1
The Type 2 Intramolecular Diels-Alder Reaction
Type 1 IntramolecularDiels-Alder Reaction
• Tether is attached to the 1 position of the diene
• Leads to fused bicycles
• Tether is attached to the 2 position of the diene
• Leads to bridged bicycles with bridgehead double bonds
• Tether can control regioselectivity, stereoselectivity, and -facial selectivity
Type 2 IntramolecularDiels-Alder Reaction
2
Hetero Type 2 Diels-Alder Reactions
• Previous work in the area of hetero type 2 Diels-Alder reactions has shown N-acyl imines to participate in the Diels-Alder reaction to provide bridgehead amides.1
• Current studies are looking to expand the scope of the type 2 hetero intramolecular Diels-Alder reactions.
• The use of a more reactive hetero dienophile is being investigated.
HN OAc
O CO2Me
200° C
xyleneN
O
CO2Me
N
O
O
3
Type 2 Intramolecular Nitroso Diels-Alder Reactions
NHOH
O
n [ox]N
O
n O
O
N
On
• The type two intramolecular Diels-Alder cycloaddition of N-acylnitroso dienophiles is currently being studied for the synthesis of bridged [n,3,1] oxazinolactams.
• In situ oxidation of hydroxamic acids provide N-acyl nitroso dienophiles which undergo cycloaddition to provide 3,6 dihydro-1,2 oxazines.
• These cycloadducts can subsequently be transformed into medium ring amides and amines.
O
N
O
NR NR
R''
'R
O
'R
4
Synthesis of Precursor Hydroxamic Acids
XCN( )n
NaI, Acetone
Δ
ICN( )n
= 1, = n x Br = 2, = n x Cl = 3, = n x Cl = 4, = n x Br
2a, 98%2b, 75%2c, 91%2d, 100 %
Li2CuCl4 , THF
MgCl
CN( )n
3a, 26%3b, 92%3c, 59%3d, 57%
, NaOH H2 / O MeOH
Δ, 48 h
CO2H( )n
4a, 80%4b, 90%4c, 79%4d, 96%
. ( )i COCl2, ( ), DMF cat CH2Cl2
. ii NH2 • , OH HCl Na2CO3, CHCl3 / H2O
( )n
5b, 58%5c, 59%
O
NHOH
CO2H, MeI K2CO3
, 16 Acetone h
CO2Me
84% 99%O
NHOHNH2 • , OH HCl KOH
, 0 °MeOH C
5
Synthesis of Bridged [n,3,1] Oxazinolactams
O
NHOH
O
NHOH
O
NHOH
O
NHOH
Et4NIO4, CHCl3
0 °Ccomplex mixture
Et4NIO4, CHCl3
0 °C
Et4NIO4, CHCl3
0 °C
Et4NIO4, CHCl3
0 °C
O
NO
75%
O
NO
80%
complex mixture
6
9, 10-Dimethylanthracene Adducts
CH2On, HCl
dioxane, Δ
Cl
Cl
LiAlH4, THF
Δ
55% 9,10-DMA
O
NHOH 9,10- , DMA Bu4NIO4
CHCl3ON
O
79%
ON
O
, PhH Δ
3 h
NO
O+
32% 28%
• 6- .Traditional route to carbon tether cycloadducts gave a complex mixture of products
• 9,10- 6- .Dimethylanthracene precursors afford carbon tether cycloadducts with greater efficacy
7
Regiochemistry of T2IMNDA
OHAcNHOH
Et4IO4
CHCl3, 0 °C41%
N
O
N
O
HO
HO
OO
+
1.0 : 1.0
• Type 2 with a cleavable tether provides the 1,3-regioisomer for comparison
OH i. CDI
ii. NH2OH•HCl, pyridine, 70%
O
O
NHOH NaIO4
H2O, 24% O
N
OO
i. KOH, EtOH66%
ii. KOH, dioxane / H2O100%
NH
O
HO AcCl, NEt3
CH2Cl2N
O
AcON
O
HO+
O O
11% 55%
8
Measuring Bridgehead Olefin Distortion
• Two parameters, and , are used to quantify the degree of distortion in a strained olefin.2
• , which represents the angle between the p-orbitals of a bond, is measured by = (1 + 2)/2 shown in composite structure V.
• , the pyramidalization angle of the constituent atoms of the system, is defined as the acute angle formed by the projection of one substituent (Z) across the atom onto the geminal substituent (Y). For an sp2.00 atom, = 0.0˚, while for an sp3.00 atom, =60.0˚.
9
X-Ray Crystal Structures
4 5
Parameter 4 5
C4-C5 6.83(9)° 3.53(9)°C5 20.3° 13.5°N1-C9 3.53(9)°N1-C10 10.35(8)°C9 0.4°C10 1.5°N1 54.8° 52.6°
O
NO
O
NO
10
Functionalization of Bridged Oxazinolactams
O
NO
O
NO
Na(Hg), Na2HPO4
EtOH
NH
O
OH
79%
NH
O
OH
Na(Hg), Na2HPO4
EtOH
93%
• NO Bond Cleavage
• other reagents including SmI2 and Mo(CO)6 gave lower yields
O
NO
O
NO
H2, 10% Pd/C
EtOH O
NO
O
NOH2, 10% Pd/C
EtOH
• Hydrogenation of the bridgehead double bond
54%
50%
11
Work in Progress
• Stereoselective synthesis of medium ring amides:
O
NO i. LDA, DMPU
ii. allyl bromide
O
NO
NH
O
OH
ON
O
O
O
NO
O
N
OOH
N
Me OH
Me
pumiliotoxin 251D
• Transannular ring closure to the 1-aza-bicyclo[4.3.0] ring system of the pumiliotoxin natural products
12
References and Acknowledgements
1. “The Type 2 Intramolecular Imino Diels-Alder Reaction. Synthesis and Structural Characterization Of Bicyclo [n,3,1] Bridgehead Olefin/Bridgehead Lactams. Shea, K.J., Lease, T.G.: J. Am. Chem. Soc. 1993, 115, 2248
2. Winkler, F. K.: Dunitz, J. D. J. Mol. Biol. 1971, 59, 169-182.
• Financial Support of this work from the Undergraduate Research Opportunities Program is gratefully acknowledged.
• Financial Support of this work from Allergan is gratefully acknowledged.
• Travel Funding from the UCI CAMP program is gratefully acknowledged.
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