Dihydropyran and oxetane formation via a transannular oxa- conjugate addition Steve Houghton Christopher Boddy Syracuse University Department of Chemistry June 15, 2007
Dihydropyran and oxetane formation via a transannular oxa-conjugate addition
Dec 31, 2015
Dihydropyran and oxetane formation via a transannular oxa-conjugate addition. Steve Houghton Christopher Boddy Syracuse University Department of Chemistry June 15, 2007. Laulimalide. Cytotoxic marine polyketide Potential anticancer agent, similar to Taxol Stabilizes microtubules - PowerPoint PPT Presentation
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Dihydropyran and oxetane formation via a transannular
oxa-conjugate addition
Steve Houghton
Christopher Boddy
Syracuse University
Department of Chemistry
June 15, 2007
Laulimalide
Cytotoxic marine polyketide Potential anticancer agent, similar to Taxol Stabilizes microtubules Isolated from sponge in trace amounts Insufficient material for clinical development
HOO
O
OHO
O
OHH
HH
H
Pacific marine sponge Cacospongia mycofijiensis
Microtubules (green) during cell division
Producing laulimalide
Engineering of a recombinant biosynthetic pathway Produce macrocyclic precursors by fermentation Several synthetic transformations will have to be validated
• install the transannular dihydropyran
• 2,3-Z olefin.
Provides new rapid and efficient strategy for total synthesis
HOO
O
OH
O
O
OHH
H
H
H
R
O
R
O
R
R
OH
fermentation chemical synthesis
Proposal for biosynthetic origin of dihydropyran
scytophycin Claulimalide
HOO
O
OH
O
O
OHH
H
H
H
O OH
O
O
MeOMeO
OMe
OH
O OMe
NCHO
Me
Pyran and cis olefin may form via a non-enzymatic method
OHR
O
OHR
O
OR
O
H Helimination
oxa-conjugate addition
OH
Hypothesis tested using model system
Can we form dihydropyrans via transannular oxa-conjugate addition in 20-membered rings?
Is oxa-conjugate addition a stereoselective reaction?
Kinetic or thermodynamically controlled?
O
OH
OH
O
O
OH
O
O O
OHH
oxa-conjugate additionelimination
O O
OH6,7-E
67
6,7-Z6
7
8.2 kcal/mol more stable
Energy calculations: DFT B3LYP/6-G31 d p level
Model System synthesis
Br
OH
Br
O
PCC
NaOAC, Celite
Br
OH
AllylMgBr
Et2O
Br
OTBS
TBSCl
Imidazole
Br
OTBSdioxane/H2O
O
AllylMgBr
Et2O
Br
OTBS
OH
TBSCl
Imidazole
Br
OTBS
OTBS
OsO4, NaIO4
Dioxane/H2O
Br
OTBSO
OTBS
Br
OTBS
OTBS
CO2EtP
EtOEtO
O
CO2Et
KOH, THF
Br
OTBS
OTBS
CO2HLiOH CsCO3
DMF
O
OTBS
OTBS
O
83% 91% 91%
64% 86% 99%
76%93%71%
52%
dr 1:1
OsO4, NaIO4
1,3-Diols are separable
Deprotection revealed 2 spots on TLC Characterized by Rychnovshky method by
preparing acetonides
O
OH
OH
O
TsOH
EtOH
O
OH
OH
O
+
75%
O
OTBS
OTBS
O
dr 1:1anti syn
Oxa-conjugate addition unexpected product
Highly strained trans oxetane is formed Under basic conditions diols are not reactive
O
OH
OH
O ClCH2CH2ClAmberlyst 15 H+
80oC
O O
O
H
H
63 %
Single diastereomer
Confirmed by COSY, HSQC, HMBC, NOESY
syn diastereomer
Energy calculations: DFT B3LYP/6-G31 d p level
14.2 kcal/mol higher energy than dihydropyran
Two possible mechanisms for oxetane formation
SN2 displacement Elimination/addition If SN2, anti diastereomer must produce cis oxetane
O
OH
OH2
O
H
O
O
O
H
H
O
OH
O
conjugate additionelimination
trans oxetaneKinetic Product
stereochemistry unknown, intermediate not observed
SN2 displacement
Anti diastereomer also produces trans oxetane
Since inversion of stereochemisty is not observed cannot be SN2 displacement
Mechanism must be elimination, oxa-conjugate addition
anti diastereomer 14.2 kcal/mol
O
OH
OH
OAmberlyst 15 H+
ClCH2CH2Cl
80oC
O
O
O
H
H
cis_oxetane
O
O
O
H
H
trans_oxetane
not observed
42%
13.3 kcal/mol
Energy calculations: DFT B3LYP/6-G31 d p level
higher energy than dihydropyran
E1cB-like mechanism
Elimination is likely rate determining Not reversible mechanism Intermediate is not observed
O
OH
OH2
O O
O
O
H
H
O
OH
Oconjugate addition
FAST
elimination RDS
trans oxetaneKinetic Product
stereochemistry unknown, intermediate not observed
H
Cis triene may access dihydropyrans
Olefin geometry may play role in oxetane formation
O
OH
OH2
O
H
O O
OH
O
OH
O
O
O
O
H
H
O O
OHH
elimination
elimination
E,E,E triene
E,E,Z triene
oxa-conjugate addition
oxa-conjugate addition
oxetane
trans intermediate can only give oxetane
cis intermediate may
access dihydropyran
dihydropyran
11.7 kcal/mol
3.5 kcal/mol
14.2 kcal/mol
0 kcal/mol
63% from diol
75% from carbonate
Energy calculations: DFT B3LYP/6-G31 d p level
Cyclic carbonate produces cis triene
Cis triene is generated under basic conditions from both syn and anti diastereomers
O
OH
ODBU
THF, 45 oC
O
OH
OH
O
THF, Et3N
N N
O
N N O O
O O
O
O
OH
ODBU
THF, 45 oC
O
OH
OH
O
THF, Et3N
N N
O
N N O O
O O
O
75% over 2 steps
84%
92%
cis triene via 1H NMR coupling constants
purification in progress
syn
anti
Cis triene produces new compound
Amberlyst conditions yields a new compound as shown by LC-MS
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.5 35.00.00
0.25
0.50
0.75
1.00
1.25
(x10,000,000)
329.00 (1.00)307.00 (1.00)
O
O
O
H
H
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.50.00
0.25
0.50
0.75
1.00
(x10,000,000)
329.00 (1.00)307.00 (1.00)
O
OH
O
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 25.0 27.5 30.0 32.50.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
(x1,000,000)
329.00 (1.00)307.00 (1.00)
trans oxetane
cis triene
uncharacterized new compound
4 hrs
Conclusions
Transannular oxa-conjugate addition can occur
High energy oxetane favored over low energy dihydropyran
Unusual regioselectivity of acid catalyzed oxa-conjugate addition
Regioselectivity could be attributed to olefin geometry of elimination (triene intermediate)
Acknowledgements
Dr. Christopher Boddy The Boddy lab members Deborah Kerwood Department of Chemistry Syracuse University
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