Transcript Laulimalide Model System

Dihydropyran and oxetane
formation via a transannular
oxa-conjugate addition
Steve Houghton
Christopher Boddy
Syracuse University
Department of Chemistry
June 15, 2007
Laulimalide
H
HO
O
H
O
H
O
OH
H
O
O
H
Pacific marine sponge Cacospongia mycofijiensis
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Cytotoxic marine polyketide
Potential anticancer agent, similar to Taxol
Stabilizes microtubules
Isolated from sponge in trace amounts
Insufficient material for clinical development
Microtubules (green) during cell division
Producing laulimalide
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Engineering of a recombinant biosynthetic pathway

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Produce macrocyclic precursors by fermentation
Several synthetic transformations will have to be validated
• install the transannular dihydropyran
• 2,3-Z olefin.
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Provides new rapid and efficient strategy for total synthesis
Proposal for biosynthetic origin of
dihydropyran
O
H
HO
O
H
O
H
O
OH
H
MeO MeO
O
O
OMe
H
O
O
OH
scytophycin C
O
OH
OH
O
laulimalide
R
OMe
O
elimination R
OH
O
oxa-conjugate
addition
R
H
O
H
OH
Pyran and cis olefin may form via a non-enzymatic method
Me
N
CHO
Hypothesis tested using model system
O
O
8.2 kcal/mol
more stable
OH
O
O
6
6,7-Z
7
elimination
O
OH
O
oxa-conjugate
addition
O
H
O
O
H
OH
6
7
6,7-E
OH
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Can we form dihydropyrans via transannular oxa-conjugate
addition in 20-membered rings?
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Is oxa-conjugate addition a stereoselective reaction?
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Kinetic or thermodynamically controlled?
Energy calculations: DFT B3LYP/6-G31 d p level
Model System synthesis
Br
Br
PCC
Et2O
NaOAC, Celite
O
83%
OH
OTBS
64%
Br
Br
Et2O
OTBS
CO2Et
EtO
EtO
Imidazole
OTBS
99%
Br
OTBS
LiOH
KOH, THF
OTBS
OTBSO
OTBS
O
CO2H
CsCO3
OTBS
71%
DMF
OTBS
93%
76%
OTBS
Dioxane/H2O
52%
Br
CO2Et
Br
OsO4, NaIO4
OH
dr 1:1
O
P
OTBS
TBSCl
86%
O
91%
OH
91%
AllylMgBr
dioxane/H2O
Br
TBSCl
Imidazole
Br
OsO4, NaIO4
Br
AllylMgBr
OTBS
OTBS
O
1,3-Diols are separable
O
O
O
TsOH
OTBS
EtOH
O
O
O
+
OH
OH
75%
OTBS
OH
anti
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dr 1:1
OH
syn
Deprotection revealed 2 spots on TLC
Characterized by Rychnovshky method by
preparing acetonides
Oxa-conjugate addition unexpected
product
O
O
Amberlyst 15 H+
ClCH2CH2Cl
O
O
80oC
63 %
OH
H
O
OH
H
syn diastereomer
Single diastereomer
Confirmed by COSY,
HSQC, HMBC, NOESY
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14.2 kcal/mol
higher energy
than dihydropyran
Highly strained trans oxetane is formed
Under basic conditions diols are not reactive
Energy calculations: DFT B3LYP/6-G31 d p level
Two possible mechanisms for
oxetane formation
O
O
O
O
SN2 displacement
OH
conjugate
addition
elimination
H
O
H
O
O
H
OH2
OH
trans oxetane
Kinetic Product
stereochemistry unknown,
intermediate not observed
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SN2 displacement
Elimination/addition
If SN2, anti diastereomer must produce cis oxetane
Anti diastereomer also produces
trans oxetane
not observed
O
O
O
O
O
O
+
Amberlyst 15 H
OH
ClCH2CH2Cl
80oC
42%
OH
H
O
H
trans_oxetane
anti diastereomer
14.2 kcal/mol
H
O
H
cis_oxetane
13.3 kcal/mol
higher energy than dihydropyran
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Since inversion of stereochemisty is not observed cannot be
SN2 displacement
Mechanism must be elimination, oxa-conjugate addition
Energy calculations: DFT B3LYP/6-G31 d p level
E1cB-like mechanism
O
O
O
elimination
RDS
OH
O
O
OH
conjugate
addition
FAST
H
O
H
OH2
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stereochemistry unknown,
intermediate not observed
H
trans oxetane
Kinetic Product
Elimination is likely rate determining
Not reversible mechanism
Intermediate is not observed
O
Cis triene may access dihydropyrans
O
O
O
oxa-conjugate
addition
elimination
O
trans
intermediate can
only give oxetane
H
O
O
O
OH
11.7 kcal/mol
63% from diol
14.2 kcal/mol
H
oxetane
E,E,E triene
OH
H
O
OH2
elimination
O
O
oxa-conjugate
addition
H
OH
O
H
3.5 kcal/mol
E,E,Z triene
O
cis
intermediate may
access dihydropyran
0 kcal/mol
dihydropyran
75% from carbonate
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Olefin geometry may play role in oxetane formation
Energy calculations: DFT B3LYP/6-G31 d p level
Cyclic carbonate produces cis triene
O
O
O
N
N
N
O
N
O
THF, 45 oC
75% over
2 steps
84%
syn
OH
O
O
O
OH
O
N
N
OH
cis triene via 1H NMR
coupling constants
O
O
N
O
N
O
O
DBU
THF, 45 oC
THF, Et3N
OH
92%
anti
OH
O
O
purification in
progress
O
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O
DBU
THF, Et3N
OH
O
Cis triene is generated under basic conditions
from both syn and anti diastereomers
O
Cis triene produces new compound
Amberlyst
conditions
yields a new
compound
as shown by
LC-MS
trans oxetane
O
O
O
O
H
O
H
cis triene
OH
4 hrs
uncharacterized
new compound
Conclusions
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Transannular oxa-conjugate addition can occur
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High energy oxetane favored over low energy
dihydropyran
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Unusual regioselectivity of acid catalyzed oxaconjugate addition
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Regioselectivity could be attributed to olefin
geometry of elimination (triene intermediate)
Acknowledgements
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Dr. Christopher Boddy
The Boddy lab members
Deborah Kerwood
Department of Chemistry
Syracuse University