number of antarafacial components involved is odd.
‡ O O O O
+ ≡
[π2s + π2a]
Generalized pericyclic selection rule. A ground-state pericyclic process involving N electron pairs and A antarafacial components is symmetry-allowed if and only if N + A is odd. This is reversed in photochemical processes. Orbital diagram of a “neutral” Diels-Alder reaction
frontier orbitals of butadiene frontier orbitals (conformation ignored) of ethene
E Y4
p* LUMO
LUMO Y3
HOMO Y2
p HOMO
Y1 Energy diagram of a “neutral” Diels-Alder reaction
In the transition state both σ-bonds are formed.
–28 kcal/mol (exothermic) Energy diagram of a “classical” Diels-Alder reaction
Y2 An electron-withdrawing substituent narrows the HOMO-LUMO energy gap. Effect of EWG substituents (and catalysis)
frontier orbitals of butadiene frontier orbitals of an (conformation ignored) electron poor alkene
EWG
E Y4
LUMO Y3 p* LUMO
HOMO Y2
p HOMO Y1
Smaller HOMO-LUMO gap through “lowering the LUMO” translates to faster reactions. The Diels-Alder reaction is regioselective
match the most stable resonance structures:
+ δ δ–
+ δ– δ
+ δ δ–
+ δ– δ The Diels-Alder reaction is stereospecific
The configuration of the starting material is reflected in the configuration of the product.
(E) trans
(Z) cis
(E)
cis (E) The Diels-Alder reaction is stereoselective
The endo product is generally preferred. This is a case of simple diastereoselection.
formed as a racemate
endo-product exo-product (preferred)
EDG and EWG OAc H OAc cis OHC OAc CHO + ≡ [Reference] OHC Me
endo-product formed as a racemate Secondary orbital interactions stabilize the endo TS
Ψ2 (HOMO) ‡
O primary H orbital secondary interactions H orbital O O interactions endo product
Ψ3 (LUMO of the “oxobutadiene”) Diels-Alder Reactions already covered in this course
O O 160 °C O O + [Reference] MeO hydroquinone MeO
MeO MeO [Reference] + cat. Cu(BF4)2 Cl CN Cl CN
OH cat. TfOH OH + [Reference] OPiv O O PivO
[Reference] Me OTBS H 10 kbar OTBS COOMe + N OTBS N COOMe Bz O TBSO Bz O OTBS TBSO The strategic value of the Diels-Alder Reaction
The strategic value of the Diels-Alder reaction lies in making highly functionalized six membered rings. The reaction is very general and has a broad scope, i.e. many substitutions are possible.
O O OH H H H Δ Al(Oi-Pr)3 Br2 Br + H H O i-PrOH H H H H H O COOMe O COOMe O O O O
[Reference]
Up to four stereocenters can be installed with with high fidelity:
O N cat. t-Bu N H H Ph [Reference] CHO Me H CHO
The reaction has found numerous applications in natural product synthesis [Nicoalou review] Cantharidin is a protein phosphatase inhibitor
Cantharidin is produced by the “Spanish Fly” (really a beetle, Lytta vesicatoria) and was used as an “aphrodisiac”. It inhibits protein phosphatase 5 (PP5) as the dicarboxylate. Retrosynthetic analysis of cantharidin
“We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems” Diels and Alder, 1930 The Stork synthesis of cantharidin
[Reference]
Me O O COOMe O O O ≡ O O
Me O O COOMe
cantharidin
a classic in stereoselective synthesis that used Diels-Alder reactions twice to overcame the “dimethylmaleic anhydride issue” O Me O
O O
Me O 1 1) MeOOC COOMe key step: Diels-Alder reaction
COOMe O COOMe with simple diastereoselection
chemoselective hydrogenation of the more 2) Pd/C, H 2 2 electron rich and accessible double bond
COOMe O COOMe
3 3) butadiene key step: diastereoselective Diels-Alder reaction
COOMe
O
COOMe
4 4) LiAlH4 ehaustive ester reduction HO Me O
O O O
Me O OH
5 5) MsCl, py mesylation
MsO
O
OMs
6 6) PhSNa displacement of mesylates with thiophenolate
PhS
O
SPh
7 7) OsO4 dihydroxylation
PhS OH O OH SPh Me O
O O
Me O 8 8) H2, Raney-Ni reductive desulfurization
Me OH O OH Me
9 9) HIO4 glycol cleavage
Me CHO O CHO Me
10 10) piperidine•HOAc intramolecular aldol condensation under Knoevenagel conditions
Me
O
Me CHO 11, 12 11) PhLi addition of phenyllithium into the aldehyde
12) HCl, dioxane isomerization to the thermodyamically more stable product
Me
O OH
Me Ph
13) stearic acid, H+ esterification 13, 14 14) Δ (240-300˚C) ester pyrolysis
Me
O
Me Ph
15 15) O3 then H2O2 key step: ozonolysis and oxidative workup
Me O
O O
Me O cantharidin The Dauben synthesis of cantharidin
[Reference]
A synthesis that beautifully exploited physicochemical principles and the logic of transient bonds to avoid steric clashes. O the anhydride can be made in 4 steps from:
COOMe O + S O MeOOC S
O
key step: Diels-Alder reaction under 1 1) DCM, 15 kbar high-pressure conditions d.r. = 85:15
O O O O S + O O S O O
2 2) H , RaNi, EtOAc reductive desulfurization and 2 reduction of the double bond
O O O
O
cantharidin Take-home message
“If substituents clash sterically, put a transient bond between them”
“Steric hinderance can be overcome with transient bonds” Twistane has D2 symmetry
• E
• one C2 axis
• two C2 axes perpendicular • chiral
[Wikipedia] The Whitlock synthesis of twistane
[Reference]
≡ + COOMe COOMe twistane NaCN
A classic in hydrocarbon chemistry. The opening Diels-Alder reaction was later modified by the Trauner group. O
OMe
0 0) cat. SiMe3 0 °C 0) This reaction works N thermally but with much Tf Tf better yield when catalyzed.
COOMe 1) LAH 1) Ester reduction 1, 2, 3 2) MeSO2Cl, py 2) Mesylation 3) NaCN 3) Substitution with cyanide
NC
4) KOH, H O 4) Nitrile hydrolysis 4, 5 2 5) I2, NaHCO3 5) Iodolactonization, via
I I O O O O I
O O
6) H2, Pt 6) Reductive deiodination 6, 7, 8 7) LAH 7) Lactone reduction 8) MeSO2Cl, py 8) Selective mesylation of the primary alcohol
OH
OMs
9 9) CrO3, H2SO4 9) Oxidation
O
OMs
10 10) NaH 10) Intramolecular α-alkylation
≡ O O ≡ O O
11 11) H2NNH2, KOH 11) Wolff-Kishner reduction, via
≡ H N N twistane Dienes
OMe OMe N
OMe
TMSO TBSO TBSO
1,3-butadiene isoprene Danishefsky diene Brassard diene Rawal diene
O SO 2 O OMe
α-pyrone cyclopentadiene Corey’s cyclopentadiene thiophene 1,1-dioxide cyclohexadiene
O O N OMe O N O a cyclohexadienone ortho-quinone furan anthracene pyridazine The Danishefsky diene
MeO O MeO O O Me Me + Δ H , H2O [Reference] TMSO TMSO O H H Danishefsky's diene endo product cis decalin compare with Robinson annulation:
can be reduced to cis or trans decalin
other examples:
[Reference]
[Reference] Highly reactive dienes
[Reference]
tetracyclone a cyclopentadieone (antiaromatic)
O H Δ O
H benzocyclobutene o-quinone aromatization dimethide
[Reference] Dienophiles
O O O O COOMe H H OMe
COOMe
acroleine methacroleine methyl acrylate a cycloalkenone acetylene dicarboxylate
O O N Cl CN NO2 S PPh3 Ph
acrylonitrile α-chloro nitroethene phenyl vinyl sulfone Schweitzer’s salt acrylonitrile
O O O COOMe COOMe O NH MeOOC COOMe O O O
dimethyl fumarate dimethyl maleate maleic anhydride maleimide para-benzoquinone Chiral dienophiles
O O O O N OH O Ph N O S OPiv Bn O O O
O O O N R O E 95:5 dr Me AlCl Bn 2 Me
[Reference]
O O N O O 93:7 dr i-Pr N Me AlCl 2 O O
Note: the chiral auxiliary (e.g. oxazolidinone) can be cleaved to make this overall an enantioselective process. The auxiliary can also be recycled A highly reactive dienophile
Used in the synthesis of a molecular machine:
[Reference] NH2
H2N
NH2 O N
OH Me2N Itami’s iptycene
CsF
OTf
SiMe3
[Reference] The Corey synthesis of prostaglandin F2α
[Reference]
CO2 HO Ph3P COOH H2CO
P(O)(OMe)2 HO OH Cl CN O PGF2α
A general approach to the prostaglandins and Corey’s most important contributions to physiology. Cp needs to be freshly cracked from its dimer
1 1) NaH, MeOCH2Cl alkylation of cyclopentene
OMe
2 2) , Cu(BF4)2 key step: Lewis-acid catalyzed Diels-Alder Cl CN reaction with a ketene equivalent
MeO
Cl CN hydrolysis of the chloronitrile moiety via:
3 3) KOH MeO
Cl MeO O NH MeO O MeO OH N NH O O regioselective Baeyer-Villiger oxidation, via 4 4) m-CPBA, NaHCO3
MeO MeO O O O O O O Ar
5 5) NaOH, H2O saponification of the lactone
HO HOOC COOH
HO OH OMe HO
6 6) KI3, NaHCO3 key step: iodolactonization, via
O O O O H I I H H OMe OMe HO HO 7) Ac O, py 7,8 2 acetylation of the secondary hydroxyl group, 8) n-Bu3SnH, AIBN, Δ reductive cleavage of the carbon-iodine bond
O O O O H H H H H Sn OMe OMe AcO AcO Corey lactone
cleavage of the methyl ether 9 9) BBr3
O HO O COOH H
H HO OH OH AcO
10 10) CrO3•2py oxidation with Collins reagent
O O H H O AcO 11 11) NaH key step: stereoselective Horner-Wadsworth-Emmons reaction (MeO)2(O)P O O O H H
AcO O chemoselective reduction of the enone carbonyl group 12 12) Zn(BH4)2 The reaction provided an equimolar mixture of allylic alcohols. O The desired diastereomer can be separated and the undesired epimer can be oxidized back to the O enone with activated MnO2 and recycled. H In later work, the reaction was carried out H diastereoselectively with reagent control.
AcO OH
13, 14 13) K2CO3, MeOH acetate hydrolysis, 14) DHP, p-TsOH double protection of the diol
O HO O COOH H H HO OH O O OTHP 15 15) DIBAL-H partial reduction of the lactone carbonyl group
OH The lactol is in equilibrium with its O hydroxy aldehyde isomer.
THPO OTHP
16 16) Ph P key step: stereoselective Wittig reaction 3 COO Note that the carboxylate is not protected HO COOH
THPO OTHP
17 17) AcOH, H2O hydrolytic removal of the THP groups
HO COOH
HO OH
(±)-PGF2α The problem with ketenes
Ketenes do not undergo Diels-Alder reactions:
O [π2s + π4s] O + X H H but rather (2+2) cycloadditions:
O [ 2s + 2a] O O π π H H
O H H H H
Solution: synthetic equivalents: O Cl CN ~ H H H H Synthetic equivalents
desired reagent/setting synthetic equivalent required transformations
O O acyl anion deprotonated addition, hydrolysis vinyl ether
O acyl anion S S deprotonated addition, hydrolysis 1,3-dithiane
CN O ketene/Diels-Alder a-chloroacrylonitrile hydrolysis Cl
allenes/Diels-Alder Schweitzer salt cycloaddition, deprotonation, PPh3 Wittig-reactions The Tömöskozï synthesis of a Corey lactone
[Reference]
O O Cl
O Cl H H OH
OH H2CO
A very efficient approach to a key prostaglandin building block that demonstrates the usefulness of ketene cycloadditions. It also features a surprisingly regio and diastereoselective Prins reaction. The Hungarian synthesis was commercialized. Cl O key step: [ 2 + 2 ]-cycloadditon of dichloroketene 1 1) Zn Cl π s π a produced reductively in situ Cl Cl O O Cl Cl O – ZnCl2 Cl Cl H H Cl ZnCl Cl Cl
reductive dechlorination 2 2) Zn, NH4Cl, MeOH
O
H H
regioselective Baeyer-Villiger oxidation 3 3) m-CPBA, NaHCO3
O
O H H O
O H H
4) 4) paraformaldehyde, AcOH key step: highly regio and diastereoselecive H2SO4, 80 °C Prins reaction, possibly via:
O 7,8 O O
O O O H H H H H H OAc O O O OAc O O O
O O ion pair in a solvent cage 5) 5) K2CO3, MeOH methanolysis
O
O for an asymmetric version that involves the H H kinetic resolution of the dichloroketene adduct OH via asymmetric Baeyer-Villiger reaction: [Reference] OH The intramolecular Diels-Alder reaction
Type I: the dienophile is attached at position 1 of the diene, leading to fused bicyclic systems.
[Reference]
[Reference] The intramolecular Diels-Alder reaction
Type II: the dienophile is attached at position 2 of the diene, leading to bridged bicyclic systems. This results in anti-Bredt compounds, i.e. compounds with a double bond at the bridgehead.
[Bredt's rule]
[Reference]
[Reference]
[Reference] Steroids
OH Me 18 O 12 Me Me Me O 11 17 H O OH 19 13 16 1 Me 9 H 14 Me H H 2 8 15 10 H H H H H H 7 HO 3 5 O HO 4 6 cholsterol cortisone estrone
Me O Me Me Me OH H Me Me H Me H
Me H H H H HO O O H lanosterol progersterone testosterone
Me HO Me COOH OH MeOH Me H Me H Me H Me H
H H H H HN H H HO OH O N H H cholic acid norgestrel stanozolol The Vollhardt-Funk synthesis of estrone
[Reference]
A prime example of a methodology-oriented synthesis. One of the first applications of transition-metal catalyzed reactions in synthesis. A demonstration of [2+2+2] reactions in the construction of arenes. The Vollhardt alkyne cyclotrimerization pattern: cat. TM overall, an addition, trimerization consider regioisomers mechanism (and dealing with regioisomers):
CoCp
metalla cyclopentadiene cobalt(III) cyclometalation cycloaddition with or oxidative additon migratory insertion
hν Co d8 Co(I)-complex cobalt(III) Co Co highly reactive intermediate CoCp OC CO or Δ or
reductive elimination an arene O
Catalysis of the Diels-Alder reaction
frontier orbitals of butadiene frontier orbitals of an (conformation ignored) electron poor alkene-LA complex
AlCl3 O O E Y4 H H
LUMO Y3 p* LUMO
HOMO Y2
p HOMO Y1
Smaller HOMO-LUMO gap through “lowering the LUMO” translates to faster reactions. Catalysis of the Diels-Alder reaction
compare:
[Reference]
[Reference] Catalytic cycle
Cl Cl Al H Cl O O
H LA complex coordination accelerated Diels-Alder
Cl Cl Cl Al H Al Cl Cl Cl LA catalyst LA product complex O
H decoordination O Asymmetric catalysis of the Diels-Alder reaction
[Reference] Catalytic cycle MacMillan amino-catalysis
O N
Ph N O H 5 % H e.r. = 97:3 + [Reference] O d.r = endo:exo = 14:1 H
O N cat. t-Bu N H H Ph [Reference] CHO Me H CHO Catalytic cycle
O N H2O Ph N O H H+ H
iminium dienophile condensation cycloaddition
O N catalyst Ph N N H H NMe
O Ph H O hydrolysis 2
H+ O H List chiral counterion asymmetric catalysis
Uses a highly acidic imidodiphosphorimidate catalyst in combination with a silyl donor”
[Reference]
Note: This works with esters where chiral Lewis acids generally give poor results. Catalytic cycle
[Reference]
* O H NTf O P N P O SiMe3 TfN O *
O * O NTf O OMe P N P O TfN O * Me Si Me Si 3 O 3 O SiMe * O NTf * O NTf 3 O O OMe P N P O P N P O OMe TfN O * TfN O *
chiral counterion
O
OMe COOMe
Ph The hetero Diels-Alder reaction
intermolecular: [Reference]
1-oxa-diene
intramolecular: O O Me H 190 °C N N O [Reference] O H
some heterodienes: Inverse electron-demand Diels-Alder reaction (IEDDA)
electron poor diene electron rich dienophile
E Y4
LUMO Y3
p* LUMO
HOMO Y2
p HOMO Y1
The LUMO is provided by the (hetero)diene. The hetero Diels-Alder reaction
[Reference]
[Reference]
some heterodienophiles: The Danishefsky synthesis of chalcose
[Reference]
OMe Me OH HO O
O O Me + Me O OH HO H , H2O O Me OH Me O O O OMe
Me O chalcose HO OMe OMe chalcomycin
A very short and stereoselective synthesis of a dideoxyhexose using a hetero Diels-Alder reaction. O
H OMe
OTMS
1) 1) BF3•OEt2, then H2O, NaHCO3 key step: hetero Diels-Alder reaction, followed by hydrolysis and elimination via:
Me O Me O OMe
O OTMS
2) 2) DIBAL-H diastereoselective carbonyl reduction
Me O
OH 3) 2) NaH, then MeI allkylation
Me O
OMe
4) 4) OsO4, NMO diastereoseletive dihydroxylation
Me O OH
OH OMe
(±)-chalcose Daphniphyllum alkaloids
O O O O O H N Me 2 H N H N H Me daphnilactone A
daphnipaxinin
Daphniphyllum macropodum
O O O O O O O OMe Me Me AcO H H H H
N N HN HN
daphniphylline methyl homodaphniphyllate secodaphniphylline methyl homosecodaphniphyllate Methyl homosecodaphniphyllate
secondary amine 5 rings COOMe methyl ester bridged ring juncture H piperidine fused ring juncture HN isopropyl side chain spiro ring juncture
"terpenoid" cyclohexane azabicyclo[2.2.2]octane
spiro[4.4]nonane
7 stereocenters
3 quaternary stereocenter, 2 contiguous
4 secondary stereocenters
2 with C-N bonds carbon skeleton Heathcock’s and Ruggieri’s brilliant insight
COOMe COOMe COOMe
H
HN HN N
typical terpenoid 1,5-dimethyl pattern
R Retrosynthetic analysis
COOMe COOMe COOMe
H
HN N N
COOMe COOMe
H H O
N O The Heathcock synthesis of methyl homosecodaphniphyllate
[Reference]
OBn COOMe N H O MeO HN O
I
One of the most celebrated syntheses. A true classic in biomimetic synthesis and synthetic planning. OBn
N
O
1) LDA key step: formation of the lithium enolate, then additon to the α,β-unsaturated ester A, 1 then MeO A then alkylation with homogeranyl iodide B O (3-component coupling) then I B
COOMe OBn N H H
O HN MeOOC
2-3 2) DIBAL-H reduction furnishes a hydroxy amide, which is
3) KOH, H2O hydrolyzed with potassium hydroxide; + then H3O subsequent acidification yields a 1:1 mixture OBn of diastereomeric δ-lactones H O
O 4,5 4) LAH reduction of the lactone to the diol 5) (COCl)2, DMSO, Et3N followed by twofold Swern oxidation
OBn H OHC OHC
6 6) NH3 formation of a 2-azadiene
OBn H
N
≡ BnO
COOMe H H
N HN 7 7) AcOH, NH4OAc key step: protonation of the azadiene triggers an intramolecular inverse electron-demand Diels-Alder reaction to form an imine, BnO which undergoes an intramolecular aza-Prins cyclization H
HN
BnO
H
HN
BnO
COOMe H H HN HN – H+
BnO
H
HN
8 8) H2, Pd-C hydrogenation of the isoprenyl double bond with concomitant debenzylation HO
H
HN
9, 10 9) CrO3, H2SO4 Jones oxidation to a carboxylic acid 10) MeOH, H2SO4 Fischer esterification
COOMe
H
HN
(±)-methyl homosecodaphniphyllate Hetero Diels Alder reactions in bioconjugation
O H stained cycloalkyne HN O
H H H site specific O incorporation
H2N COOH BCNK
tetrazine
N N N N N N N R R N R fluorogenic N N retro Diels-Alder rct.
– N IEDDA 2 H H H H
O O
[Reference] Hetero Diels Alder reactions in bioconjugation
N N N O N R ≡ N N N O O O N HN O COO O HN N N N N O HN NH O N N O HN N N N N O NH
H H
O
[Reference] Diels-Alder-retro-Diels-Alder cascades
[Reference]
From Baran’s synthesis of haouamine A [Reference]: Domino Diels-Alder reactions
The first Diels-Alder reaction enables the next.
[Reference]
diene transmissive:
[Reference] Dodecahedrane, the most symmetric hydrocarbon Retrosynthetic analysis Strategic disconnections R.B Woodward’s dream
triquinacene C10H10
dodecahedrane C20H20 Paquette’s powerful opening step Dealing with curvature The Norrish-Young cyclization
[Reference] The Paquette synthesis of dodecahedrane
[Reference]
COOMe SPh2
Ni
COOMe SPh2
One of the most celebrated total syntheses, which capped a decades-long effort by many laboratories. A triumph of the human imagination. Ni Nickelocene contains 2 out of 12 five-membered rings and 12 of 20 carbons.
nickelocene Key step. Flash vacuum pyrolysis triggers red. elim., yields dicyclopentadiene (A), 1 1) 950 °C then then double Diels Alder via B. MeOOC COOMe Four of 12 five-membered rings are made, the central bond is superfluous. COOMe
≡ A E B E E E COOMe
Sulfur ylides and and the Corey-Chaykovsky reaction
S S S C O O O C-C epoxidation:
O O S [Reference]
O O O S S C S C-C cyclopropanation:
S SPh O 2 H O O COOMe COOMe S H [Reference] H O LiBF4 lactonization
A possible mechanism An alternative mechanism
The Prinzbach synthesis of pagodane and dodecahedrane
[Reference]
Cl Cl Cl Cl
Cl Cl
O O O O S Cl S Cl Cl Cl
Cl Cl Cl Cl
A “playful” synthesis that provided many interesting structures. The connection with dodecahedrane was probably not pursued from the beginning. Cl Cl Cl Cl Isodrin was once used as an insecticide.
Cl Cl isodrin Cl Cl 1 1) , Δ Key step. Diels-Alder cycloaddition, then chelotropic elimination of SO2, then intramolecular Cl S Cl Cl hydrogen transfer and aromatization. Cl O O Cl Cl tetrachloro Cl thiophene dioxide Cl SO2 Cl Cl Cl Cl
– SO2
Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl
Cl Cl Cl Cl Cl Cl Cl Cl Cl 2 2) Li, t-BuOH Exhaustive reductive dehalogenation
Cl Cl 3 3) , Δ Key step. Diels-Alder cycloaddition, then chelotropic elimination of SO2 Cl S Cl O O Cl Cl Cl Cl
4 4) Li, t-BuOH Exhaustive reductive dehalogenation
H H
5 5) Pd/C, 250 °C Dehydrogenation and aromatization
This step was difficult due to the inaccessibility of the hydrogens. 6 6) hν Key step. Photochemical cycloaddition A 2:1 PSS in favor of the diarene is established.
The tetraene is much higher in energy than the diarene but kineticaly stable and isolable.
, 7 7) O O O Δ Key step. Domino Diels-Alder reaction via:
O O O O O O
8 8) Cu2O, bipyridyl Double decarboxylation via copper carboxylate. All carbons (+2) are there.
9) B H , NaOH; then H O Twofold hydroboration 9, 10 2 6 2 2 10) CrO3 twofold oxidation Note the (inconsequential) regioselectivity.
O O
Twofold Claisen condensation 11) NaH, HCOOMe 11, 12 12) TsN3, NEt3 Twofold Regitz diazo transfer with concomitant deformylation
N 2 O O N2
13) hν, MeOH 13, 14 Key step. Twofold Wolff rearrangement with 14) LiOH, THF/H2O ring-contraction, then saponification HOOC COOH
Twofold Hunsdiecker-Borodin type iodo- 15 15) Pb(OAc)4, I2, hν decarboxylation.
I I
+ stereoisomers
16 16) Na-K; then t-BuOH Reductive deiodination
pagodane pagodane C20H20
The isomerization can be achieved under 17 17) Pd, Al2O3, Δ various conditions. Unfortunately, it only proceeds in 2-8% yield and requires painstaking purification.
dodecahedrane C20H20 (stabilomer) Wolff and Favorskii rearrangements
Wolff rearrangement: O O O O OH N hν 2 H2O
– N2
diazoketone acyl carbene ketene ring-contracted carboxylic acid
Favorskii rearrangement:
O O O O O KOH Br Br – Br 2π OH electrocycl. bromoketone oxidoallylic cyclopropanone cation
O H O O O ring-contracted carboxylic acid Stabilomers conceptual:
H H ≡
C20H20 C20H20
Diels-Alder H2, Pd-C cat. AlCl3
adamantane 2 cyclopentadiene biscyclopentadiene C10H16 C10H16 C10H12 [Reference] Highly symmetric hydrocarbons have theoretical and aesthetic value
(parent not realized)
Henning Hopf “Classics in Hydrocarbon Chemistry”, Wiley-VCH 2000. The Eaton synthesis of cubane
[Reference]
O
O
A classical synthesis that made Phil Eaton famous. Cubane can be produced on a very large scale and has been evaluated as a fuel. O
1) Allylic bromination via a photoinitiated 1 1) NBS, h ν radical pathway Br
O
2 2) Br2 2) Bromination of the double bond
Br Br
Br O
3) Double dehydrobromination via E1cB 3 3) Et3N, - 20 °C pathways (protons α and α' to the carbonyl are acidic). The cyclopentadienone is antiaromatic.
Br O 4 4) –20 °C 4) Key Step. Spontaneous Diels-Alder dimerization
O The synthesis of cubane starts from the Diels- Br Alder adduct of 2-bromocyclopentadienone to itself. 2-bromocyclopentadienone is formed by bromination/dehydrobromination of cyclo- pentenone. Br O All carbons (+2) are there.
5) (CH OH) , H+ 5) Acetal protection of both carbonyl groups 5 2 2 6) aq. HCl 6) Selective acetal hydrolysis
O O Br
Br O
7 7) hν Key step. [2+2] photoaddition The first two cyclobutane rings are formed; 2 cyclopentanones need to be "decarbonylated". O O Br O O ≡ O Br Br Br O Key step. Favorskii ring contraction forming the 8 8) KOH third cyclobutane ring
O O Br HOOC
9) SOCl 9) Acid chloride formation 9, 10 2 10) (CH3)3COOH•py 10) Conversion to a perester
O O (H3C)3C O Br O O
11) Radical decarboxylation removing the first 11 11) cumene, 152 °C extra carbon. H Cumene serves as hydrogen donor. O O Br 12 12) H2SO4 12) Acetal cleavage
O
Br
Key step. Another Favorskii ring contraction to 13 13) KOH form the last cyclobutane ring
COOH
14) SOCl2 14) Acid chloride formation 14, 15, 16 15) (CH3)3COOH, py 15) Conversion of into a perester 16) diisopropylbenzene, 100 °C 16) Radical decarboxylation
cubane Wolff and Favorskii rearrangements
Wolff rearrangement: O O O O OH N hν 2 H2O
– N2
diazoketone acyl carbene ketene ring-contracted carboxylic acid
Favorskii rearrangement:
O O O O O KOH Br Br – Br 2π OH electrocycl. bromoketone oxidoallylic cyclopropanone cation
O H O O O ring-contracted carboxylic acid