the diels-alder reaction - massey universitygjrowlan/stereo2/lecture10.pdf · 123.702 organic...
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123.702 Organic Chemistry
The Diels-Alder reaction
• 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
1
NMe2
+CO2Me
NMe2CO2Me
NMe2CO2Me
HOMO LUMO
Me
+CO2Me
Δ +
MeCO2Me
Me
CO2Memajor minor
Me+
CHOΔ
Me
CHO+
Me CHO
toluene, 120°C, no catalystbenzene, 25°C, SnCl4
5996
::
414 Lewis acid
improves selectivity
regioselectivity often follows simple electronic argument (consider which C is δ+ve or δ–ve)
δ+ δ–
δ+δ–
δ+δ–
δ+ δ–
δ+
δ–
δ+
δ–
δ+ δ–
δ+δ–
δ+
δ–
123.702 Organic Chemistry
B
A
D
C B
AH
HDHC
H AC
DB
≡exo
exo
B
AH
DHCH
H AC
DB
≡
endo
B
A
D
Cendo
B
AC
D
Endo vs. exo selectivity
• 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
2
favoured
secondary orbital overlap
123.702 Organic Chemistry
Diels-Alder reaction
• 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
3
draw a cube
add the diene
add dienophile (endo product has
substituents directly under diene)
remember other substituents
present
do reaction (make new
bonds)
A
B CD B
A
CD B
AH
H
HH C
D
A
B
should be able to see relative stereochemistry
CD
A
B
H
HH
H CD
HH
HHB
A
≡
OMe
NO2
+
HMeO
H
O2N NO2
H
HMeO
123.702 Organic Chemistry
+ O N O
O
MeMe
single(ish) diastereoisomer
Et2AlClR
R = H 86% deR = Me 90% de>98% endo
achiral diene
ON
O
MeMe
O
R
chiral dienophile
Cl
O
OHN
O
MeMe
(S)-valine derivative
R
1 : 1 mixture of enantiomers
O OBn
+
O OBnCl
O BnOH
OBn
O
achiral diene
+
achiral dienophile +
Chiral auxiliaries on the dienophile
• 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
4
O OBn
BnOH
single enantiomer
R
123.702 Organic Chemistry
ON
O
MeMe
OAl
Et Et
NO
Et2Al O
OH
MeMe
Et2AlCl2
ON
O
MeMe
O
NO
Et2Al O
OH
MeMe
NO
Et2Al O
OH
MeMe
Explanation of diastereoselectivity
• 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
5
lower face blocked
s-cis favoured
s-trans disfavoured
123.702 Organic Chemistry
Me Me
NS O
R
O O TiLn
Me Me
NS
OO
O
R +TiCl4–78°C
RH
NOO2S
MeMeR = H 99% deR = Me >97% de>98% endo
Camphor-derived auxiliary
• A range of auxiliaries can be utilised• Most give good diastereoselectivities
6
Me Me
NSO2 O
R
123.702 Organic Chemistry
Me
O
O MeMe
BnO
CO2R
H
BnO
≡Me
O
O MeMe
HH
OBn ≡
BnOMe
O
O MeMe
AlCl3+
Chiral auxiliaries II
• It is possible to attach the chiral auxiliary to the diene as well
7
O
O OH
O
OOMe
H Ph +B(OAc)3
O
O
OHO
O
H
H
MeO
H Ph
>95% deendo
phenyl group blocks lower face
diene approaches from the top
123.702 Organic Chemistry
Chiral auxiliary controlled DA in total synthesis
• 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
8
S S
PMBO
N
O
OO
Me
Ph
Me2AlCl
S S
HO
NR2*
H
PMBON
O
H
H
MeO
HMe
H
(–)-stenine
123.702 Organic Chemistry
Chiral catalysis and the Diels-Alder reaction
• 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
9
MeON
O
O
Me
Br+cat.
N
O
O
Me
Br
H
H
MeO
>97% ee
NAl
N
Me
SO2CF3F3CO2S
Me
Me Me
Me
123.702 Organic Chemistry
i. KOHii. HCl
O
H
H
O
OH
+ HOEt
O
O
cat 2-5mol%
72%97%ee
O
CO2Et
H
MeH
HO
R2N
HO N
MeH
O
O
same as
Me Me
OOCu
N N
OO
O N Me
MeMe
MeMeMe
Me
2+NO Me
OO
+
N
OMe Me
N
O
MeMe
Me MeMe
Me
CuTfO OTf
cat 5-10mol%92%
97%ee
Bis(oxazoline)-based catalysts & the DA reaction
• 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
10
Diels-Alder reaction
Hetero-Diels-Alder reaction (HDA)
123.702 Organic Chemistry
TBSO
OBn
+
TBDPSO
O
H
NCr
O
Me
O Cl
NCr
O
Me
O
TBDPSO H
O
TBSO
OBnneat, 25°C64%
97%ee
O
OBn
OTBDPSTBSO
Catalytic enantioselective HDA in total synthesis
• From the synthesis of (+)-ambruticin by Ping Liu and Eric N. Jacobsen, J. Am. Chem. Soc. 2001, 123, 10772
11
TESO
Et
+
OTBS
O
HMe
ent-catneat, 25°C
64%97%ee
O
Et
OTBSTESO
Me
123.702 Organic Chemistry
Catalytic enantioselective HDA in total synthesis
• (+)-Ambruticin is an antifungal agent extracted from the myxobacterium Polyangium cellulsoum
• It has shown activity against Coccidioides immitis the cause of coccidioimycosis...
12
OCO2H
OHOH
Me MeO
Me
Et
Me(+)-ambruticin
123.702 Organic Chemistry
OMeN
N
Et
ArO Me
N
NMeO
OMeEt
96% eeendo / exo >200 : 1
cat. (20%)HClO4
OMe
+Et
O COEt
OMe
Organocatalysis and the Diels-Alder reaction
• 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
13
NH
NMe
Ph
O
O Me
123.702 Organic Chemistry
Organocatalysis and total synthesis
• The marine metabolite solanapyrone D is a phytotoxic polyketide isolated from the fungus Altenaria solani
14
CHO
Me
MeCHOH
H
Me
H
H
O
OMe
O
H
O
solanapyrone D
cat 20mol%
71%>20:1 dr90%ee
N
NH
Bn t-Bu
MeO
123.702 Organic Chemistry
TFA
OPh
OO
O
TBS
Me
OH
O
HPh
H
N N
PhPh
TfTf
TBSO
MeO
TBSO
OMe O
HO
Ph+1. cat. (10%)2. TFA
O
OPh
O87% ee
Organocatalysis and the Diels-Alder reaction
• 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
15
OPh
OO
O
TBS
MeH
NH H
N
Ph Ph
Tf Tf
123.702 Organic Chemistry
O
Ph
NMeMe
TBSOO
HO H O H O
H
Ph
HO
TBSO
NO
H Ph
MeMe
+1. cat. (10%)2. AcCl
O
PhO
>98% ee
Organocatalysis
• 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
16
AcClOHOHO
O
Ph Ph
Ph Ph
MeMe